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  • 1.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Yu, ZQ
    Persson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lysosomes, iron and oxidative stress2003In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 37, p. 34-34Conference paper (Other academic)
  • 2.
    Eklund, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Larsson, Marie C.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients2013In: International Journal of Mycobacteriology, ISSN 2212-5531, Vol. 2, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB), the bacterium responsible for tuberculosis (TB), has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs) from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100 nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL)-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha) and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth.

  • 3.
    Ekstrom, Magnus Pär
    et al.
    Lund Univ, Sweden.
    Blomberg, Anders
    Umea Univ, Sweden.
    Bergström, Göran
    Univ Gothenburg, Sweden.
    Brandberg, John
    Univ Gothenburg, Sweden.
    Caidahl, Kenneth
    Univ Gothenburg, Sweden.
    Engström, Gunnar
    Lund Univ, Sweden.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Eriksson, Maria
    Karolinska Inst, Sweden.
    Gränsbo, Klas
    Lund Univ, Sweden.
    Hansen, Tomas
    Uppsala Univ, Sweden.
    Jernberg, Tomas
    Karolinska Inst, Sweden.
    Nilsson, Lars
    Umea Univ, Sweden.
    Nilsson, Ulf
    Umea Univ, Sweden.
    Olin, Anna-Carin
    Univ Gothenburg, Sweden.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Rosengren, Annika
    Univ Gothenburg, Sweden.
    Sandelin, Martin
    Uppsala Univ, Sweden.
    Sköld, Magnus
    Karolinska Inst, Sweden; Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Sundström, Johan
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Söderberg, Stefan
    Umea Univ, Sweden.
    Tanash, Hanan A.
    Lund Univ, Sweden.
    Torén, Kjell
    Sahlgrens Univ Hosp, Sweden.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, "Primary Health Care in Motala".
    Lindberg, Eva
    Uppsala Univ, Sweden.
    The association of body mass index, weight gain and central obesity with activity-related breathlessness: the Swedish Cardiopulmonary Bioimage Study2019In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 74, no 10, p. 958-964Article in journal (Refereed)
    Abstract [en]

    Introduction Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) amp;gt;30 kg/m(2)) is rapidly increasing globally and its impact on breathlessness is unclear. Methods This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score amp;gt;= 1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex. Results We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m(2); and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; pamp;lt;0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness. Conclusion Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes.

  • 4.
    Ghafouri, Bijar
    et al.
    Linköping University, Department of Medical and Health Sciences, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Persson, H Lennart
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Tagesson, Christer
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Intriguing bronchoalveolar lavage proteome in a case of pulmonary langerhans cell histiocytosis2013In: The American journal of case reports, ISSN 1941-5923, Vol. 14, p. 129-133Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease associated with tobacco smoke exposure. New insights into its pathogenesis and how it differs from that of chronic obstructive pulmonary disease (COPD) may be provided by proteomic studies on bronchoalveolar lavage fluid (BALF).

    CASE REPORT: We present the BALF proteome in a biopsy-proven case of PLCH and compare it with typical proteomes of COPD and of the healthy lung. The BALF proteins were separated by two-dimensional gel electrophoresis (2-DE) and the protein patterns were analyzed with a computerized 2-DE imaging system. As compared to the healthy subject and the COPD case, the PLCH case showed a strikingly different 2-DE pattern. There was much more IgG (heavy chain) and orosomucoid, and less α1-antitrypsin, surfactant protein-A, haptoglobin, cystatin-S, Clara cell protein 10, transthyretin and gelsolin. Moreover, no apolipoprotein-A1, pro-apolipoprotein-A1, amyloid P, calgranulin A, or calgranulin B was detected at all.

    CONCLUSIONS: This case of PLCH presents with an extreme BALF proteome lacking significant amounts of protective and anti-inflammatory proteins. Thus, the intriguing BALF proteome opens up new lines of research into the pathophysiology of PLCH and how its pathogenesis differs from that in COPD.

  • 5.
    Kentson, Magnus
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Division of Medicine, Ryhov Hospital, Jönköping, Sweden.
    Leanderson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Jacobson, Petra
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Persson, Hans Lennart
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Oxidant status, iron homeostasis, and carotenoid levels of COPD patients with advanced disease and LTOT2018In: European Clinical Respiratory Journal, ISSN 2001-8525, Vol. 5, no 1Article in journal (Refereed)
    Abstract [en]

    Background: The pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with oxidative stress. Both iron (Fe) and oxygen are involved in the chemical reactions that lead to increased formation of reactive oxygen species. Oxidative reactions are prevented by antioxidants such as carotenoids. Objective: To study the differences in Fe status, carotenoid levels, healthy eating habits, and markers of inflammation and oxidative damage on proteins in subjects with severe COPD ± long-term oxygen therapy (LTOT) and lung-healthy control subjects. Methods: Sixty-six Caucasians with advanced COPD (28 with LTOT) and 47 control subjects were included. Questionnaires about general health, lifestyle, and dietary habits were answered. Lung function tests and blood sampling were performed. Results: COPD subjects (±LTOT) did not demonstrate increased oxidative damage, assessed by protein carbonylation (PC), while levels of soluble transferrin receptors (sTfRs) were slightly elevated. Soluble TfRs, which is inversely related to Fe status, was negatively associated with PC. Levels of carotenoids, total and ß-cryptoxanthin, a- and ß-carotenes, were significantly lower in COPD subjects, and their diet contained significantly less fruits and vegetables. Lutein correlated inversely with IL-6, lycopene correlated inversely with SAT, while ß-carotene was positively associated with a Mediterranean-like diet. Conclusions: Fe could favor oxidative stress in COPD patients, suggesting a cautious use of Fe prescription to these patients. COPD subjects ate a less healthy diet than control subjects did and would, therefore, benefit by dietary counseling. COPD patients with hypoxemia are probably in particular need of a lycopene-enriched diet.

  • 6.
    Kentson, Magnus
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Division of Medicine, Ryhov Hospital, Jönköping, Sweden.
    Leandersson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Jacobson, Petra
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    The influence of disease severity and lifestyle factors on the peak annual 25(OH)D value of COPD patients2018In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 13, p. 1389-1398Article in journal (Refereed)
    Abstract [en]

    Background: The prevalence of individuals deficient in vitamin D (defined as a serum level of the stable metabolite 25(OH)D amp;lt; 50 nmol/L) is increasing in countries with low annual ultraviolet (UV) radiation and among individuals unable to perform outdoor activities, for example, COPD patients. Objective: To assess the role of vitamin D deficiency, independently of seasonal variation, the peak annual value of 25(OH)D was measured in subjects with advanced COPD +/- long-term oxygen therapy (LTOT) and lung healthy control subjects. A method to grade the individual annual UV light exposure was designed and tested. Subjects and methods: Sixty-six Caucasians with advanced COPD (28 with LTOT) and 47 control subjects were included, and the levels of 25(OH)D were determined in late summer/ early fall when the annual peak was assumed. Questionnaires about COPD symptoms, general health, lifestyle, dietary habits and QoL were used to collect data. Lung function tests and blood sampling were performed. Results: The peak annual 25(OH)D of COPD subjects was significantly lower than in the control subjects, but there was no significant difference between COPD patients with and without LTOT. Ongoing vitamin D supplementation was the single most important intervention to maintain 25(OH)D levels amp;gt;= 50 nmol/L. Among vitamin D-deficient COPD subjects, 25(OH)D correlated positively with forced expiratory volume in 1 second as % predicted, Modified British Medical Research Council score, blood oxygenation, food portion size, Mediterranean Diet Score and Ultraviolet Score. Conclusion: Vitamin D deficiency was common among healthy individuals and COPD subjects. Peak annual 25(OH)D levels of COPD subjects correlated with clinically important outcomes. The present study emphasizes the need to routinely monitor vitamin D status among patients with advanced COPD and to consider to medicate those with vitamin D deficiency with vitamin D supplementation.

  • 7.
    Lind, Leili
    et al.
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering. SICS East Swedish ICT, Linköping, Sweden.
    Carlgren, Gunnar
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Mudra, Jacqueline
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Synnergren, Henrik
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Hilding, Niclas
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Karlsson, daniel
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering.
    Wiréhn, Ann-Britt
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Preliminary results of a telemonitoring study: COPD and heart failure patients exhibit great difference in their need of health care2015In: European Respiratory Journal: Official Scientific Journal of ERS / [ed] Marc Humbert, European Respiratory Society , 2015, Vol. 46/suppl 59, p. PA2790-PA2790Conference paper (Other academic)
    Abstract [en]

    Background: Growing populations of elderly patients with advanced stages of COPD or heart failure (HF) urge the need for specialized health care in the patients' home. A telemonitoring study has been initiated including patients using digital pens. Health care was provided by the specialized home care unit at a university hospital. Through an IT system the staff checked all daily patient reports. We hypothesized that the two groups of patients, advanced COPD or HF, would exhibit differences regarding exacerbations and the need of health care.

    Objective: To study exacerbations of COPD or HF, and patient health care consumption.

    Methods: A tele-monitoring system, the Health diary, which is based on digital pen technology, was employed. Exacerbations were identified using information provided through the telemonitoring system. Consumed health care was assessed as the number of patient contacts (home visits or telephone consultations).

    Results: Presently, 33 patients with advanced disease are enrolled (13 COPD and 20 HF patients) of which 11 patients (6 COPD and 5 HF patients) have completed the 1-yr study period or have died during the study period (2 COPD and 4 HF patients). Exacerbations were 2.8 and 0.8 and patient contacts were 96 and 42 per COPD and HF patient, respectively. While HF patients were significantly older than COPD patients, the two groups demonstrated no difference regarding gender distribution and comorbidity.

    Conclusions: COPD patients exhibit exacerbations more frequently and demand much more home health care than patients with HF do. It seems that this difference of health care consumption is mainly due to disease characteristics.

  • 8.
    Lind, Leili
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Lyth, Johan
    Region Östergötland, Regional Board, Research and Development Unit.
    Karlsson, Daniel M. G.
    Linköping University, Department of Biomedical Engineering.
    Wiréhn, Ann-Britt
    Region Östergötland, Regional Board, Research and Development Unit.
    Persson, Lennart
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    COPD patients require more health care than heart failure patients2018In: ERS International Congress 2018, 2018Conference paper (Refereed)
    Abstract [en]

    Background: Populations of elderly patients with advanced stages of chronic obstructive pulmonary disease (COPD) or heart failure (HF) are growing, urging the need for specialized health care in the patients’ home. A 4 year (2013-2017) telehealth intervention single-centre clinical study has been completed. We hypothesized that the two groups of patients, advanced COPD or HF, would exhibit differences regarding exacerbations and the need of health care.

    Objective: To study exacerbations of COPD or HF, and patients’ need of health care.

    Methods: A telemonitoring system, the Health Diary, which is based on digital pen technology, was employed. Patients with at least 2 hospital admissions the previous year were included. Responsible nurses and physicians at a specialized home care unit at a university hospital checked all daily patient reports. Physicians identified exacerbations using information provided through the telemonitoring system and patient contacts. Consumed health care was assessed as the number of patient contacts (home visits or telephone consultations).

    Results: Totally, 94 patients with advanced disease were enrolled (36 COPD and 58 HF patients) of which 53 patients (19 COPD and 34 HF patients) completed the 1-yr study period. The major reason for not completing the study was death (13 COPD, 15 HF patients). Average numbers of exacerbations were 3.1 and 0.8 and patient contacts were 94 and 67 per COPD and HF patient, respectively.

    Conclusions: Compared to HF patients, COPD patients exhibit exacerbations more frequently and demand much more home health care. This difference of health care consumption is mainly due to disease characteristics.

  • 9.
    Lind, Leili
    et al.
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. RISE SICS East.
    Wiréhn, Ann-Britt
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Region Östergötland.
    Carlgren, Gunnar
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Mudra, Jacqueline
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Synnergren, Henrik
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Hilding, Niclas
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Lyth, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Region Östergötland.
    Karlsson, Daniel
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Re-organising care of elderly, multi-morbid COPD and heartfailure patients with low digital literacy: —a 4 year Swedishtelehealth intervention study2016In: Health—exploring complexity: an interdisciplinary systems approach HEC2016 / [ed] Grill, E., Müller, M. & Mansmann, U., Munich, Germany, 2016, Vol. 31, p. 118-118Conference paper (Refereed)
  • 10.
    Lyth, Johan
    et al.
    Region Östergötland, Regional Board, Research and Development Unit.
    Lind, Leili
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Karlsson, Daniel
    The National Board of Health and Welfare, Department for Knowledge-Based Policy of Social Services, eHealth and Structured Information Unit, Stockholm, Sweden.
    Persson, Lennart Hans
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Wiréhn, Ann-Britt
    Region Östergötland, Regional Board, Research and Development Unit.
    Can a telemonitoring system lead to decreased hospital admissions in elderly patients?2018Conference paper (Refereed)
    Abstract [en]

    Background: Populations of elderly patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF) are growing. To prevent exacerbations leading to inpatient care, a 4 year (2013-2017) telehealth intervention non-randomized single-centre clinical study was performed. We hypothesized that the patients, grouped by advanced COPD or HF, would exhibit decreased need of hospital admissions.

    Objective: To study hospital admissions in patients with COPD or HF using a telemonitoring system, the Health Diary.

    Methods: A telemonitoring system, the Health Diary, based on digital pen technology, was employed. Patients with COPD or HF treated at the University Hospital in Linköping were included if they had at least 2 hospital admissions the previous year. Data on hospital admissions was obtained from the administrative healthcare database. Expected number of hospital admissions for the study year was calculated using 5-year data for a group of patients with matching diagnosis and history of hospital admissions and was compared to the actual value in the intervention group using Poisson regression.

    Results: Together with the included patients, 159 HF and 136 COPD non-intervention patients was used to calculate the expected values for hospital admissions. For the 58 included HF patients, the average number of hospital admissions of 0.81 was 32.8 percent (p=0.04) lower than expected. For the 36 included COPD patients, the average number of hospital admissions of 1.44 was 37.0 percent (p=0.02) lower than expected.

    Conclusions: Use of the telemonitoring system, the Health Diary, decreases hospital admissions in elderly with COPD and HF.

  • 11.
    Norberg, Pernilla
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Persson, H Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Schmekel, Birgitta
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Alm Carlsson, Gudrun
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Wahlin, Karl
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Sandborg, Michael
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Gustafsson, Agnetha
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Does quantitative lung SPECT detect lung abnormalities earlier than lung function tests?: Results of a pilot study2014In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, no 39, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Background: Heterogeneous ventilation in lungs of allergic individuals, cigarette smokers, asthmatics and chronic obstructive pulmonary disease (COPD) patients has been demonstrated using imaging modalities such as PET, MR and SPECT. These individuals suffer from narrow and/or closed airways to various extents. By calculating regional heterogeneity in lung ventilation SPECT images as the coefficient of variation (CV) in small elements of the lung, heterogeneity maps and CV-frequency curves can be generated and used to quantitatively measure heterogeneity. This work explores the potential to use such measurements to detect mild ventilation heterogeneities in lung healthy subjects.

    Method: Fourteen healthy subjects without documented lung disease or respiratory symptoms, and two patients with documented airway disease, inhaled on average approximately 90 MBq 99mTc-Technegas immediately prior to the 20 min SPECT acquisition. Variation in activity uptake between subjects was compensated for in resulting CV values. The area under the compensated CV frequency curve (AUC), for CV values greater than a threshold value CVT, AUC(CV> CVT), was used as the measure of ventilation heterogeneity.

    Results: Patients with lung function abnormalities, according to lung function tests, generated higher AUC(CV>20%) values compared to healthy subjects (p=0.006). Strong linear correlations with the AUC(CV>20%) values were found for age (p=0.006) and height (p=0.001). These demonstrated that ventilation heterogeneities increased with age and that they depend on lung size. Strong linear correlations were found for the lung function value related to indices of airway closure/air trapping, RV/TLC (p=0.009), and DLCOc (p=0.009), a value partly related to supposed ventilation/perfusion mismatch. These findings support the association between conventional lung function tests and the AUC(CV>20%) value.

    Conclusions: Among the healthy subjects there is a group with increased AUC(CV>20%) values, but with normal lung function tests, which implies that it might be possible to differentiate ventilation heterogeneities earlier in a disease process than by lung function tests.

  • 12.
    Norberg, Pernilla
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Alm Carlsson, Gudrun
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Bake, Björn
    Sahlgrenska Academy at University of Gothenburg.
    Kentson, Magnus
    Ryhov Hospital.
    Sandborg, Michael
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Gustafsson, Agnetha
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Quantitative lung SPECT applied on simulated early COPD and humans with advanced COPD2013In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 3, no 28Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:Reduced ventilation in lung regions affected by chronic obstructive pulmonary disease (COPD), reflected as inhomogeneities in the single-photon emission computed tomography (SPECT) lung image, is correlated to disease advancement. An analysis method for measuring these inhomogeneities is proposed in this work. The first aim was to develop a quantitative analysis method that could discriminate between Monte Carlo simulated normal and COPD lung SPECT images. A second aim was to evaluate the ability of the present method to discriminate between human subjects with advanced COPD and healthy volunteers.

    METHODS:In the simulated COPD study, different activity distributions in the lungs were created to mimic the healthy lung (normal) and different levels of COPD. Gamma camera projections were Monte Carlo simulated, representing clinically acquired projections of a patient who had inhaled 125 MBq 99mTc-Technegas followed by a 10-min SPECT examination. Reconstructions were made with iterative ordered subset expectation maximisation. The coefficient of variance (CV) was calculated for small overlapping volumes covering the 3D reconstructed activity distribution. A CV threshold value (CVT) was calculated as the modal value of the CV distribution of the simulated normal. The area under the distribution curve (AUC), for CV values greater than CVT, AUC(CVT), was then calculated. Moreover, five patients with advanced emphysema and five healthy volunteers inhaled approximately 75 MBq 99mTc-Technegas immediately before the 20-min SPECT acquisition. In the human study, CVT was based on the mean CV distribution of the five healthy volunteers.

    RESULTS:A significant difference (p < 0.001) was found between the Monte-Carlo simulated normal and COPD lung SPECT examinations. The present method identified a total reduction of ventilation of approximately 5%, not visible to the human eye in the reconstructed image. In humans the same method clearly discriminated between the five healthy volunteers and five patients with advanced COPD (p < 0.05).

    CONCLUSIONS:While our results are promising, the potential of the AUC(CVT) method to detect less advanced COPD in patients needs further clinical studies.

  • 13.
    Norberg, Pernilla
    et al.
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine UHL.
    Schmekel, Birgitte
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Sandborg, Michael
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
    Kentson, Magnus
    Lungmedicin, Länsjukhuset Ryhov, Jönköping.
    Gustafsson, Agnetha
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
    The potential of quantitative lung SPECT in identifying humans with COPD using the CVT-method: a Pilot Study of advance disease2012Conference paper (Other academic)
  • 14.
    Norberg, Pernilla
    et al.
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Sandborg, Michael
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
    Alm Carlsson, Gudrun
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
    Gustafsson, Agnetha
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine UHL.
    Bake, Björn
    Avdelningen för intermedicin, Institutionen för medicin, Sahlgrenska Akademin vid Göteborgs Universitet, Göteborg.
    Kentson, Magnus
    Avdelningen för Lungmedicin, Länssjukhuset Ryhov, Jönköping .
    Quantitative lung-SPECT applied on simulated early COPD and humans with advanced COPD2012Conference paper (Other academic)
  • 15.
    Persson, H L
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Vainikka, Linda K
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lysosomal iron in pulmonary alveolar proteinosis: a case report.2009In: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, ISSN 1399-3003, Vol. 33, no 3, p. 673-679Article in journal (Refereed)
    Abstract [en]

    Pulmonary alveolar proteinosis is characterised by accumulation of surfactant-like material in the distal air spaces. Since lysosomes play a crucial role for degradation of large biomolecules taken up from the cell's environment, it was hypothesised that oxidant-induced lysosomal disruption and ensuing cell death might play a role in disease development. In the present study, alveolar macrophages, harvested by whole-lung lavage from a patient diagnosed with pulmonary alveolar proteinosis, are shown to contain large amounts of undigested material within lysosomes, and the same organelle exhibits increased amounts of haemosiderin-bound iron. Compared with murine macrophage-like J774 cells (iron exposed or not), the status of human macrophages was pro-oxidative, i.e. macrophages exhibited a low level of the antioxidant glutathione and large amounts of iron available for Fenton-type chemistry. As a consequence, macrophageal lysosomes were particularly fragile when exposed to physiological concentrations of hydrogen peroxide (generated by glucose oxidase in culture medium). Such lysosomal disruption resulted in extensive cell death by both necrosis and apoptosis independent of caspase-3 activation. Considering the potential role of iron-catalysed oxidant-induced lysosomal rupture and ensuing cell killing for pulmonary alveolar proteinosis pathology and disease progression, whole-lung lavage might be considered early in those cases in which cytochemical staining reveals great numbers of haemosiderin-laden alveolar macrophages.

  • 16.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Alveolar macrophages from patients with tuberculosis exhibit reduced capacity of restricting growth of Mycobacterium tuberculosis: a pilot study of vitamin D stimulation in vitro2013In: HOAJ Biology, ISSN 2050-0874Article in journal (Refereed)
    Abstract [en]

    Background: The role of vitamin D supplementation as adjuvant treatment of tuberculosis (TB) has lately attracted increasing interest. Our aim was to investigate the capacity of alveolar macrophages (AMs) from patients with or without exposure to TB to control intracellular growth of virulent Mycobacterium tuberculosis (Mtb).

    Methods: AMs were freshly harvested from the bronchoalveolar lavage fluid of 7 patients with a history of TB (4 patients with previous TB and 3 patients with current TB) and 4 non-TB subjects. The H37Rv strain, genetically modified to express Vibrio harveyi luciferase, was used to determine the growth of Mtb by luminometry in the AMs from study subjects. Cytokine levels in culture supernatants were determined using a flow cytometry-based bead array technique.

    Results: AMs from patients with a TB history were less efficient in restricting Mtb growth. Stimulation with 100 nM1, 25-dihydroxyvitamin D (1,25D3) did not significantly influence the capacity of AMs from any study subjects to control the infection. Out of the cytokines evaluated (TNF-α, IL-1β, IL-10 and IL-12p40) only TNF-α demonstrated detectable levels in culture supernatants, but did not respond to stimulation with 1,25D3.

    Conclusions: We conclude that AMs of TB-patients show reduced ability to control mycobacterial growth in vitro, and, that AMs in this pilot study do no respond to 1, 25D3-stimulation. The former observation supports the concept that innate immunity is crucial for the control of TB infection.

  • 17.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Increased lysosomal membrane permeabilization in oxidant-exposed macrophages of human fibrotic lungs2013In: Journal of Cell Death, ISSN 1179-0660, Vol. 6, no 1, p. 69-74Article in journal (Refereed)
    Abstract [en]

    A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.

  • 18.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wennerstrom, Urban
    Hospital Vastervik, Sweden .
    TNF-alpha-stimulated macrophages protect A549 lung cells against iron and oxidation2013In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 65, no 1-2, p. 81-89Article in journal (Refereed)
    Abstract [en]

    Previously, we have shown that TNF-alpha protects iron-exposed J774 macrophages against iron-catalyzed oxidative lysosomal disruption and cell death by increasing reduced glutathione and H-ferritin in cells. Because J774 cells are able to harbor large amounts of iron, which is potentially harmful in a redox-active state, we hypothesized that TNF-alpha-stimulated J774 macrophages will prevent iron-driven oxidative killing of alveolar epithelial A549 cells in co-culture. In the present study, iron trichloride (which is endocytosed by cells as hydrated iron-phosphate complexes) was mainly deposited inside the lysosomes of J774 macrophages, while A549 cells, equally iron exposed, accumulated much less iron. When challenged by oxidants, however, reactive lysosomal iron in A549 cells promoted lysosomal disruption and cell death, particularly in the presence of TNF-alpha. This effect resulted from an elevation in ROS generation by TNF-alpha, while a compensatory upregulation of protective molecules (H-ferritin and/or reduced glutathione) by TNF-alpha was absent. A549 cell death was particularly pronounced when iron and TNF-alpha were present in the conditioned medium during oxidant challenge; thus, iron-driven oxidative reactions in the culture medium were a much greater hazard to A549 cells than those taking place inside their lysosomes. Consequently, the iron chelator, deferoxamine, efficiently prevented A549 cell death when added to the culture medium during an oxidant challenge. In co-cultures of TNF-alpha-stimulated lung cells, J774 macrophages sequestered iron inside their lysosomes and protected A549 cells from oxidative reactions and cell death. Thus, the collective effect of TNF-alpha on co-cultured lung cells was mainly cytoprotective.

  • 19.
    Persson, H.Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine.
    Kurz, Tino
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Radiation-induced cell death: Importance of lysosomal destabilization2005In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 389, no 3, p. 877-884Article in journal (Refereed)
    Abstract [en]

    The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO.) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce 'reparative autophagocytosis', causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy radiation dose increased the 'loose' iron content of the (still viable) cells approx. 5-fold when assayed 24 h later. Cytochemical staining revealed that most redox-active iron was within the lysosomes. The increase of intralysosomal iron was associated with 'reparative autophagocytosis', and sensitized cells to Iysosomal rupture and consequent apoptotic/necrotic death following a second, much lower dose of radiation (20 Gy) 24 h after the first one. A high-molecular-mass derivative of desferrioxamine, which specifically localizes intralysosomally following endocytic uptake, added to the culture medium before either the first or the second dose of radiation, stabilized lysosomes and largely prevented cell death. These observations may provide a biological rationale for fractionated radiation. © 2005 Biochemical Society.

  • 20.
    Persson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Iron-dependent lysosomal destabilization initiates silica-induced apoptosis in murine macrophages2005In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 159, no 2, p. 124-133Article in journal (Refereed)
    Abstract [en]

    Alveolar macrophages play a critical role in silica-induced lung fibrosis, and apoptotic mechanisms have been implicated in silica-induced pathogenesis. Here, employing a model of murine macrophages (J774 cells), it is shown that serum-coated α-quartz silica particles cause lysosomal rupture and apoptosis following endocytotic uptake. The loss of lysosomal integrity involves intralysosomal iron-catalyzed peroxidative damage to lysosomal membranes. Thus, lysosomal damage is most pronounced in cells exposed to silica particles with high amounts of surface-bound iron, whereas silica particles previously treated with the iron chelator desferrioxamine only induce modest rupture. Furthermore, inhibition of intralysosomal Fenton type chemistry, either by pre-treatment with desferrioxamine complexed to starch - an iron chelator targeted to the lysosomal compartment - or by concomitant treatment with diphenylene iodonium - a potent inhibitor of NADPH oxidase - both prevent silica-induced lysosomal leakage and ensuing apoptotic cell death. This study also demonstrates that silica-induced lysosomal rupture is a very early apoptotic event, preceding activation of caspases, disruption of transmembrane mitochondrial potential and DNA fragmentation. Indeed, these later apoptotic events appear to be directly correlated to the magnitude of lysosomal leakage, and are not observed in cells treated with high molecular weight desferrioxamine or diphenylene iodonium. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 21.
    Persson, Lennart
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Department of Neuroscience and Locomotion, Speech and Language Pathology. Linköping University, Faculty of Health Sciences.
    Prevention of oxidant-induced cell death by intralysosomal iron binding2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The lung is particularly prone to oxidative stress by its exposure to ambient oxygen and inhaled environmental oxidants. Abnormal assimilation and accumulation of iron are found in many lung disorders, which in redox-active form will exacerbate oxidative tissue damage. It may be that the most important cellular pool of redox -active iron exists within lysosomes. As a result, these organelles are very vulnerable to oxidative stress and may burst due to peroxidative membrane destabilization. Support for the importance of intralysosomal iron in cellular oxidant damage includes the observation that the iron chelator, desferrioxamine, which almost exclusively localizes within the lysosomal compartment, will protect cells against oxidati ve challenge. Iron chelators targeted to the lysosomes may therefore be a particularly efficient therapeutic strategy for cells under conditions of substantial oxidative stress.

    The present study, employing cultures of human respiratory epithelial cells and murine macrophage-like cells, explores the protective effects by iron binding agents upon H202 and gamma radiation-induced lysosomal damage and cell death. Using these in vitro models, the present study shows: (1) that chelation of intralysosomal iron efficiently prevents lysosomal rupture and ensuing cell death induced by either H202 or gamma radiation; (2) that cell permeable lysosomotropic iron-chelators are much more efficient than those being internalized by endocytosis; (3) that intralysosomal iron is the most important cellular pool of redox-active iron for chelation therapy; (4) that ironcatalyzed peroxidative lysosomal destabilization is a decisive and early event in the apoptotic machinery.

    Although apoferritin and desferrioxarnine suppress the reactivity of lysosomal iron, their efficacy is considerably restrained by their uptake by fluid-phase endocytosis. Apoferritin is digested intralysosomally which further decreases its iron sequestering potential, while desferrioxamine by its intralysosomal retention may disturbe normal cellular functions and cause iron-starvation. Amongst cell permeable iron-binding agents we tested a-lipoic acid, alipoamide, and a synthetic amine derivative of α-lipoarnide, α-lipoic acid-plus (5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl) amide). The large difference in the protective potential of these cell permeant iron-chelators derives from their being localized in different cellular compartments, which lends further support that lysososomes contain the most important pool of chelatable redox-active iron. Indeed, a-lipoic acid-plus by its lysosomotropism was by all means the most efficient iron chelator. On a molar basis α-lipoic acid-plus was 4,000 to 5,000 times more effective than desferrioxamine to prevent lysosomal rupture and cell death induced by H202 or gamma radiation.

    We conclude that iron chelating therapy targeted to the lysosomes is an efficient strategy to protect oxidatively stressed cells in vitro. A corresponding efficacy of such treatment in vivo, and in iron dependent pulmonary disorders in particular, needs to be explored.

    List of papers
    1. Novel cellular defenses against iron and oxidation: ferritin and autophagocytosis preserve lysosomal stability in airway epithelium
    Open this publication in new window or tab >>Novel cellular defenses against iron and oxidation: ferritin and autophagocytosis preserve lysosomal stability in airway epithelium
    2001 (English)In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, no 1, p. 57-63Article in journal (Refereed) Published
    Abstract [en]

    Adsorbed to a variety of particles, iron may be carried to the lungs by inhalation thereby contributing to a number of inflammatory lung disorders. Redox-active iron is a potent catalyst of oxidative processes, but intracellularly it is bound primarily to ferritin in a non-reactive form and probably is catalytically active largely within the lysosomal compartment. Damage to the membranes of these organelles causes the release to the cytosol of a host of powerful hydrolytic enzymes, inducing apoptotic or necrotic cell death. The results of this study, using cultured BEAS-2B cells, which are adenovirus transformed human bronchial epithelial cells, and A549 cells, which have characteristics similar to type II alveolar epithelial cells, suggest that the varying abilities of different types of lung cells to resist oxidative stress may be due to differences in intralysosomal iron chelation. Cellular ferritin and iron were assayed by ELISA and atomic absorption, while plasma and lysosomal membrane stability were evaluated by the acridine orange uptake and trypan blue dye exclusion tests, respectively. Normally, and also after exposure to an iron complex, A549 cells contained significantly more ferritin (2.26 ± 0.60 versus 0.63 ± 0.33 ng/μg protein, P <0.001) and less iron (0.96 ± 0.14 versus 1.48 ± 0.21 ng/μg protein, P <0.05) than did BEAS-2B cells. Probably as a consequence, iron-exposed A549 cells displayed more stable lysosomes (P <0.05) and better survival (P <0.05) following oxidative stress. Following starvation-induced autophagocytosis, which also enhances resistance to oxidant stress, the A549 cells showed a significant reduction in ferritin, and the BEAS-2B cells did not. These results suggest that intralysosomal ferritin enhances lysosomal stability by iron-chelation, preventing Fenton-type chemistry. This notion was further supported by the finding that endocytosis of apoferritin, added to the medium, stabilized lysosomes (P <0.001 versus P <0.01) and increased survival (P <0.01 versus P <0.05) of iron-loaded A549 and BEAS-2B cells. Assuming that primary cell lines of the alveolar and bronchial epithelium behave in a similar manner as these respiratory cell lines, intrabronchial instillation of apoferritin-containing liposomes may in the future be a treatment for iron-dependent airway inflammatory processes.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25287 (URN)10.1179/135100001101536049 (DOI)9727 (Local ID)9727 (Archive number)9727 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    2. α-lipoic acid and α-lipoamide prevent oxidant-induced lysosomal rupture and apoptosis
    Open this publication in new window or tab >>α-lipoic acid and α-lipoamide prevent oxidant-induced lysosomal rupture and apoptosis
    2001 (English)In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, no 5, p. 327-334Article in journal (Refereed) Published
    Abstract [en]

    α-Lipoic acid (LA) and its corresponding derivative, α-lipoamide (LM), have been described as antioxidants, but the mechanisms of their putative antioxidant effects remain largely uncharacterised. The vicinal thiols present in the reduced forms of these compounds suggest that they might possess metal chelating properties. We have shown previously that cell death caused by oxidants may be initiated by lysosomal rupture and that this latter event may involve intralysosomal iron which catalyzes Fenton-type chemistry and resultant peroxidative damage to lysosomal membranes. Here, using cultured J774 cells as a model, we show that both LA and LM stabilize lysosomes against oxidative stress, probably by chelating intralysosomal iron and, consequently, preventing intralysosomal Fenton reactions. In preventing oxidant-mediated apoptosis, LM is significantly more effective than LA, as would be expected from their differing capacities to enter cells and concentrate within the acidic lysosomal compartment. As previously reported, the powerful iron-chelator, desferrioxamine (Des) (which also locates within the lysosomal compartment), also provides protection against oxidant-mediated cell death. Interestingly, although Des enhances the partial protection afforded by LA, it confers no additional protection when added with LM. Therefore, the antioxidant actions of LA and LM may arise from intralysosomal iron chelation, with LM being more effective in this regard.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-47165 (URN)10.1179/135100001101536472 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
    3. Prevention of oxidant-induced cell death by lysosomotropic iron chelators
    Open this publication in new window or tab >>Prevention of oxidant-induced cell death by lysosomotropic iron chelators
    Show others...
    2003 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1295-1305Article in journal (Refereed) Published
    Abstract [en]

    Intralysosomal iron powerfully synergizes oxidant-induced cellular damage. The iron chelator, desferrioxamine (DFO), protects cultured cells against oxidant challenge but pharmacologically effective concentrations of this drug cannot readily be achieved in vivo. DFO localizes almost exclusively within the lysosomes following endocytic uptake, suggesting that truly lysosomotropic chelators might be even more effective. We hypothesized that an amine derivative of α-lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (α-lipoic acid-plus [LAP]; pKa = 8.0), would concentrate via proton trapping within lysosomes, and that the vicinal thiols of the reduced form of this agent would interact with intralysosomal iron, preventing oxidant-mediated cell damage. Using a thiol-reactive fluorochrome, we find that reduced LAP does accumulate within the lysosomes of cultured J774 cells. Furthermore, LAP is approximately 1,000 and 5,000 times more effective than LM and DFO, respectively, in protecting lysosomes against oxidant-induced rupture and in preventing ensuing apoptotic cell death. Suppression of lysosomal accumulation of LAP (by ammonium-mediated lysosomal alkalinization) blocks these protective effects. Electron paramagnetic resonance reveals that the intracellular generation of hydroxyl radical following addition of hydrogen peroxide to J774 cells is totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2 μM) whereas LM (200 μM) is much less effective.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27105 (URN)10.1016/S0891-5849(03)00106-0 (DOI)11752 (Local ID)11752 (Archive number)11752 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    4. Chelation of intralysosomal redox-active iron protects against ionizing radiation damage
    Open this publication in new window or tab >>Chelation of intralysosomal redox-active iron protects against ionizing radiation damage
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The mechanisms involved in cellular injury and death caused by ionizing radiation remain incompletely understood. Although DNA damage - especially to actively dividing cells - is certainly a critical component, other types of damage may also be important. Ionizing radiation generates reactive oxygen species (ROS) and 'loose' (i.e., redox-active) iron amplifies the damaging effects of ROS. The major pool of reactive intracellular iron may reside within the acidic vacuolar compartment (lysosomes and late endosomes). Lysosomes are responsible for the continuous digestion of ferruginous materials such as fenitin, mitochondria, and various metalloproteins. We have investigated the possible importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury using macrophage-like J774 cells. We find: (i) Gamma radiation of cells greatly enhances the intracellular pool of reactive iron, which increase ≈ 5-fold 24 hours following a non-lethal single dose of radiation (40 Gy). (ii) Using a special staining procedure (the sulfide-silver method or auto-metallography), we find that most redox-active iron resides within the lysosomal compartment both before and after radiation. The dramatically increased intralysosomal iron following radiation probably derives from reparatin· autophagocytosis, whereby damaged iron-containing cellular constituents are digested intralysosomally. (iii) This increased lysosomal iron sensitizes cells to a second dose of radiation (20 Gy), which results in lysosomal rupture and ensuing apoptosis or necrosis. The enhanced sensitivity to radiation-induced lysosomal rupture is very likely linked to lysosomal iron: two chemically distinct iron chelators, HMW-DFO and LAP, which specifically localize within the lysosomal compartment, stabilize lysosomes and prevent cell death. These observations provide a biological rationale for fractionated radiation, in that a primary dose of radiation causes increased intralysosomal iron and synergizes the damage from a second dose of radiation. The resultant lysosomal rupture may not only lead directly to cell death, as we have proposed elsewhere, but iron released from lysosomes may relocate to the nucleus, intensifying radiation-mediated DNA damage. These findings should be useful in the design of more effective regimens of fractionated radiation and in designing new therapeutic modalities for the prevention of incidental radiationinduced death of normal tissues.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84369 (URN)
    Available from: 2012-10-05 Created: 2012-10-05 Last updated: 2012-10-05Bibliographically approved
  • 22.
    Persson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Radiation-induced lysosomal iron reactivity: Implications for radioprotective therapy2006In: IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology, ISSN 1521-6543, E-ISSN 1521-6551, Vol. 58, no 7, p. 395-401Article in journal (Refereed)
    Abstract [en]

    A novel mechanism of radiosensitization involves radiation-enhanced autophagy of damaged mitochondria and various metalloproteins, by which iron accumulates within lysosomes. Hydrogen peroxide, formed by the radiolytic cleavage of water, generates in the presence of lysosomal redox-active iron extremely reactive hydroxyl radicals by Fenton-type chemistry. Subsequent peroxidative damage of lysosomal membranes initiates release of harmful content from ruptured lysosomes that triggers a cascade of events eventuating in DNA damage and apoptotic or necrotic cell death. This article reviews the role of lysosomal destabilization in radiation-induced cell damage and death. The potential effects of iron chelation therapy targeted to the lysosomes for protection of normal tissues against unwanted effects by radiation is also discussed. © 2006 IUBMB.

  • 23.
    Persson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    A lysosomotropic form of alpha-lipoic acid: a possible therapy of diabetic complications?2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. A175-A175Article in journal (Other academic)
    Abstract [en]

    n/a

  • 24.
    Persson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ferritin protects aitway epithelium against iron and oxidation2001In: XL Nordin Lung Congress,2001, 2001, p. P07-06-P07-06Conference paper (Other academic)
  • 25.
    Persson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Eaton, John
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Lysosomotropic agents: a possible new class of site-directed anti-oxidant, anti-inflammatory and radioprotectant drugs2002In: European Research on Functional Effects of Dietary Antioxidants: Benefits and Risks,2002, 2002, p. 92-92Conference paper (Other academic)
  • 26.
    Persson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Eaton, John
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Prevention of oxidant-induced cell death by lysosomotropic iron chelators2002In: European Research on Functional Effects of Dietary Antioxidants: Benefits and Risks,2002, 2002, p. 123-124Conference paper (Other academic)
  • 27.
    Persson, Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Chelation of intralysosomal redox-active iron protects against ionizing radiation damageManuscript (preprint) (Other academic)
    Abstract [en]

    The mechanisms involved in cellular injury and death caused by ionizing radiation remain incompletely understood. Although DNA damage - especially to actively dividing cells - is certainly a critical component, other types of damage may also be important. Ionizing radiation generates reactive oxygen species (ROS) and 'loose' (i.e., redox-active) iron amplifies the damaging effects of ROS. The major pool of reactive intracellular iron may reside within the acidic vacuolar compartment (lysosomes and late endosomes). Lysosomes are responsible for the continuous digestion of ferruginous materials such as fenitin, mitochondria, and various metalloproteins. We have investigated the possible importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury using macrophage-like J774 cells. We find: (i) Gamma radiation of cells greatly enhances the intracellular pool of reactive iron, which increase ≈ 5-fold 24 hours following a non-lethal single dose of radiation (40 Gy). (ii) Using a special staining procedure (the sulfide-silver method or auto-metallography), we find that most redox-active iron resides within the lysosomal compartment both before and after radiation. The dramatically increased intralysosomal iron following radiation probably derives from reparatin· autophagocytosis, whereby damaged iron-containing cellular constituents are digested intralysosomally. (iii) This increased lysosomal iron sensitizes cells to a second dose of radiation (20 Gy), which results in lysosomal rupture and ensuing apoptosis or necrosis. The enhanced sensitivity to radiation-induced lysosomal rupture is very likely linked to lysosomal iron: two chemically distinct iron chelators, HMW-DFO and LAP, which specifically localize within the lysosomal compartment, stabilize lysosomes and prevent cell death. These observations provide a biological rationale for fractionated radiation, in that a primary dose of radiation causes increased intralysosomal iron and synergizes the damage from a second dose of radiation. The resultant lysosomal rupture may not only lead directly to cell death, as we have proposed elsewhere, but iron released from lysosomes may relocate to the nucleus, intensifying radiation-mediated DNA damage. These findings should be useful in the design of more effective regimens of fractionated radiation and in designing new therapeutic modalities for the prevention of incidental radiationinduced death of normal tissues.

  • 28.
    Persson, Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Lyth, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Operations management Region Östergötland, Research and Development Unit.
    Wiréhn, Ann-Britt
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Operations management Region Östergötland, Research and Development Unit.
    Lind, Leili
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Elderly patients with COPD require more health care than elderly heart failure patients do in a hospital-based home care setting2019In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 14, p. 1569-1581Article in journal (Refereed)
    Abstract [en]

    Background: Elderly patients with advanced stages of COPD or chronic heart failure (CHF) often require hospitalization due to exacerbations. We hypothesized that telemonitoring supported by hospital-based home care (HBHC) would detect exacerbations early, thus, reducing the number of hospitalization. We also speculated that patients with advanced COPD or CHF would present differences regarding exacerbation frequency and the need of HBHC. Methods: The Health Diary system, based on digital pen technology, was employed. Patients aged amp;gt;= 65 years with amp;gt;= 2 hospitalizations the previous year were included. Exacerbations were categorized and treated as either COPD or CHF exacerbation by an experienced physician. All HBHC contacts (home visits or telephone consultations) were registered. Results: Ninety-four patients with advanced diseases were enrolled (36 COPD and 58 CHF subjects) of which 53 subjects (19 COPD and 34 CHF subjects) completed the 1-year study period. Death was the major reason for not finalizing the study. Compared to the 1-year prior inclusion, the intervention significantly reduced hospitalization. Although COPD subjects were younger with less comorbidity, exacerbations and HBHC contacts were significantly greater in this group. Conclusions: COPD subjects exhibit exacerbations more frequently, mainly due to disease characteristics, thus, demanding much more HBHC.

  • 29.
    Persson, Lennart
    et al.
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, K. J.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Novel cellular defenses against iron and oxidation: ferritin and autophagocytosis preserve lysosomal stability in airway epithelium2001In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, no 1, p. 57-63Article in journal (Refereed)
    Abstract [en]

    Adsorbed to a variety of particles, iron may be carried to the lungs by inhalation thereby contributing to a number of inflammatory lung disorders. Redox-active iron is a potent catalyst of oxidative processes, but intracellularly it is bound primarily to ferritin in a non-reactive form and probably is catalytically active largely within the lysosomal compartment. Damage to the membranes of these organelles causes the release to the cytosol of a host of powerful hydrolytic enzymes, inducing apoptotic or necrotic cell death. The results of this study, using cultured BEAS-2B cells, which are adenovirus transformed human bronchial epithelial cells, and A549 cells, which have characteristics similar to type II alveolar epithelial cells, suggest that the varying abilities of different types of lung cells to resist oxidative stress may be due to differences in intralysosomal iron chelation. Cellular ferritin and iron were assayed by ELISA and atomic absorption, while plasma and lysosomal membrane stability were evaluated by the acridine orange uptake and trypan blue dye exclusion tests, respectively. Normally, and also after exposure to an iron complex, A549 cells contained significantly more ferritin (2.26 ± 0.60 versus 0.63 ± 0.33 ng/μg protein, P <0.001) and less iron (0.96 ± 0.14 versus 1.48 ± 0.21 ng/μg protein, P <0.05) than did BEAS-2B cells. Probably as a consequence, iron-exposed A549 cells displayed more stable lysosomes (P <0.05) and better survival (P <0.05) following oxidative stress. Following starvation-induced autophagocytosis, which also enhances resistance to oxidant stress, the A549 cells showed a significant reduction in ferritin, and the BEAS-2B cells did not. These results suggest that intralysosomal ferritin enhances lysosomal stability by iron-chelation, preventing Fenton-type chemistry. This notion was further supported by the finding that endocytosis of apoferritin, added to the medium, stabilized lysosomes (P <0.001 versus P <0.01) and increased survival (P <0.01 versus P <0.05) of iron-loaded A549 and BEAS-2B cells. Assuming that primary cell lines of the alveolar and bronchial epithelium behave in a similar manner as these respiratory cell lines, intrabronchial instillation of apoferritin-containing liposomes may in the future be a treatment for iron-dependent airway inflammatory processes.

  • 30.
    Persson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Richardson, DR
    Iron-binding drugs targeted to lysosomes: A potential strategy to treat inflammatory lung disorders2005In: Expert Opinion on Investigational Drugs, ISSN 1354-3784, E-ISSN 1744-7658, Vol. 14, no 8, p. 997-1008Article in journal (Refereed)
    Abstract [en]

    In many inflammatory lung disorders, an abnormal assimilation of redox-active iron will exacerbate oxidative tissue damage. It may be that the most important cellular pool of redox-active iron exists within lysosomes, making these organelles vulnerable to oxidative stress. In experiments employing respiratory epithelial cells and macrophages, the chelation of intra-lysosomal iron efficiently prevented lysosomal rupture and the ensuing cell death induced by hydrogen peroxide, ionising radiation or silica particles. Furthermore, cell-permeable iron-binding agents (weak bases) that accumulate within lysosomes due to proton trapping were much more efficient for cytoprotection than the chelator, desferrioxamine. On a molar basis, the weak base α-lipoic acid plus was 5000 times more effective than desferrioxamine at preventing lysosomal rupture and apoptotic cell death in cell cultures exposed to hydrogen peroxide. Thus, iron-chelating therapy that targets the lysosome might be a future treatment strategy for inflammatory pulmonary diseases. © 2005 Ashley Publications Ltd.

  • 31.
    Persson, Lennart
    et al.
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, A. I.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    α-lipoic acid and α-lipoamide prevent oxidant-induced lysosomal rupture and apoptosis2001In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, no 5, p. 327-334Article in journal (Refereed)
    Abstract [en]

    α-Lipoic acid (LA) and its corresponding derivative, α-lipoamide (LM), have been described as antioxidants, but the mechanisms of their putative antioxidant effects remain largely uncharacterised. The vicinal thiols present in the reduced forms of these compounds suggest that they might possess metal chelating properties. We have shown previously that cell death caused by oxidants may be initiated by lysosomal rupture and that this latter event may involve intralysosomal iron which catalyzes Fenton-type chemistry and resultant peroxidative damage to lysosomal membranes. Here, using cultured J774 cells as a model, we show that both LA and LM stabilize lysosomes against oxidative stress, probably by chelating intralysosomal iron and, consequently, preventing intralysosomal Fenton reactions. In preventing oxidant-mediated apoptosis, LM is significantly more effective than LA, as would be expected from their differing capacities to enter cells and concentrate within the acidic lysosomal compartment. As previously reported, the powerful iron-chelator, desferrioxamine (Des) (which also locates within the lysosomal compartment), also provides protection against oxidant-mediated cell death. Interestingly, although Des enhances the partial protection afforded by LA, it confers no additional protection when added with LM. Therefore, the antioxidant actions of LA and LM may arise from intralysosomal iron chelation, with LM being more effective in this regard.

  • 32.
    Persson, Lennart
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pulmonary Medicine . Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    TNF-alpha preserves lysosomal stability in macrophages: A potential defense against oxidative lung injury2010In: TOXICOLOGY LETTERS, ISSN 0378-4274, Vol. 192, no 2, p. 261-267Article in journal (Refereed)
    Abstract [en]

    Iron-catalyzed oxidative damage on the respiratory epithelium is prevented by alveolar macrophages depositing iron inside their lysosomes. Bound in an un-reactive state to various metalloproteins, e.g. ferritin, most lysosomal iron is kept separated from reactive oxygen species (ROS) by intracellular anti-oxidative enzyme systems. Some ROS may, however, escape this protective shield of antioxidants, react with small amounts of free redox-active iron within lysosomes, thereby causing peroxidative damage on lysosomes and possibly also ensuing cell death. Since macrophages, containing large amounts of lysosomal iron, are very resistant to TNF-alpha, we hypothesized that this cell type has developed specific defense mechanisms against TNF-alpha-induced ROS generation. Murine macrophages were exposed (or not) to non-toxic concentrations of TNF-alpha and/or iron and were then challenged with H2O2. Iron-exposed oxidatively stressed cells exhibited extensive lysosomal disruption resulting in pronounced cell death. In contrast, TNF-alpha stabilized lysosomes and protected cells, particularly those iron-exposed, by reducing cellular iron and increasing H-ferritin. Intracellular generation of H2O2 under oxidative stress was kept unchanged by TNF-alpha and/or iron. However, TNF-alpha increased basal levels of glutathione by up-regulating the synthesis of gamma-glutamylcystein synthetase, thereby strengthening the anti-oxidative capacity. TNF-alpha inhibitors would block this novel anti-oxidative defense system, possibly explaining their adverse effects on the lung.

  • 33.
    Persson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine UHL.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Hanna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Wennerstrom, Urban
    Hospital Vastervik.
    Lane-Hamilton Syndrome Ferritin Protects Lung Macrophages Against Iron and Oxidation2011In: CHEST, ISSN 0012-3692, Vol. 139, no 2, p. 361-367Article in journal (Refereed)
    Abstract [en]

    Background: Lysosomal disruption and consequent apoptosis have been implicated in lung diseases characterized by iron overload. Free reactive iron in lysosomes sensitizes cells to oxidative stress. Apoptosis is prevented by heavy-chain (H)-ferritin, which can incorporate lysosomal iron into ferritin molecules. Tumor necrosis factor (TNF)-alpha stimulates the synthesis of H-ferritin. Idiopathic pulmonary hemosiderosis presents with the accumulation of iron and the upregulation of ferritin synthesis. We therefore analyzed the lysosomal response to oxidants and the role of H-ferritin synthesis in lung macrophages (LMs) harvested from the first Swedish case, to our knowledge, of Lane-Hamilton syndrome. Methods: Iron-exposed murine macrophages were used as a reference. Both cell types were stimulated with TNF-alpha (or not), then iron was assessed cytochemically and by atomic absorption spectrophotometry. H-ferritin expression was analyzed by Western blot and reduced glutathione (GSH) by spectrofluorometry. Following exposure to hydrogen peroxide, lysosomal membrane integrity and DNA degradation were analyzed by flow cytometry, whereas morphologic signs of apoptosis and necrosis were assessed by light microscopy. Results: GSH levels were approximately equal in LMs and murine macrophages. Although LMs contained much more iron than murine macrophages, lysosomal iron was bound in a harmless unreactive state by ample amounts of ferritin and hemosiderin, its lysosomal degradation product. Therefore, lysosomes of LMs were more oxidant resistant, and these cells were more adept at surviving oxidative stress. In both cell types, TNF-alpha prevented oxidant-induced lysosomal damage and cell death by upregulating synthesis of H-ferritin and GSH. Conclusions: Iron-overloaded LMs are equipped with an efficient armor of antioxidative mechanisms of which H-ferritin and hemosiderin seem to be particularly important.

  • 34.
    Persson, Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Sege, Maria
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Wennerström, Urban
    Division of Medicine, Hospital of Västervik, Västervik, Sweden.
    Dam-Larsen, Sören
    Division of Medicine, Hospital of Eksjö, Eksjö, Sweden.
    Persson, Jenny
    Division of Pulmonary Medicine, Ryhov Hospital, Jönköping, Sweden.
    Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage2012In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 13, no 83Article in journal (Refereed)
    Abstract [en]

    Background: Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation. The macrolide antibiotic azithromycin (AZM) accumulates 1000-fold inside the acidic lysosomes and may interfere with the lysosomal pool of Fe. Objective: Oxidative lysosomal leakage was assessed in lung macrophages from lung transplant recipients without or with AZM treatment and from healthy subjects. The efficiency of AZM to protect lysosomes and cells against oxidants was further assessed employing murine J774 macrophages. Methods: Macrophages harvested from 8 transplant recipients (5 without and 3 with ongoing AZM treatment) and 7 healthy subjects, and J774 cells pre-treated with AZM, a high-molecular-weight derivative of the Fe chelator desferrioxamine or ammonium chloride were oxidatively stressed. LMP, cell death, Fe, reduced glutathione (GSH) and H-ferritin were assessed. Results: Oxidant challenged macrophages from transplants recipients without AZM exhibited significantly more LMP and cell death than macrophages from healthy subjects. Those macrophages contained significantly more Fe, while GSH and H-ferritin did not differ significantly. Although macrophages from transplant recipients treated with AZM contained both significantly more Fe and less GSH, which would sensitize cells to oxidants, these macrophages resisted oxidant challenge well. The preventive effect of AZM on oxidative LMP and J774 cell death was 60 to 300 times greater than the other drugs tested. Conclusions: AZM makes lung transplant macrophages and their lysososomes more resistant to oxidant challenge. Possibly, prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action.

  • 35.
    Persson, Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Yu, Zhengquan
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Tirosh, Oren
    Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Prevention of oxidant-induced cell death by lysosomotropic iron chelators2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1295-1305Article in journal (Refereed)
    Abstract [en]

    Intralysosomal iron powerfully synergizes oxidant-induced cellular damage. The iron chelator, desferrioxamine (DFO), protects cultured cells against oxidant challenge but pharmacologically effective concentrations of this drug cannot readily be achieved in vivo. DFO localizes almost exclusively within the lysosomes following endocytic uptake, suggesting that truly lysosomotropic chelators might be even more effective. We hypothesized that an amine derivative of α-lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (α-lipoic acid-plus [LAP]; pKa = 8.0), would concentrate via proton trapping within lysosomes, and that the vicinal thiols of the reduced form of this agent would interact with intralysosomal iron, preventing oxidant-mediated cell damage. Using a thiol-reactive fluorochrome, we find that reduced LAP does accumulate within the lysosomes of cultured J774 cells. Furthermore, LAP is approximately 1,000 and 5,000 times more effective than LM and DFO, respectively, in protecting lysosomes against oxidant-induced rupture and in preventing ensuing apoptotic cell death. Suppression of lysosomal accumulation of LAP (by ammonium-mediated lysosomal alkalinization) blocks these protective effects. Electron paramagnetic resonance reveals that the intracellular generation of hydroxyl radical following addition of hydrogen peroxide to J774 cells is totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2 μM) whereas LM (200 μM) is much less effective.

  • 36.
    Sioutas, Apostolos
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kentson, Magnus
    Division of Medicine, Ryhov Hospital, Jönköping, Sweden.
    Dam-Larsen, Sören
    Division of Medicine, Hospital of Eksjö, Eksjö, Sweden.
    Wennerström, Urban
    Division of Medicine, Hospital of Västervik, Västervik, Sweden.
    Jacobson, Petra
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Oxidant-induced autophagy and ferritin degradation contribute to epithelial-mesenchymal transition through lysosomal iron2017In: Journal of Inflammation Research, ISSN 1178-7031, E-ISSN 1178-7031, Vol. 10, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor (TGF)-ß1 triggers epithelial-mesenchymal transition (EMT) through autophagy, which is partly driven by reactive oxygen species (ROS). The aim of this study was to determine whether leaking lysosomes and enhanced degradation of H-ferritin could be involved in EMT and whether it could be possible to prevent EMT by iron chelation targeting of the lysosome.

  • 37.
    Sköld, Carl Magnus
    et al.
    Department of Medicine Solna, Karolinska Institutet, Lung-Allergy Clinic, Karolinska University Hospital Solna, Stockholm, Sweden.
    Janson, Christer
    Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    Klackenberg Elf, Åsa
    InterMune Nordics AB, Stockholm, Sweden; Roche AB, Stockholm, Sweden.
    Fiaschi, Marie
    Roche AB, Stockholm, Sweden.
    Wiklund, Kerstin
    PCG Clinical Services, Uppsala, Sweden.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    A retrospective chart review of pirfenidone-treated patients in Sweden: the REPRIS study2016In: European Clinical Respiratory Journal, E-ISSN 2001-8525, Vol. 3, no 1, article id 32035Article in journal (Refereed)
    Abstract [en]

    Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that usually results in respiratory failure and death. Pirfenidone was approved as the first licensed therapy for IPF in Europe based on phase III trials where patients with a forced vital capacity (FVC) greater than50% of predicted were included. The aim of this study was to characterise patients treated with pirfenidone in Swedish clinical practice and to describe the adherence to the reimbursement restriction since reimbursement was only applied for patients with FVC below 80% of predicted.less thanbr /greater thanMethods: This was a retrospective, observational chart review of IPF patients treated with pirfenidone from three Swedish university clinics. Patients initiated on treatment during the period 28 June 2012 to 20 November 2014 were included. Data on patient characteristics, basis of diagnosis, treatment duration, quality of life, and adverse drug reactions (ADRs) were collected from medical charts.less thanbr /greater thanResults: Forty-four patients were screened and 33 were included in the study. The mean treatment duration from start of pirfenidone until discontinuation or end of study was 38 weeks. At the initiation of pirfenidone treatment, FVC was 62.7% (12.1) [mean (SD)], diffusion capacity (DLco) was 45.1% (13.8) of predicted, and the ratio of forced expiratory volume on 1 sec (FEV1) to FVC was 0.78 (0.1). The percentage of patients with an FVC between 50 and 80% was 87%. Ten of the patients had ADRs including gastrointestinal and skin-related events, cough and signs of impaired hepatic function, but this led to treatment discontinuation in only two patients.less thanbr /greater thanConclusion: Data from this chart review showed that adherence to the Swedish reimbursement restriction was followed in the majority of patients during the study period. At the start of pirfenidone treatment, lung function, measured as FVC, was lower in the present cohort of Swedish IPF patients compared with other registry and real-life data. About a third of the patients had ADRs, but discontinuation of the treatment because of ADRs was relatively uncommon.

  • 38.
    Toren, K.
    et al.
    University of Gothenburg, Sweden.
    Bake, B.
    University of Gothenburg, Sweden.
    Olin, A-C
    University of Gothenburg, Sweden.
    Engstrom, G.
    Lund University, Sweden.
    Blomberg, A.
    Umeå University, Sweden.
    Vikgren, J.
    University of Gothenburg, Sweden.
    Hedner, J.
    University of Gothenburg, Sweden.
    Brandberg, J.
    University of Gothenburg, Sweden.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Sköld, C. M.
    Karolinska Institute, Sweden.
    Rosengren, A.
    University of Gothenburg, Sweden.
    Bergstrom, G.
    University of Gothenburg, Sweden.
    Janson, C.
    Uppsala University, Sweden.
    Measures of bronchodilator response of FEV1, FVC and SVC in a Swedish general population sample aged 50-64 years, the SCAPIS Pilot Study2017In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 12, p. 973-980Article in journal (Refereed)
    Abstract [en]

    Background: Data are lacking from general population studies on how to define changes in lung function after bronchodilation. This study aimed to analyze different measures of bronchodilator response of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and slow vital capacity (SVC). Materials and methods: Data were derived from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) Pilot study. This analysis comprised 1,050 participants aged 50-64 years from the general population. Participants were investigated using a questionnaire, and FEV1, FVC and SVC were recorded before and 15 minutes after inhalation of 400 mu g of salbutamol. A bronchodilator response was defined as the relative change from baseline value expressed as the difference in units of percent predicted normal. Predictors of bronchodilator responses were assessed using multiple linear regression models. Airway obstruction was defined as FEV1/FVC ratio below lower limit of normal (LLN) before bronchodilation, and COPD was defined as an FEV1/FVC ratio below LLN after bronchodilation. Physician-diagnosed asthma was defined as an affirmative answer to " Have you ever had asthma diagnosed by a physician?". Asymptomatic never-smokers were defined as those not reporting physician-diagnosed asthma, physician-diagnosed COPD or emphysema, current wheeze or chronic bronchitis and being a lifelong never-smoker. Results: Among all subjects, the greatest bronchodilator responses (FEV1, FVC and SVC) were found in subjects with asthma or COPD. The upper 95th percentile of bronchodilator responses in asymptomatic never-smokers was 8.7% for FEV1, 4.2% for FVC and 5.0% for SVC. The bronchodilator responses were similar between men and women. In a multiple linear regression model comprising all asymptomatic never-smokers, the bronchodilator response of FEV1 was significantly associated with airway obstruction and height. Conclusion: When the bronchodilator response in asymptomatic never-smokers is reported as the difference in units of predicted normal, significant reversibility of FEV1, FVC and SVC to bronchodilators is 9%, 4% and 5%, respectively.

  • 39.
    Toren, Kjell
    et al.
    University of Gothenburg, Sweden.
    Olin, Anna-Carin
    University of Gothenburg, Sweden.
    Lindberg, Anne
    Umeå University, Sweden.
    Vikgren, Jenny
    University of Gothenburg, Sweden.
    Schioler, Linus
    University of Gothenburg, Sweden.
    Brandberg, John
    University of Gothenburg, Sweden.
    Johnsson, Ase
    University of Gothenburg, Sweden.
    Engstrom, Gunnar
    Department Clin Science, Sweden; University of Lund, Sweden.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Skold, Magnus
    Karolinska Institute, Sweden.
    Hedner, Jan
    University of Gothenburg, Sweden.
    Lindberg, Eva
    Uppsala University, Sweden.
    Malinovschi, Andrei
    Uppsala University, Sweden.
    Piitulainen, Eeva
    University of Lund, Sweden.
    Wollmer, Per
    University of Lund, Sweden.
    Rosengren, Annika
    University of Gothenburg, Sweden.
    Janson, Christer
    Uppsala University, Sweden.
    Blomberg, Anders
    Umeå University, Sweden.
    Bergstrom, Goran
    University of Gothenburg, Sweden.
    Vital capacity and COPD: the Swedish CArdioPulmonary bioImage Study (SCAPIS)2016In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 11, p. 927-933Article in journal (Refereed)
    Abstract [en]

    Background: Spirometric diagnosis of chronic obstructive pulmonary disease (COPD) is based on the ratio of forced expiratory volume in 1 second (FEV1)/vital capacity (VC), either as a fixed value &lt;0.7 or below the lower limit of normal (LLN). Forced vital capacity (FVC) is a proxy for VC. The first aim was to compare the use of FVC and VC, assessed as the highest value of FVC or slow vital capacity (SVC), when assessing the FEV1/VC ratio in a general population setting. The second aim was to evaluate the characteristics of subjects with COPD who obtained a higher SVC than FVC. Methods: Subjects (n=1,050) aged 50-64 years were investigated with FEV1, FVC, and SVC after bronchodilation. Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPDFVC was defined as FEV1/FVC &lt;0.7, GOLDCOPD(VC) as FEV1/VC &lt;0.7 using the maximum value of FVC or SVC, LLNCOPDFVC as FEV1/FVC below the LLN, and LLNCOPDVC as FEV1/VC below the LLN using the maximum value of FVC or SVC. Results: Prevalence of GOLDCOPD(FVC) was 10.0% (95% confidence interval [CI] 8.2-12.0) and the prevalence of LLNCOPDFVC was 9.5% (95% CI 7.8-11.4). When estimates were based on VC, the prevalence became higher; 16.4% (95% CI 14.3-18.9) and 15.6% (95% CI 13.5-17.9) for GOLDCOPD(VC) and LLNCOPDVC, respectively. The group of additional subjects classified as having COPD based on VC, had lower FEV1, more wheeze and higher residual volume compared to subjects without any COPD. Conclusion: The prevalence of COPD was significantly higher when the ratio FEV1/VC was calculated using the highest value of SVC or FVC compared with using FVC only. Subjects classified as having COPD when using the VC concept were more obstructive and with indications of air trapping. Hence, the use of only FVC when assessing airflow limitation may result in a considerable under diagnosis of subjects with mild COPD.

  • 40.
    Wajda, Aldona
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Engström, Helena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Persson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Medical talc pleurodesis: which patient with cancer benefits least?2014In: Journal of Palliative Medicine, ISSN 1096-6218, E-ISSN 1557-7740, Vol. 17, no 7, p. 822-828Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE:

    Successful talc pleurodesis (TP) for malignant pleural effusion (MPE) gives symptom relief, but may be too exhaustive in cases with poor performance status. The selection of eligible patients is therefore a challenging task. The study was undertaken to evaluate frequency of successful TPs, side effects, complications, performance status, hospitalization time, remaining time alive, and the responsible physician's prediction of a successful TP judged by radiologic findings prior to TP.

    METHODS:

    Side effects of TPs performed during a 1-year period were consecutively recorded and the TP outcomes were retrospectively evaluated 6 years later.

    RESULTS:

    TP success rate was 56% and 79% among best support of care subjects (BSC; n=10) and subjects eligible for cancer therapy (non-BSC; n=19), respectively, while side effects did not differ. Performance status was poorer and survival shorter among BSC subjects. Time spent in hospital of the remaining time alive for BSC and non-BSC subjects was 42%±27% and 4%±4%, respectively. Poor performance status of subjects with lung cancer correlated with short survival time, which in turn correlated with many days at hospital for TP. The physician's prediction of a successful TP was correct in 50% of all cases.

    CONCLUSIONS:

    Performance status of BSC subjects are probably too poor for TP and these subjects have to spend too much time at hospital during the procedure. The responsible physician is able to correctly predict a successful TP outcome in only every second case, supporting the need of additional predictive analysis.

  • 41. Xu, X
    et al.
    Persson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Richardson, DR
    Molecular pharmacology of the interaction of anthracyclines with iron2005In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 68, no 2, p. 261-271Article in journal (Refereed)
    Abstract [en]

    Although anthracyclines such as doxorubicin are widely used antitumor agents, a major limitation for their use is the development of cardiomyopathy at high cumulative doses. This severe adverse side effect may be due to interactions with cellular iron metabolism, because iron loading promotes anthracyclineinduced cell damage. On the other hand, anthracycline-induced cardiotoxicity is significantly alleviated by iron chelators (e.g., desferrioxamine and dexrazoxane). The molecular mechanisms by which anthracyclines interfere with cellular iron trafficking are complex and still unclear. Doxorubicin can directly bind iron and can perturb iron metabolism by interacting with multiple molecular targets, including the iron regulatory proteins (IRP) 1 and 2. The RNA-binding activity of these molecules regulates synthesis of the transferrin receptor 1 and ferritin, which are crucial proteins involved in iron uptake and storage, respectively. At present, it is not clear whether doxorubicin affects IRP1-RNA-binding activity by intracellular formation of doxorubicinol and/or by generation of the doxorubicin-iron(III) complex. Furthermore, doxorubicin prevents the mobilization of iron from ferritin by a mechanism that may involve lysosomal degradation of this protein. Prevention of iron mobilization from ferritin would probably disturb vital cellular functions as a result of inhibition of essential iron-dependent proteins, such as ribonucleotide reductase. This review discusses the molecular interactions of anthracyclines with iron metabolism and the development of cardioprotective strategies such as iron chelators. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.

  • 42.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
    Persson, Lennart
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    The radioprotective agent, amifostine, suppresses the reactivity of intralysosomal iron2003In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 8, no 6, p. 347-355Article in journal (Refereed)
    Abstract [en]

    Amifostine (2-[(3-aminopropyl)amino]ethane-thiol dihydrogen phosphate ester; WR-2721) is a radioprotective agent used clinically to minimize damage from radiation therapy to adjacent normal tissues. This inorganic thiophosphate requires dephosphorylation to produce the active, cell-permeant thiol metabolite, WR-1065. The activation step is presumably catalyzed by membrane-bound alkaline phosphatase, activity of which is substantially higher in the endothelium of normal tissues. This site-specific delivery may explain the preferential protection of normal versus neoplastic tissues. Although it was developed several decades ago, the mechanisms through which this agent exerts its protective effects remain unknown. Because WR-1065 is a weak base (pKa = 9.2), we hypothesized that the drug should preferentially accumulate (via proton trapping) within the acidic environment of intracellular lysosomes. These organelles contain abundant 'loose' iron and represent a likely initial target for oxidant- and radiation-mediated damage. We further hypothesized that, within the lysosomal compartment, the thiol groups of WR-1065 would interact with this iron, thereby minimizing iron-catalyzed lysosomal damage and ensuing cell death. A similar mechanism of protection via intralysosomal iron chelation has been invoked for the hexadentate iron chelator, desferrioxamine (DFO; although DFO enters the lysosomal compartment by endocytosis, not proton trapping). Using cultured J774 cells as a model system, we found substantial accumulation of WR-1065 within intracellular granules as revealed by reaction with the thiol-binding fluorochrome, BODIPY FL L-cystine. These granules are lysosomes as indicated by co-localization of BODIPY staining with LysoTracker Red. Compared to 1 mM DFO, cells pre-treated with 0.4 ?M WR-1065 are protected from hydrogen peroxide-mediated lysosomal rupture and ensuing cell death. On a molar basis in this experimental system, WR-1065 is approximately 2500 times more effective than DFO in preventing oxidant-induced lysosomal rupture and cell death. This increased effectiveness is most likely due to the preferential concentration of this weak base within the acidic lysosomal apparatus. By electron spin resonance, we found that the generation of hydroxyl radical, which normally occurs following addition of hydrogen peroxide to J774 cells, is totally blocked by pretreatment with either WR-1065 or DFO. These findings suggest a single and plausible explanation for the radioprotective effects of amifostine and may provide a basis for the design of even more effective radio- and chemoprotective drugs.

  • 43.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Persson, Lennart
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Intralysosomal iron: a major determinant of oxidant-induced cell death2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1243-1252Article in journal (Refereed)
    Abstract [en]

    As a result of continuous digestion of iron-containing metalloproteins, the lysosomes within normal cells contain a pool of labile, redox-active, low-molecular-weight iron, which may make these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes with release of hydrolytic enzymes into the cell cytoplasm can lead to a cascade of events eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult). To assess the importance of the intralysosomal pool of redox-active iron, we have temporarily blocked lysosomal digestion by exposing cells to the lysosomotropic alkalinizing agent, ammonium chloride (NH4Cl). The consequent increase in lysosomal pH (from ca. 4.5 to > 6) inhibits intralysosomal proteolysis and, hence, the continuous flow of reactive iron into this pool. Preincubation of J774 cells with 10 mM NH4Cl for 4 h dramatically decreased apoptotic death caused by subsequent exposure to H2O2, and the protection was as great as that afforded by the powerful iron chelator, desferrioxamine (which probably localizes predominantly in the lysosomal compartment). Sulfide-silver cytochemical detection of iron revealed a pronounced decrease in lysosomal content of redox-active iron after NH4Cl exposure, probably due to diminished intralysosomal digestion of iron-containing material coupled with continuing iron export from this organelle. Electron paramagnetic resonance experiments revealed that hydroxyl radical formation, readily detectable in control cells following H2O2 addition, was absent in cells preexposed to 10 mM NH4Cl. Thus, the major pool of redox-active, low-molecular-weight iron may be located within the lysosomes. In a number of clinical situations, pharmacologic strategies that minimize the amount or reactivity of intralysosomal iron should be effective in preventing oxidant-induced cell death.

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