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  • 1. Andresen, Olga
    et al.
    Sörenson, Sverre
    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.
    Bergman, Bengt
    Sundström, Stein
    Vilsvik, Jan
    Aasebb, Ulf
    Bremnes, Roy
    Gilleryd, Mona
    Duration of chemotherapy and survival in advanced non-small cell lung cancer (NSCLC). A multicenter prospective randomised study.2003In: Lungcancer,2003, 2003, p. 528-529Conference paper (Refereed)
  • 2.
    Bendtsen, Preben
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science.
    Leijon, M
    Sommer, Ann-Sofie
    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.
    Kristenson, Margareta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science.
    A s6-monthcontrolled naltrexonestudy: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence2003In: Health and Quality of Life Outcomes, ISSN 1477-7525, E-ISSN 1477-7525, Vol. 11Article in journal (Other (popular science, discussion, etc.))
  • 3.
    Bendtsen, Preben
    et al.
    Linköping University, Department of Department of Health and Society. Linköping University, Faculty of Health Sciences.
    Leijon, Margareta
    Linköping University, Department of Department of Health and Society. Linköping University, Faculty of Health Sciences.
    Sommer, Ann Sofie
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Kristenson, Margareta
    Linköping University, Department of Department of Health and Society. Linköping University, Faculty of Health Sciences.
    Measuring health-related quality of life in patients with chronic obstructive pulmonary disease in a routine hospital setting: Feasibility and perceived value2003In: Health and Quality of Life Outcomes, ISSN 1477-7525, E-ISSN 1477-7525, Vol. 1, no 5Article in journal (Refereed)
    Abstract [en]

    Background

    Assessment of health-related quality of life is so far mainly used in specific research settings and not widely accepted in the routine care of patients. Lack of trust in accuracy and reliability and lack of knowledge concerning the questionnaires used, methods, terminology, are just some of the perceived barriers for a more widespread dissemination of these instruments into routine health care. The present study was undertaken in order to test the feasibility of a computerised system for collecting and analysing health-related quality of life in a routine clinical setting and to examine the thoughts and attitudes among physicians concerning the value of these measurements.

    Methods

    Seventy-four patients with chronic pulmonary lung disease were asked to assess their health-related quality of life with a computerised version of the SF-36 questionnaire before a regular the visit to a physician. The results were immediately available for the physician during the consultation for comparison of information given by the patients and the physician's evaluation of the patients overall health status. A focus group interview with the physicians was performed before and after the implementation of routine measurements of health-related quality of life.

    Results

    The systematic assessment concept worked satisfactorily. All patients approached agreed to participate and completed the assessment on the touch screen computer. A weak correlation was found between patients' self-rated health and pulmonary function and between physicians' evaluation and pulmonary function. The physicians appreciated the SF-36 assessments and the value of the patients' perspective although only a few could pinpoint new clinical decisions based upon this new information.

    Conclusion

    Physicians' clinical evaluation and patients' self-rating of health status offer unique and important information that are complementary.

  • 4. Bergman, Bengt
    et al.
    Sörenson, Sverre
    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.
    Stephens, Richard
    Andresen, Olga
    Bremnes, Roy
    Sundström, Stein
    Visvik, Jan
    Gilleryd, Mona
    Aasebo, Ulf
    Quality of life as related to duration of chemotherapy in advanced non-small cell lung cancer: a randomised study comprising 297 patients.2003In: Lungcancer,2003, 2003, p. 519-520Conference paper (Refereed)
  • 5. Bergqvist, Michael
    et al.
    Sörenson, Sverre
    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.
    Brattström, Baniel
    Mok, Tony
    Henriksson, Roger
    Role of non-taxane-containing chemotherapy in advanced non-small cell lung cancer2006In: American Journal of Cancer, ISSN 1175-6357, E-ISSN 2230-6064, Vol. 5, no 4, p. 223-244Article in journal (Refereed)
    Abstract [en]

    Treatment for advanced-stage NSCLC generally includes the use of systemic chemotherapy as well as biologic therapies (targeted therapy) at later stages of the disease. However, in general, NSCLC is moderately sensitive to the currently available cytotoxic drugs, so the intention of chemotherapeutic treatment in the advanced setting is mainly palliative. Several treatment regimens are available, but in the first-line setting, treatment traditions differ both within countries and between various parts of the world. The role of taxaneplatinum chemotherapeutic combinations (mainly used in North America) has been questioned in the palliative setting since these combinations are known to cause neutropenia, skin and nail problems, as well as neurological toxicity. This review aims to summarize the current knowledge about the role of non-taxane therapy for patients with advanced NSCLC, with a focus on gemcitabine, vinorelbine, etoposide, pemetrexed, irinotecan, epidermal growth factor receptor (EGFR)-inhibiting agents, angiogenesis inhibitors, and small molecules. The compilation of literature in the present review indicates that the use of non-taxane treatment for patients with advanced NSCLC has an anti-tumor effect that is not different from that which can be seen with various taxane combinations. Furthermore, the combination of cisplatin with gemcitabine or vinorelbine seems to be a most compelling regimen in the first-line setting because of its modest toxicity (when administered by experienced staff), favorable clinical response, and relatively low drug cost. It is also clear that the novel therapies (EGFR inhibitors and inhibitors of angiogenesis) that have been approved so far will be of great clinical value, however, their use will be restricted to small, well defined, subpopulations of patients. The great challenge now is to define the populations benefiting from these novel therapies. © 2006 Adis Data Information BV. All rights reserved.

  • 6.
    Broström, Anders
    et al.
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Hübbert, Laila
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Per
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Peter
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Fridlund, Bengt
    Department of Nursing, Lund University, Lund, Sweden and School of Social and Health Sciences, Halmstad University, Halmstad, Sweden.
    Dahlström, Ulf
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Effects of long-term nocturnal oxygen treatment in patients with severe heart failure2005In: Journal of Cardiovascular Nursing, ISSN 0889-4655, E-ISSN 1550-5049, Vol. 20, no 6, p. 385-396Article in journal (Refereed)
    Abstract [en]

    Sleep-disordered breathing (SDB) is common in patients with heart failure (HF) and leads to disturbed sleep. The objective of this study was to determine the persistent effects of long-term nocturnal oxygen treatment in patients with severe HF regarding (1) objective outcomes, such as sleep, SDB, cardiac function, and functional capacity; (2) subjective outcomes, such as self-assessed sleep difficulties, daytime sleepiness, and health-related quality of life (HRQOL); and (3) the relationship between objective and subjective outcomes. In this open nonrandomized experimental study, 22 patients, median age 71 years, with severe HF were studied before and after 3 months of receiving nocturnal oxygen. The measures used were overnight polysomnography, echocardiography, 6-minute walk test, self-assessed sleep difficulties (Uppsala Sleep Inventory-HF), daytime sleepiness (Epworth Sleepiness Scale), and HRQOL (36-Item Short Form Health Survey and Minnesota Living with Heart Failure Questionnaire). SDB, with a 90% dominance of central sleep apnea, occurred in 41% of the patients with severe HF before intervention. After intervention, functional capacity improved for both the whole group of patients with HF (P < .01) and HF patients with SDB (P < .05). No improvements regarding cardiac function, objective sleep, subjective sleep, or SDB were seen, except for a decrease of > or = 4% desaturations (P < .05). HRQOL did not differ significantly between HF patients with and without SDB before or after intervention with nocturnal oxygen. Long-term nocturnal oxygen treatment improved functional capacity in patients with severe HF, with or without SDB. No improvements were seen regarding sleep, daytime sleepiness, SDB, cardiac function, or HRQOL.

  • 7. Faager, G
    et al.
    Söderlund, K
    Sköld, CM
    Rundgren, S
    Tollbäck, A
    Jakobsson, Per
    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.
    Creatine supplementation and physical training in patients with COPD: A double blind, placebo controlled study2006In: International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, Vol. 1, p. 445-453Article in journal (Refereed)
  • 8.
    Ferdousi, Hosne Ara
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Munir, Abdul Kashem Mohamma
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Zetterström, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Dreborg, Sten
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Seasonal differences of peak expiratory flow rate variability and mediators of allergic inflammation in non-atopic adolescents2001In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 12, no 5, p. 238-246Article in journal (Refereed)
    Abstract [en]

    Variations in peak expiratory flow (PEF) and serum eosinophil mediators were studied in healthy adolescents. Twenty-five boys and 31 girls, 11–16 years of age (mean age 14.3 years), were selected and investigated during the birch pollen season of 1995; 45 were also investigated during the autumn of the same year. The PEF was measured twice daily and eosino-phil mediators in serum and in urine were measured by radioimmunoassay (RIA) once during the birch pollen season and once in autumn. The type values of the daily PEF variation, expressed in amplitude percentage mean, were 6.4 and 3.9%, mean values were 7.35 and 6.74%, and the 95th percentiles were 18 and 14%, during the birch pollen season and autumn, respectively. The 95th percentiles were 41 and 38 µg/l for serum eosinophil cationic protein (s-ECP), 74 and 62 µg/l for serum eosinophil protein X (s-EPX), 987 and 569 µg/l for serum myeloperoxidase (s-MPO), and 165 and 104 µg/mmol for urinary eosinophil protein X/urinary creatinine (u-EPX/u-creatinine), during the birch pollen season and autumn, respectively. The levels of the eosinophil mediators decreased significantly from May (n = 56) to November (n = 45), for s-ECP from a median value of 14 µg/l to 7 µg/l (p= 0.001), for s-EPX from a median value of 28 µg/l to 20 µg/l (p= 0.001), and for the neutrophil mediator, s-MPO, from a median value of 440 g/l to 292 g/l (p< 0.001). The PEF variability decreased significantly (p= 0.037), from spring (n = 55; median 8%, 95% confidence interval [CI] 7.8–10.19) to autumn (n = 44; median 6%, 95% CI 6.1–8.9). A significant correlation was found between the levels of s-ECP and s-EPX (rs = 0.7, p< 0.001), between s-ECP and s-MPO (rs = 0.6, p< 0.001), between s-EPX and s-MPO (rs = 0.4, p< 0.005), and between s-EPX and u-EPX/u-creatinine (rs = 0.6, p< 0.0001), in the birch pollen season (n = 56) and in the autumn (n = 45). There was a positive correlation found in PEF variability between the two seasons (n = 43; rs = 0.5, p= 0.0006). No other correlation was found between PEF variability and any other parameters. The difference in the levels of eosinophil mediators between seasons in non-atopic, healthy children is unexplained. Normal limits for mediators were higher and PEF variability was almost the same as has been reported in adults. When using normal values, seasonal influences should be considered.

  • 9.
    Ferdousi, Hosne Ara
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Zetterström, Olle
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Dreborg, Sten
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Bronchial hyper-responsiveness predicts the development of mild clinical asthma within 2 yr in school children with hay-fever2005In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 16, no 6, p. 478-486Article in journal (Refereed)
    Abstract [en]

    In children with mild asthma, symptoms are not always apparent. Therefore, results of tests play an important role for the diagnosis. First, to investigate whether children with bronchial hyper-responsiveness (BHR) but no symptoms of asthma in 1992 had developed clinical asthma at follow up in 1994. The second aim was to find out the diagnostic properties of tests for asthma/allergic inflammation, using either doctor diagnosed asthma (DDA), self-assessed symptoms of asthma or iso-capnic hyperventilation of cold air (IHCA), as the standard, to diagnose asthma in a group of children with hay fever. Twenty-eight children with pollinosis, 12 of them with a history of asthma for the first time during the season 1992, were studied during the birch pollen season and in the autumn of 1994. During both periods, the bronchial hyper-reactivity was estimated by methacholine bronchial provocation tests (MBPT), bronchial variability by peak expiratory flow rate variability, subjective symptoms of asthma by visual analogue scale (VAS) and bronchial inflammation by serum and urine levels of inflammatory mediators. In 1994 IHCA was added during both seasons. Eight of 16 children with BHR but without clinical asthma in 1992 had developed asthma in 1994, 14 of 16 reacted to IHCA and 13 to MBPT. All 12 children with DDA in 1992 had still asthma in 1994 and 14 children with BHR in 1992 had persistent BHR in 1994. Of 23 children with BHR in 1992, 17 had DDA in 1994 and all maintained their BHR. Furthermore, 20 of them reacted to IHCA in 1994. In 1994, 24 of 28 hay-fever children had a positive IHCA tests and 24 had positive MBPT. In relation to VAS, the sensitivity of IHCA and MBPT to predict present asthma was high, but the specificity low, whereas the specificity of most other tests was high, but based on few individuals. In relation to DDA both the IHCA test (65–80%) and the MBPT test (79–85%) had a high sensitivity and it was three to six times more likely to find a positive test among asthmatics than in non-asthmatics. Children with hay fever without clinical asthma have a high risk of developing asthma within 2 yr. In relation to DDA, inhalation of cold air and the MBPT showed a high sensitivity.

  • 10.
    Fransson, Sven Göran
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Fransson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine.
    Ohälsa- och hypokondri - präglade Verner von Heidenstams liv2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, p. 1987-1989Article in journal (Other academic)
  • 11.
    Fransson, Sven Göran
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Fransson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine.
    Rahm, M
    Verner von Heidenstam. En tänkbar epikris2005In: Riksstämma,2005, 2005Conference paper (Other academic)
  • 12. Helsing, Martin
    et al.
    Thaning, Lars
    Sederholm, Christer
    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.
    Lamberg, Kristina
    Martinsson, Jan-Erik
    Ek, Lars
    Månsson, Tryggve
    Andersson, Lars
    Hero, Ulf
    Anjedani, Dariush
    Svensson, Gunnar
    Treatment with paclitaxel 1-h infusion and carboplatin of patients with advanced non-small-cell lung cancer: a phase II multicentre trial1999In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 24, p. 107-113Article in journal (Refereed)
  • 13.
    Jacobsson, Per
    Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Skeletal muscle metabolism in patients with severe chronic obstructive pulmonary disease: A study of carbohydrate and fat metabolism1995Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In chronic obstructive pulmonary disease (COPD) deterioration of skeletal muscle metabolism is reported in both respiratory and non-respiratory muscles. This deterioration may contribute to both the development of respiratory failure and general disability often seen in severe COPD patients. The aim of this study was to obtain more information on carbohydrate and fat metabolism in advanced, stable COPD patients and to investigate the possible association between muscle glycogen and estimates of malnuttition. Furthermore, the effect of long-term oxygen therapy on the metabolic state was studied. Using the needle biopsy technique, muscle specimens were obtained from the quadriceps femoris muscle for analysis of muscle metabolites, glycolytic and oxidative enzyme activities and skeletal muscle fibre composition. Blood fuel metabolites were studied at rest, during exercise and recovery. Lipolysis was studied using a tracer technique and the response of lipolysis to insulin, as well as insulin resistance in peripheral tissues were studied using the euglycaernic, hyperinsulinaernic glucose clamp technique.

    Depletion of glycogen, A TP and creatine phosphate and increased concentrations of creatine and lactate were observed in the quadriceps femoris muscle. Metabolite concentrations correlated to anerial blood gas values- the lower the Pa02 and the higher the PaC02 the greater the deterioration of the metabolic state. Muscle glycogen concentration correlated to estimates of malnuttition. The correlation between glycogen concentration and prealbumin concentration was strong - the lower the glycogen concentration the lower the prealbumin concentration. After 8 months of long-term oxygen therapy (L TOT) the high energy phosphate state had improved. There was a verylow percentage "oxidative" Type I muscle fibres in the quadriceps femoris muscle. Analysis of enzyme activity also showed adaptation in the form of augmented glycolysis and decreased aerobic metabolism. No changes in enzyme activity were observed after 7 months of LTOT. The turnover rate of free fatty acids (FFA) and plasma FFA concentration were increased in the fasting state. There was a significant positive  correlation between turnover rate ofFFA and FFA concentration in arterial plasma. The results also suggest a reduction in the inhibitory effect of inulin on lipolysis. A few hours after a light breakfast FFA, glycerol and 3-hydroxybutyrate concentrations were lower in COPD patients with chronic respiratory failure (CRF) that in COPD patients without CRF at rest, during exercise and recovery, indicating decreased lipolysis in the CRF patients compared to COPD patients without CRF. In patients with severe COPD and muscle glycogen depletion no resistance to insulin in peripheral tissues was observed.

    In conclusion, skeletal muscle depletion exists in patients with severe, stable COPD. Skeletal muscle glycogen concentration is associated with concentrations of serum proteins. Adaptation of muscle metabolism in the form of augmented glycolysis and reduced aerobic metabolism was observed. Lipolysis is increased in the fasting state and the results suggest a reduction in the inhibitory effect of insulin on lipolysis. No resistance to insulin in peripheral tissues was found. LTOT may improve the muscle energy state of hypoxaemic COPD patients.

  • 14.
    Jakobsson, Per
    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.
    Jorfeldt, Lennart
    Stockholm.
    Oxygen supplementation increases glucose tolerance during euglycaemic hyperinsulinaemic glucose clamp procedure in patients with severe COPD and chronic hypoxaemia2006In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 26, no 5, p. 271-274Article in journal (Refereed)
    Abstract [en]

    Investigations in chronic obstructive pulmonary disease (COPD) patients have shown impaired glucose tolerance in hypoxic COPD patients, compared with COPD patients with normal arterial blood gases. In healthy subjects, hypoxaemia or stay at altitude, have been shown to alter glucose metabolism. At altitude the effect seems to be dependent on duration of stay. A short stay is associated with insulin resistance, a longer stay gives rise to increased glucose uptake. The euglycaemic hyperinsulinaemic glucose clamp technique is a method to study glucose tolerance and enables determinations of glucose clearance in peripheral tissues. We investigated six COPD patients [forced expiratory volume in 1 s 0.7 ± 0.2 l (mean ± SD)] with chronic hypoxaemia (PaO2 7.9 ± 0.6 kPa at rest, breathing air), with and without oxygen supplementation, using the glucose clamp technique. Net peripheral glucose uptake was 5.5 ± 1.2 and 7.1 ± 1.6 mg (kg*min)-1 (+29%) breathing air and supplemental oxygen, respectively (P = 0.03). The tissue sensitivity to insulin increased 32% (P = 0.03) with oxygen supplementation. The results indicate that normalization of oxygen saturation in COPD patients with chronic hypoxaemia may have an immediate effect on glucose tolerance and tissue sensitivity to insulin in these patients. © 2006 Blackwell Publishing Ltd.

  • 15.
    Koch, Andrea
    et al.
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL. Lungeavdelingen, Haukeland Universitetssykehus, Bergen, Norge.
    Sörenson, Sverre
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL. Lungeavdelingen, Haukeland Universitetssykehus, Bergen, Norge.
    Askeland, Asgeir
    Yrkesmedisinsk avdeling, Haukeland Universitetssykehus, Bergen, Norge.
    Aasen, Tor
    Yrkesmedisinsk avdeling, Haukeland Universitetssykehus, Bergen, Norge.
    Rapportering av yrkesrelatert lungekreft.2003In: Lungeforum, ISSN 0803-4079, E-ISSN 1891-1587, Vol. 13, p. 12-16Article in journal (Other academic)
  • 16.
    Lindberg, Malou
    et al.
    Linköping University, Department of Department of Health and Society, General Practice. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ekström, Tommy
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Jonsson, Dick
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Möller, Margareta
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Asthma nurse practice improves outcomes and reduces costs in primary health care2002In: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 16, no 1, p. 73-78Article in journal (Refereed)
    Abstract [en]

    Objective. The aim of this study was to elucidate the care of patients with asthma in primary health care from medical, patient self-management, health, quality of live, and health economic perspectives.

    Methods. Asthma nurse practice (ANP), an alternative asthma self-management strategy, was compared with traditional asthma care in primary health care in southern Sweden regarding medical history, lifestyle, self-management, symptoms caused by asthma, effects on sick leave, state of health, quality of life and health care costs. The first part of the investigation comprised a retrospective study of a randomly selected sample of patient records of asthmatics (n=152). The second part, lasting 3 months, was prospective and included consecutive patients visits (n=347).

    Results. The ANP approach showed better results in most of the evaluated outcomes such as asthma quality documentation and self-management and the number of asthma symptoms was significantly lower. From a health economic perspective the results were encouraging with respect to ANP.

    Conclusion. This alternative asthma strategy, ANP, improved asthma care in primary health care and resulted in economic advantages in the health care sector. However the result may only be generalized to other practices working with asthma nurses in the same way.

  • 17.
    Lindberg, Malou
    et al.
    Linköping University, Department of Department of Health and Society, General Practice. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ekström, Tommy
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Möller, Margareta
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Patient questionnaires in primary health care: Validation of items used in asthma care2000In: International Journal for Quality in Health Care, ISSN 1353-4505, E-ISSN 1464-3677, Vol. 12, no 1, p. 19-24Article in journal (Refereed)
    Abstract [en]

    Objective.To evaluate each item in a patient questionnaire for the purpose of investigating whether the validity of each item is acceptable.

    Design.The questionnaire was completed by the patients at an ordinary follow-up visit for their asthma, and within 1 week a nurse interviewed them by telephone with the aim of analysing the validity of each item through the use of predetermined criteria.

    Settings.Patients with asthma in primary health care settings in Sweden.

    Study participants.Fifty-one patients were consecutively included from three different primary health care units.

    Results.Nine of 13 items had an acceptable validity. The four items that were not found to have acceptable validity were developed further.

    Conclusion.Evaluating each item in a questionnaire by means of interviews with the specific patient population is a useful method of assuring that the intention of the patient questionnaire has been met.

  • 18.
    Lindberg, Malou
    et al.
    Linköping University, Department of Department of Health and Society, General Practice. Linköping University, Faculty of Health Sciences.
    Ekstrom, Tommy
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Moller, Margareta
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Asthma care and factors affecting medication compliance: the patient's point of view2001In: International Journal for Quality in Health Care, ISSN 1353-4505, E-ISSN 1464-3677, Vol. 13, no 5, p. 375-383Article in journal (Refereed)
    Abstract [en]

    Objective. To identify important factors that can influence patient compliance with prescribed medication and to elucidate aspects of asthma care from the patient's point of view.

    Design. Field investigation; the interviewer used a semi‐structured questionnaire.

    Setting. Patients with asthma in primary health care settings in Sweden.

    Study participants. A sample of 77 patients was randomly selected from 11 primary health care centres in southern Sweden; 63 of these patients participated in the study.

    Conclusion. The factors of importance for self‐reported compliance with prescribed medication were age, gender, duration of the disease, the attitude of the staff and information/education about asthma. The patients expressed important aspects of care, and these are in accordance with how an asthma nurse practice functions in Sweden.

  • 19.
    Lindberg, Malou
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, General Practice.
    Ekström, Tommy
    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.
    Möller, Margareta
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Astma care and factors affectin medication comliance; the patient's point of view2001In: International Journal for Quality in Health Care, ISSN 1353-4505, E-ISSN 1464-3677, Vol. 13, p. 375-383Article in journal (Refereed)
  • 20.
    Munir, Abdul Kashem Mohamma
    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.
    Indoor allergens a cause of public health problem2001In: Recent Res Dev Allerg Clin Immunol,2001, 2001, p. 119-129Conference paper (Refereed)
  • 21.
    Munir, Abdul Kashem Mohamma
    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.
    Einarsson, R
    Dreborg, S
    Variability of airborne cat allergen, Fel d1, in a public place2003In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 13, no 4, p. 353-358Article in journal (Refereed)
    Abstract [en]

    Allergen exposure is a risk to develop an IgE-mediated sensitization. The amount of allergen inhaled per unit time should be related to the amount present in the air, i.e. airborne allergen. Thus, measuring allergen levels in the air would be more relevant than measuring allergen levels in dust. Allergens are present in the air in very minute quantities and usually become airborne after disturbance. Large variation of allergen levels have been found in dust. In this study, we measured variability of airborne cat allergen, Fel d1, in a public place using a high-volume air-sampler. We also studied the distribution and relationship between dust and airborne cat allergens in homes and schools. Air samples were collected at three different airflow rates, i.e. 55, 40, and 30 m3 of air per hour. The concentration of airborne Fel d1 in the community gymnastic hall varied from 1 to 10 pg/m3 within a period of 3 weeks, at airflow rates 55-30 m3/h. The coefficient of variation for repeated samplings was 14-43% (day-to-day variation) and 27-38% (within-day variation). As expected, higher levels of airborne cat allergens were found in homes with cats than in cat-free environments. There was a significant relationship between cat allergen levels in dust and air (r = 0.7, P < 0.01). Our study demonstrates that when measuring airborne cat allergen a large variation is observed within a day and between days. The large variability of measurement may be explained by the disturbance in the environments. We suggest, that when exposure assessment is made the environment in question should be analyzed, if possible in several occasions.

  • 22.
    Nayeri, Fariba
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Millinger, Eva
    Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Ingela
    Departments of Clinical Chemistry, County Hospital, Kalmar, Sweden.
    Zetterström, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences.
    Brudin, Lars
    Departments of Clinical Physiology, County Hospital, Kalmar, Sweden.
    Forsberg, Pia
    Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia2002In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 96, no 2, p. 115-119Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is a protein produced by mesenchymal cells in many organs, which can stimulate epithelial growth. An enhanced production and concentration of HGF is observed after injuries. The lung is one of the major sources of HGF. By cooling exhaled air, a condensate is formed containing molecules from bronchi and alveoli. In order to investigate HGF concentration and time course in pneumonia, paired serum and exhaled breath condensate was collected from 10 patients with pneumonia, 10 patients with non-respiratory infections and 11 healthy controls. The concentration of HGF was measured by an immunoassay kit. In the acute phase HGF-levels in breath condensate and serum were significantly higher in the patients with pneumonia compared to the control groups. Similar concentrations in breath condensate were seen in healthy controls and in patients with non-respiratory infections. In the patients with pneumonia a decrease in serum HGF was seen already after 4–7 days while HGF values in breath condensate remained elevated even after 4–6 weeks. These results might imply local production of HGF in the lungs and a long repair and healing process after pneumonia.

  • 23.
    Olejnicka, Beata
    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.
    Dalen, H.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Minute oxidative stress is sufficient to induce apoptotic death of NTT insulinoma cells.1999In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 107, p. 747-761Article in journal (Refereed)
  • 24.
    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.

  • 25.
    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
  • 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.
    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)
  • 27.
    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)
  • 28.
    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)
  • 29.
    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.

  • 30.
    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.

  • 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 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.

  • 33. Prifti Saethre, Reita
    et al.
    Sörenson, Sverre
    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.
    Den lungmedisinske diagnosen2003In: Lungeforum, ISSN 0803-4079, Vol. 13, p. 27-30Article in journal (Other (popular science, discussion, etc.))
  • 34.
    Rutberg, Hans
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Sommer, AnnSofie
    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.
    Skau, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Vascular surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Kvalitet inom sjukvården. Vad är det och hur mäts den?2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, p. 3044-3045Article in journal (Other (popular science, discussion, etc.))
  • 35.
    Sederholm, Christer
    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.
    Gemcitabine versus gemcitabine/carboplatin in advanced non-small cell lung cancer: Preliminary findings in a phase III trial of the Swedish Lung Cancer Study Group2002In: Seminars in Oncology, ISSN 0093-7754, E-ISSN 1532-8708, Vol. 29, no 3 SUPPL. 9, p. 50-54Article in journal (Refereed)
    Abstract [en]

    Gemcitabine is an active agent in non-small cell lung cancer, with single-agent treatment producing response rates of approximately 20% and median survivals of approximately 7 to 9 months. In a pilot trial in advanced non-small cell lung cancer, the gemcitabine/ carboplatin combination produced a response rate of 43% and median survival of 12 months with good tolerability. Preliminary results of a phase III trial comparing gemcitabine alone with gemcitabine/carboplatin in 332 patients with stage IIIB or IV non-small cell lung cancer are now available. Patients were randomized to receive gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days or the same gemcitabine regimen plus carboplatin at an area under the concentration-time curve of 5 mg/mL/min on day 1 for a maximum of six cycles. Hematologic toxicity was more common in the combination arm, grade 4 thrombocytopenia occurred in 23.5% v 5.3% of patients, but infrequently resulted in clinical complications. Nonhematologic toxicity was moderate and similar in frequency in the combination and gemcitabine arms (25% and 28%, respectively). Among 275 patients, overall response rates were 30% (2% complete response and 28% partial response) in the combination arm and 12% (all partial responses) in the gemcitabine arm. Median time to disease progression was 6 months in the combination arm and 4 months in the gemcitabine arm. Median survival in the study population was 9 months, a promising finding given the high proportion of elderly patients in the study (37% = 70 years of age). Full mature results of the trial, including comparative survival results and data on quality of life, are awaited. Copyright 2002, Elsevier Science (USA). All rights reserved.

  • 36.
    Sörenson, Sverre
    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.
    BLANK-studien2003In: Lungeforum, ISSN 0803-4079, Vol. 13, p. 21-26Article in journal (Other (popular science, discussion, etc.))
  • 37.
    Sörenson, Sverre
    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.
    IRIS-studien2003In: Lungeforum, ISSN 0803-4079, Vol. 13, p. 22-22Article in journal (Other (popular science, discussion, etc.))
  • 38.
    Sörenson, Sverre
    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.
    Lungor2004Other (Other (popular science, discussion, etc.))
    Abstract [sv]

    Kliniska färdigheter. Stefan Lindgren, Kurt Aspegren (red). Studentlitteratur 2004 sidan 63-72

  • 39.
    Sörenson, Sverre
    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.
    Rapport from American Society of Clinical Oncololgy (ASCO)2002Report (Other academic)
  • 40.
    Sörenson, Sverre
    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.
    Sederholm, Christer
    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.
    Den solitära lungtumören2003In: Lungeforum, ISSN 0803-4079, Vol. 13, p. 24-28Article in journal (Other (popular science, discussion, etc.))
  • 41. ten Bokkel Huinink, Willem W
    et al.
    Bergman, Bengt
    Chemaissani, Assad
    Dornoff, Wolfgang
    Drings, Peter
    Kellokumpu-Lehtinen, Piikko-Liisa
    Liippo, K
    Mattson, Karin
    von Pawel, Joachim
    Ricci, Sergio
    Sederholm, Christer
    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.
    Stahel, Rolf A
    Wagenius, Gunnar
    v Walree, N
    Manegold, Christian
    Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer1999In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 26, p. 85-94Article in journal (Refereed)
  • 42.
    Theander, Kersti
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science.
    Jakobsson, Per
    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.
    Torstensson, O
    Unosson, Mitra
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science.
    Fatigue and quality of life among patients with COPD2005In: European Respiratory Society Copenhagen 2005 Congress,2005, 2005Conference paper (Other academic)
  • 43.
    Theander, Kersti
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science.
    Unosson, Mitra
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science.
    Jakobsson, Per
    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.
    Functional impact of fatigue in patients with chronic obstructive pulmonary disease2004In: 12th Biennal Conference of the Workgroup of European Nurses Researchers,2004, 2004Conference paper (Other academic)
  • 44.
    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.

  • 45.
    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.

1 - 45 of 45
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