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  • 151.
    Persson, Ingrid
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Växter mot smärta och inflammation2010In: Smärta, no 2, p. 8-10Article in journal (Other academic)
  • 152.
    Persson, Ingrid A L
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective.2011In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 57, no 1, p. 44-50Article in journal (Refereed)
    Abstract [en]

    Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P < 0.01) and significant increase of NO (P < 0.001) were seen in HUVEC. In the study subjects, a significant inhibition of ACE activity (mean 18%) 3 hours after intake of dark chocolate was seen, but no significant change in NO was seen. According to ACE genotype, significant inhibition of ACE activity was seen after 3 hours in individuals with genotype insertion/insertion and deletion/deletion (mean 21% and 28%, respectively). Data suggest that intake of dark chocolate containing high amount of cocoa inhibits ACE activity in vitro and in vivo.

  • 153.
    Persson, Ingrid A-L
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The Pharmacological Mechanism of Angiotensin-converting Enzyme Inhibition by Green Tea, Rooibos and Enalaprilat - A Study on Enzyme Kinetics2012In: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 26, no 4, p. 517-521Article in journal (Refereed)
    Abstract [en]

    Green tea (Camellia sinensis L.) and Rooibos (Aspalathus linearis Dahlg.) inhibit angiotensin-converting enzyme (ACE) in vitro and in vivo. The ACE inhibitor enalaprilat has been described previously as a competitive inhibitor and sometimes as a non-competitive inhibitor. The aim of this study was to investigate the pharmacological mechanism of ACE inhibition of green tea and Rooibos by enzyme kinetics, and to compare this with enalaprilat. A MichaelisMenten kinetics and LineweaverBurk graph showed mean values of Vmax?=?3.73 mu m and Km?=?0.71 mu m for green tea, of Vmax?=?6.76 mu m and Km?=?0.78 mu m for Rooibos, of Vmax?=?12.54 mu m and Km?=?2.77 mu m for enalaprilat, and of Vmax?=?51.33 mu m and Km?=?9.22 mu m for the PBS control. Incubating serum with green tea or Rooibos saturated with zinc chloride did not change the inhibitory effect. Enalaprilat preincubated with zinc chloride showed a decrease in the inhibitory effect. In conclusion, green tea, Rooibos and enalaprilat seem to inhibit ACE activity using a mixed inhibitor mechanism.

  • 154.
    Persson, Ingrid A-L
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of green tea, black tea and Rooibos tea on angiotensin-converting enzyme and nitric oxide in healthy volunteers2010In: Public Health Nutrition, ISSN 1368-9800, E-ISSN 1475-2727, Vol. 13, no 5, p. 730-737Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Tea has been reported to reduce cardiovascular mortality, but the underlying mechanisms are largely unknown. The aim of the current project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos tea (South Africa) on angiotensin-converting enzyme (ACE) and nitric oxide (NO). DESIGN: Seventeen healthy volunteers received a single oral dose of 400 ml green tea, black tea or Rooibos tea in a randomized, three-phase, crossover study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 min) in all phases. ACE activity was analysed by means of a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition, ACE genotype was determined using a PCR method. RESULTS: Oral intake of a single dose of Rooibos tea significantly inhibited ACE activity after 30 min (P < 0.01) and after 60 min (P < 0.05). A significant inhibition of ACE activity was seen with green tea for the ACE II genotype 30 min after intake of the tea (P < 0.05) and for the ACE ID genotype 60 min after intake (P < 0.05). A significant inhibition of ACE activity was also seen with Rooibos tea for the ACE II genotype 60 min after intake (P < 0.05). No significant effect on NO concentration was seen. CONCLUSIONS: These results suggest that green tea and Rooibos tea may have cardiovascular effects through inhibition of ACE activity.

  • 155.
    Persson, Ingrid
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lindén, Erica
    Linköping University, Department of Medicine and Health Sciences, Physiotherapy. Linköping University, Faculty of Health Sciences.
    Andersson, Malin
    Östergötlands Läns Landsting.
    Persson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Effects of Ginkgo biloba extract EGb 761 and its terpenelactones on angiotensin converting enzyme activity and nitric oxide production in human endothelial cells2008In: Journal of traditional medicines, ISSN 1880-1447, Vol. 3, no 2, p. 42-51Article in journal (Refereed)
    Abstract [en]

    The effects of Ginkga bi/aba (Ginkgoaceae), its terpene-Iactones (ginkgolide A, B, C and bilobalide), biflavonols (quercetin), biflavones (sciadopitysin) and proanthocyanidins (procyanidin) on angiotensin-converting enzyme (ACE) activity and nitric oxlde (NO) production in cultured human endothelial cells from umbilical veins (HUVEC) were investigated. A dose-dependent significant inhibition of the ACE activity was observed arter 10 min incubation with Ginkga bi/aba extract EGb  761 and quercetin. No significant effects due to terpene-Iactones or sciadopitysin were seen. Incubation with Ginkga bi/aba extract, quercetin, sciadopitysin and procyanidin for 24 hr significantly Increased NO production. No significant effects were seen with ginkgollde A, B and C, while bilobalide induced a dose-dependent decrease in NO production. In conclusion, this study shows that Ginkga bi/aba extract Inhibits ACE activlty and increases NO production from HUVEC. A flavonol (quercetin and/or homologs) is the main component responsible for the inhibitory effect ofACE activity. Quercetin and a proanthocyandin (procyanidin) are responsible for the increases seen in NO production. These results may explain the positive effects of Ginkga bi/aba on the cardiovascular system and on cognitive function.

  • 156.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Fiction and film as teaching instruments in higher health care education2008In: Journal of Further and Higher Education, ISSN 0309-877X, E-ISSN 0013-1326, Vol. 32, no 2, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Teaching of the sciences of behaviour in higher health care education is sparse. The authors believe that students with increased knowledge and education of the human mind and soul would have a wider understanding of the human nature. Physiology describes the anatomy and function of the body, but in order to describe life/the living human, they were looking for a tool to describe the mind/soul as well as the body; to describe the connection between the two. Their intention was to teach the knowledge of the human being as an exciting experience and not just as a patient but as a larger concept; a human being in all its dimensions.

    To understand the multidimensional structure of behaviour, as many perspectives as possible are needed. In using film and fiction in education, the authors want the students to use their own sensory systems and emotions to learn about behaviour. As fiction and film expose the microcosmos, the audience will experience the microcosmos in the spotlight. The purpose of this article is to stimulate and inspire other teachers to use these means in higher health care education.

  • 157.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Horse Chestnut (Aesculus hippocastanum L.)2009In: Recent Progress in Medical Plants, 2009, p. 159-171Chapter in book (Other (popular science, discussion, etc.))
    Abstract [en]

    Abstract

    Extract from seeds and bark of the horse chestnut tree Aesculushippocastanum L. (Hippocastanaceae) is today used as herbal medicine in Europe against chronic venous insufficiency (CVI; i.e. varicose veins accompanied with pain, oedema, pruritus and a sense of heaviness). Administration is oral (e.g. Venastat®, Venokan®) or topical (Reparil). Recommended oral dose is 50 mg aescin twice a day. The standardized extract mostly used is D.H.E. (Bernett, Milan, Italy; standardized for 16-22% triterpene saponins). Prior to treatment, other diseases (e.g. venous thrombosis) should be excluded. Oral administration with horse chestnut capsules has in clinical studies been shown to be more effective than placebo and as effective as compression stockings in CVI. The main constituents of horse chestnut are triterpene saponins (i.e. aescin), flavonoids (e.g. quercetin, kaempherol, epicatechin, proanthocyanidin A anthocyanins) and coumarins (e.g. esculin, esculetin). Aescin (also called escin) is actually a mixture of more than 30 different triterpene saponin glycosides of which the main component is suggested to be the active component and is the major content of pharmaceutical products. Mainly three effects of horse chestnut extract on CVI can be identified: anti-oedomatous, anti-inflammatory and venotonic. The anti-inflammatory effect includes free oxygen radical scavenging and decreased vascular permeability. Also, inhibition of elastase, collagenase 2,b-aescin (C55H86O24). b-aescin is and hyaluronidase in the vascular wall has been observed. Adverse effects are few and include gastrointestinal symptoms, nausea, headache, dizziness and allergy. Possible contraindications and drug interactions have not been studied.

     

  • 158.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Letter to Editor: The Pharmaceutist in the Roll as Educationalist/informant - Programme Description of Drugpedagogics2010In: International Journal of Pharmacy and Pharmaceutical Sciences, ISSN 0975-1491, Vol. 2, no suppl 4, p. 1-2Article in journal (Other academic)
    Abstract [en]

    This is a description of a 7.5 ECTS credits course in drug-pedagogics suitable for pharmacy students. The aim of this course is to provide the students with skills as informants/communicators concerning drugs and use at individual, group and community levels. The course includes advanced studies in drug-pedagogics from psychological, sociological and pharmacological perspective. The examination consists of an individual implementation of oral drug information to a group.

  • 159.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Liquorice, Glycyrrhiza glabra Inhibits angiotensin-converting Enzyme Activity and Increases Nitric Oxide Production in Human Endothelial Cells2009In: Phytopharmacology and Therapeutic Values V: V K Singh och J N Govil (red.), Houston: Studium Press LLC, USA , 2009, 1, p. 171-179Chapter in book (Refereed)
    Abstract [en]

    This book contains 27 research and review papers that cover the recent progress in medicinal plant research, e.g. therapeutic efficacy of Bidens pilosa var. radiata and Galinsoga parviflora in experimentally induced diarrhoea in mice, new antioxidant flavonoids from Atriplex lentiformis and analysis of polyphenols with potential antioxidant properties in wines from Croatia.

    Up to 138 more results found for "phytopharmacology AND therapeutic values v''"

  • 160.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Plant-Derived Substances as ACE Inhibitors - Biosynthesis-Activity Relationship of Flavonoids, Terpenes and Sterols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells2009In: Angiotensin Converting Enzyme Inhibitors, Nova Science Publishers , 2009, 1, Chapter 3, p. 1-31Chapter in book (Refereed)
    Abstract [en]

    Flavonoids, carotenoids and tocopherols are antioxidants with alleged positive effect on the cardiovascular system. To investigate other possible pharmacological mechanisms, we examined common substances from these groups and others derived from the same biosynthesis pathway concerning their effect on angiotensin-converting enzyme (ACE) activity in human endothelial cells.

    Cultered human endothelial cells from umbilical veins (HUVEC) were used and incubated for 10 minutes with flavonoids, terpenes, sterols and precursor molecules. The flavonoids tested were the isoflavone genistein, the flavonol quercetin, the epi-flavan-3-ols epicatechin, epicatechingallate, epigallocatechin, epigallocatechingallate, procyanidin and the biflavan sciadopitysin. The terpenoids tested were the diterpenes α-tocopherol and ginkgolides A, B, C, the sesquiterpene bilobalide, the triterpenes ginsenoside Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and the tetraterpene β-carotene. The sterols tested were stigmasterol, lanosterol and cholesterol. The biosynthesis precursor molecules tested were mevalonic acid, malonic acid, shikimic acid, chorismic acid and the progenitor squalene. 

     

     

     

  • 161.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effect of Vaccinium myrtillus and Its Polyphenols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells2009In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, E-ISSN 1520-5118, Vol. 57, no 11, p. 4626-4629Article in journal (Refereed)
    Abstract [en]

    This study investigates if the connection between Vaccinium myrtillus and angiotensin-converting enzyme (ACE) might be an explanation of the pharmacological effects on circulation. Cultured endothelial cells from human umbilical veins were incubated with bilberry 25E extract. The main anthocyanidins combined in myrtillin chloride and separately in cyanidin, delphinidin, and malvidin, respectively, were examined concerning their effects on ACE. After 10 min of incubation with bilberry 25E, a significant, dose-dependent inhibition of ACE activity was seen, and after incubation with myrtillin chloride a significant inhibition was seen. No effect was seen with the anthocyanidins. The effect seems to be dependent on this specific mixture of anthocyanins in the bilberry. V. myrtillus may thus have the potential to prevent and protect against cardiovascular diseases.

  • 162.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers2009In: in Planta Medica(ISSN 0032-0943), 2009, Vol. 75, no 9, p. 1030-1030Conference paper (Refereed)
    Abstract [en]

    Tea has been reported to reduce cardiovascular mortality, but the mechanisms behind are largely unknown. The aim of this project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos on angiotensin-converting enzyme and nitric oxide. Seventeen healthy volunteers received a single oral dose of either 400 ml green tea, black tea or Rooibos tea in a randomized three-phase cross over study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 minutes) in all phases. ACE activity was analysed with a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition ACE genotype was determined using a PCR method. Oral intake of a single dose of Rooibos significantly inhibited ACE activity, p<0.01 after 30 min and p<0.05 after 60 min. A significant inhibition of ACE activity was seen with green tea for the ACE genotype II (p<0.05), 30 minutes after intake of the tea and for the ACE genotype ID (p<0.05), 60 minutes after intake. A significant inhibition of ACE activity was also seen with Rooibos for the ACE genotype II (p<0.05), 60 minutes after intake. No significant effect on NO concentration was seen.

  • 163.
    Persson, Karin
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors1998In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 32, no 2, p. 306-313Article in journal (Refereed)
    Abstract [en]

    Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10-10-10-8 M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nω-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10-6 M). Bradykinin (>10-7M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9 [Leu8] bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

  • 164.
    Persson, Karin
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries1999In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.

  • 165.
    Persson, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Sauma, Lilian
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Safholm, Annette
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    LDL and UV-oxidized LDL induce upregulation of iNOS and NO in unstimulated J774 macrophages and HUVEC2009In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Oxidized low-density lipoprotein (LDL) diminishes NO production from activated macrophages. The interaction between LDL and inactivated macrophages is neglected and controversial. This study examines the effect of LDL, 7-oxysterols and iron compounds on NO production in unstimulated J774 macrophages. J774 cells and human umbilical vein endothelial cells (HUVEC) were either incubated for 24 h with native LDL (LDL) or ultraviolet (UV)-oxidized LDL (UVoxLDL), in the absence or presence of an inducible nitric oxide synthase (iNOS)- or an endothelial constitutive nitric oxide synthase (eNOS)-inhibitor. J774 cells were also incubated with lipopolysaccharide (LPS), in the absence or presence of an iNOS- or an eNOS-inhibitor. Nitrite was analysed as a marker of NO production. The mRNA levels of iNOS were evaluated by reverse transcriptase polymerase chain reaction. LDL and UVoxLDL significantly increased NO production from unstimulated J774 macrophages. This increase in NO was accompanied by enhanced expression of iNOS mRNA, and was inhibited by the iNOS inhibitor. Furthermore, NO production was elevated and angiotensin-converting enzyme (ACE) activity was reduced in HUVEC following the exposure to LDL and UVoxLDL. In conclusion, LDL may serve as an important inflammatory activator of macrophages and HUVEC, inducing inducible nitric oxide production but diminishing ACE. After its oxidation, this function of LDL may be further enhanced and may contribute to the regulation and progression of atheroma formation.

  • 166.
    Persson, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per A.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Nyhlén, Kristina
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Jacobsson-Strier, Monica
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Glindell, Maria
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitroManuscript (preprint) (Other academic)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme (ACE) activity, and platelet aggregation. The NO donor S-nitroso N-acetylpenicillamine SNAP (10-8-10-6 M) significantly and dose-dependently inhibited serum ACE activity. The concomitant addition of SNAP to ACE inhibitor-treated (captopril or enalaprilat) serum, further reduced ACE activity. In cultured endothelial cells from human umbilical veins (HUVEC), both SNAP and 3-morpholinosydnonimine (SIN-1) significantly reduced ACE activity. An additative effect was seen with a combined treatment of captopril and SNAP. Treatment with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) did not affect ACE activity. Thrombin inhibited endothelial ACE activity, an effect that was abolished when cells were pretreated with L-NMMA. ADP-induced platelet aggregation was inhibited with SNAP, SIN-1 and nitroglycerine (GTN). Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M ACE inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-I and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human ACE activity. NO donors and ACE inhibitors act in concert to inhibit ACE and platelet aggregation. 

  • 167.
    Persson, Karin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Nyhlén, Kristina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Nursing Science.
    Jacobsson-Strier, M.
    Glindell, M.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Nitric oxide donors and angiotensin-converting enzyme inhibitors act in concert to inhibit human angiotensin-converting enzyme activity and platelet aggregation in vitro2000In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 406, no 1, p. 15-23Article in journal (Refereed)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme activity and platelet aggregation. The NO donor S-nitroso-N-acetylpenicillamine (10-8-10-6 M) significantly and dose-dependently inhibited serum angiotensin-converting enzyme activity. The concomitant addition of S-nitroso-N-acetylpenicillamine to angiotensin-converting enzyme inhibitor-treated (captopril or enalaprilat) serum, further reduced angiotensin-converting enzyme activity. In cultured endothelial cells from human umbilical veins (HUVECs), both S-nitroso-N-acetylpenicillamine and 3-morpholinosydnonimine (SIN-1) significantly reduced angiotensin-converting enzyme activity. An additative effect was seen with a combined treatment of captopril and S-nitroso-N-acetylpenicillamine. Treatment with the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) did not affect angiotensin-converting enzyme activity. Thrombin inhibited endothelial angiotensin-converting enzyme activity, an effect that was abolished when cells were pretreated with L-NMMA. Adenosine 5'-diphosphate (ADP)-induced platelet aggregation was inhibited with S-nitroso-N-acetylpenicillamine, SIN-1 and nitroglycerine. Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M angiotensin-converting enzyme inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-1 and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human angiotensin-converting enzyme activity. NO donors and angiotensin-converting enzyme inhibitors act in concert to inhibit angiotensin-converting enzyme and platelet aggregation. Copyright (C) 2000 Elsevier Science B.V.

  • 168.
    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

  • 169.
    Ragnehed, Mattias
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Dahlqvist Leinhard, Olof
    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.
    Pihlsgård, Johan
    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.
    Wirell, Staffan
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Sökjer, Hannibal
    Linköping University, Department of Computer and Information Science, MDI - Interaction and Service Design Research Group. Linköping University, The Institute of Technology.
    Fägerstam, Patrik
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Jiang, Bo
    Linköping University, Department of Medical and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Radiation Physics. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Visual Grading of 2D and 3D fMRI compared to image based descriptive measures2010In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 20, no 3, p. 714-724Article in journal (Refereed)
    Abstract [en]

    A prerequisite for successful clinical use of functional Magnetic Resonance Imaging (fMRI) is the selection of an appropriate imaging sequence. In this paper, 2D and 3D fMRI sequences were compared using different image quality assessment methods. Descriptive image measures, such as activation volume and temporal signal-to-noise ratio (TSNR), were compared with results from Visual Grading Characteristics (VGC) analysis of the fMRI results. It was found that significant differences in activation volume and TSNR were not directly reflected by differences in VGC scores. The results suggest that better performance on descriptive image measures is not always an indicator of improved diagnostic quality of the fMRI results. In conclusion, in addition to descriptive image measures, it is important to include measures of diagnostic quality when comparing different fMRI data acquisition methods.

  • 170.
    Rodgers, Kenneth J
    et al.
    University of Sydney.
    Ford, Justin L
    University of Sydney.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Heat shock proteins: keys to healthy ageing?2009In: REDOX REPORT, ISSN 1351-0002, Vol. 14, no 4, p. 147-153Article, review/survey (Other academic)
    Abstract [en]

    Organisms produce reactive species throughout their lives, and this may result in damage to proteins and other biological molecules. Oxidatively damaged proteins are normally selectively degraded and replaced, but this process appears to be less efficient in senescent, long-lived post-mitotic cells, as is evidenced by their accumulation in the form of lipofuscin inside the lysosomal compartment. A great deal of research has focused on changes to the proteolytic machinery in the ageing cells in particular the proteasomes although failure of heat shock proteins (HSPs) to bind and deliver oxidised proteins efficiently to the degradation machinery could also contribute to their aggregation and accumulation. Oxidised proteins can be protease-resistant and may even directly inhibit the proteolytic machinery of the cellu The critical role that is played by HSPs in preventing accumulation of oxidised proteins is often overlooked. In this reviews we examine the key role played by HSPs in recognising, removing and preventing the formation of oxidised and damaged proteins in cells. We also examine the evidence supporting the view that failure of one of these pathways could underlie ageing and age-related diseases. Finally, we discuss how modulation of HSP-activity could influence the ageing process and the progression of age-related diseases.

  • 171.
    Samuelsson, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hanås, Ragnar
    Barnkliniken NÄL, Uddevalla.
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Do high blood glucose peaks contribute to higher HbA1c? Results from repeated continuous glucose measurements in children2008In: World Journal of Pediatrics, ISSN 1708-8569, Vol. 4, no 3, p. 215-221Article in journal (Refereed)
    Abstract [en]

    Background: HbA1c levels are infl uenced by the glycemic control of previous 2-3 months. Sometimes patients have surprisingly low HbA1c in spite of many correctly measured high blood glucose values, which is diffi cult to explain. As glucose sensors give an objective picture based on glucose readings several times per minute over 24 hours, we used the area under the curve (AUC) of such subcutaneous glucose profi les to evaluate their relationship with HbA1c. Methods: Thirty-two patients were randomized into two study arms, one open and the other blinded. Both arms had 8 pump users and 8 patients with multiple daily injections (MDI). After three months the two arms crossed over. Both study arms wore a continuous glucose monitoring system (CGMS) for 3 days every 2 weeks. HbA1c was determined before and after each 3-month study period. Results: There was no relationship between HbA1c and s.c. glucose AUC or between HbA1c and the number of peaks >15.0 mmol/L when all CGMS profi les during the 6 months were taken together. Children on MDI showed a positive relationship between HbA1c and AUC (P<0.01) as well as the number of peaks (P<0.01). Children with a negative relationship between HbA1c and AUC generally had fewer fluctuations in blood glucose values, whereas children with a positive relationship had wide fluctuations. Conclusions: Although there was no relationship between s.c. glucose AUC and HbA1c, the results indicate that wide blood glucose fluctuations may be related to high HbA1c values. Therefore, complications and therapeutic interventions should aim at reducing such fluctuations. © Springer 2008.

  • 172.
    Schmitt, U
    et al.
    Johannes Gutenberg University Mainz.
    Schoenfelder, Y
    Johannes Gutenberg University Mainz.
    Karlsson, L
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Kugelberg, F C
    National Board of Forensic Medicine.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Hiemke, C
    Johannes Gutenberg University Mainz.
    Forced swim-test-related antidepressant effects depend on P-glycoprotein expression in the Blood-Brain-Barrier2009In: in PHARMACOPSYCHIATRY, ISSN 0176-3679, vol 42, issue 5, 2009, Vol. 42, no 5, p. 241-241Conference paper (Refereed)
    Abstract [en]

    n/a

  • 173.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Genes that link nephritis to autoantibodies and innate immunity.2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 7, p. 679-680Article in journal (Other academic)
  • 174.
    Segelmark, Mårten
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Dahlberg, Per
    Department of Medicine, NÄL Hospital, Trollhättan, Sweden.
    Wieslander, Jörgen
    Eurodiagnostica AB, Malmö, Sweden.
    Anti-GBM disease with a mild relapsing course and low levels ofanti-GBM autoantibodies2012In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 5, no 6, p. 549-551Article in journal (Refereed)
    Abstract [en]

    Anti-glomerular basement membrane disease (anti-GBM) is usually characterized by rapidly progressive glomerulonephritis, and when autoantibody production has ceased, relapses are rare. Here, we report a 71-year-old women diagnosed at a stage of mild renal insufficiency. Over a period of 10 years, she experienced three mild relapses with return of anti-GBM antibodies, haematuria and slight elevations in serum creatinine level. All three relapses responded to immunosuppressive therapy, and all were preceded by peaks of myeloperoxidase-antineutrophil cytoplasm antibodies (MPO-ANCA). This case shows that long-term follow-up is warranted in patients treated for anti-GBM-mediated disease, but urinary dipsticks may be sufficient for early detection of relapses.

  • 175.
    Sjöwall, Christoffer
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Askendal, Agneta
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP-C1q interaction2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 1, p. 251-258Article in journal (Refereed)
    Abstract [en]

    C-reactive protein (CRP) interacts with phosphorylcholine (PC), Fcγ receptors, complement factor C1q and cell nuclear constituents, yet its biological roles are insufficiently understood. The aim was to characterize CRP-induced complement activation by ellipsometry. PC conjugated with keyhole limpet hemocyanin (PC-KLH) was immobilized to cross-linked fibrinogen. A low-CRP serum with different amounts of added CRP was exposed to the PC-surfaces. The total serum protein deposition was quantified and deposition of IgG, C1q, C3c, C4, factor H, and CRP detected with polyclonal antibodies. The binding of serum CRP to PC-KLH dose-dependently triggered activation of the classical pathway. Unexpectedly, the activation was efficiently down-regulated at CRP levels >150 mg/L. Using radial immunodiffusion, CRP–C1q interaction was observed in serum samples with high CRP concentrations. We propose that the underlying mechanism depends on fluid-phase interaction between C1q and CRP. This might constitute another level of complement regulation, which has implications for systemic lupus erythematosus where CRP is often low despite flare-ups.

  • 176.
    Skoglund, Caroline
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Platelets in inflammation: Role of complement protein C1q, C-reactive proteinand toll-like receptors2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Platelets are proven essential in haemostasis, however, they are now also increasingly recognized as cells with important immunomodulatory properties, e.g. through interaction with leukocytes and several species of bacteria and by release inflammatory mediators upon activation. Moreover, platelets express receptors involved in immunity and inflammation such as Fcγ‐receptor IIa, complement protein C1q‐receptors (gC1qR, cC1qR, CD93 and α2β1) and toll‐like receptors (TLR‐1, ‐2, ‐4, ‐6 and ‐9). C1q, C‐reactive protein (CRP) and TLRs are all pattern recognition molecules able to recognize non‐self structures and initiate an immune response. Uncontrolled or misdirected activation of platelets and the immune response is involved in the onset and progress of several conditions with an inflammatory component, such as coronary artery disease and autoimmune diseases.

    Hence, the aims of the present thesis were to investigate the effects and q mechanisms of C1and CRP on platelet activation, and to clarify the intracellular signaling events provoked by TLR‐2 stimulation of platelets. Platelet interaction with immune complexes is poorly understood, however by utilizing well‐characterized model surfaces with adsorbed IgG and microscopy, we show that both C1q and CRP are able to inhibit FcγR‐mediated platelet adhesion and spreading. Using isolated platelets in suspension and flow cytometry, we also found that C1q triggers a rapid, moderate and transient up‐regulation of P‐selectin that is sensitive to blockade of gC1qR and protein kinase C (PKC), but not blockade of α2β1. Additionally, subsequent platelet activation by collagen or collagen‐related peptide (GPVI specific) is inhibited by C1q, suggesting a role for GPVI in C1q‐mediated regulation of collagen‐induced platelet activation. Whole blood studies revealed that C1q inhibits total cell aggregation, formation of platelet‐leukocyte aggregates, and potentiates the production of reactive oxygen species (ROS), all in a platelet‐dependent manner. Furthermore, using the TLR‐2/1 agonist Pam3CSK4 we found that TLR‐2/1‐activation of platelets is mediated via a P2X1‐dependent increase in intracellular free Ca2+, P2Y1 and P2Y12 –receptor ligation, and activation of cyclooxygenase. We also found that platelets express IRAK‐1, however, without being rapidly phosphorylated upon Pam3CSK4 stimulation and thus probably not involved in the early aggregation/secretion response. Furthermore, TLR‐2/6 stimulation does not lead to platelet activation but instead inhibits TLR‐2/1‐provoked activation. Taken together, these findings further strengthen the role of platelets as key players in inflammatory processes.

    List of papers
    1. C-reactive protein and C1q regulate platelet adhesion and activation on adsorbed immunoglobulin G and albumin
    Open this publication in new window or tab >>C-reactive protein and C1q regulate platelet adhesion and activation on adsorbed immunoglobulin G and albumin
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    2008 (English)In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 86, no 5, p. 466-474Article in journal (Refereed) Published
    Abstract [en]

    Blood platelets and C-reactive protein (CRP) are both used clinically as markers of ongoing inflammation, and both participate actively in inflammatory responses, although the biological effects are still incompletely understood. Rapidly adhering platelets express receptors for complement factor 1q (C1q) and the Fc part of immunoglobulin G (IgG), and CRP is known to activate/regulate complement via C1q binding, and to ligate FcγRs. In the present study, we used normal human IgG pre-adsorbed to a well-characterized methylated surface as a model solid-phase immune complex when investigating the effects of CRP and C1q on platelet adhesion and activation. Protein adsorption was characterized using ellipsometry and polyclonal antibodies, and human serum albumin (HSA) and non-coated surfaces were used as reference surfaces. Platelet adhesion to IgG and HSA was inhibited by both C1q and CRP. Furthermore, CRP (moderately) and C1q (markedly) decreased the spreading of adhering platelets. The combination of C1q and CRP was slightly more potent in reducing cell adhesion to IgG, and also impaired the adhesion to HSA and non-coated surfaces. Platelet production of thromboxane B2 (TXB2) was also reduced by C1q both in the presence and absence of CRP, whereas CRP alone had no effect on TXB2 production. We conclude that CRP and C1q regulate the behaviour of platelets, and that this may be an important immunoregulatory mechanism during inflammatory conditions. © 2008 Australasian Society for Immunology Inc. All rights reserved.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-44320 (URN)10.1038/icb.2008.9 (DOI)76311 (Local ID)76311 (Archive number)76311 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets
    Open this publication in new window or tab >>C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets
    2010 (English)In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 215, no 12, p. 987-995Article in journal (Refereed) Published
    Abstract [en]

    Blood platelets are emerging as important immunomodulatory cells, but complement interaction with platelets is not well understood. Several platelet structures have been described as complement protein 1q (C1q) binding receptors, such as C1qRp/CD93 and gC1qR. However, there are conflicting results whether these receptors are C1q binding structures, or even at all expressed on the cell surface. Recently, the collagen-binding integrin alphaIIbetaI was reported to bind C1q on mast cells, and this receptor is also present on platelets. The aim of this study was to further characterize the effects of C1q on platelets, by quantifying the platelet surface expression of P-selectin (CD62P) and monitoring the formation of platelet-neutrophil aggregates. Using flow cytometry, we found that C1q dose-dependently triggered a rapid but moderate and transient up-regulation of P-selectin already within 5s of C1q exposure. Pre-incubation with an antibody directed against gC1qR significantly inhibited (with 57% compared to control) the up-regulation, whereas an antibody towards the alphaIIbetaI-integrin showed no effect. Stimulation with C1q did not change the cytosolic calcium-levels, as measured with the fluorescent ratiometric probe Fura-2, however, a protein kinase C inhibitor (GF109203x) blocked the C1q-induced P-selectin expression. Furthermore, pre-incubation of platelets with C1q diminished both the collagen as well as the collagen-related peptide-induced up-regulation of P-selectin, most evident after 90s of stimulation. This indicates that C1q may regulate platelet activation via the GPVI receptor, which is a novel finding. Moreover, C1q antagonized the collagen-induced formation of platelet-neutrophil aggregates, indicating a reduced interaction between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1(PSGL-1/CD162). In summary, C1q induces a moderate rapid platelet P-selectin expression, modulates subsequent collagen and collagen-related peptide stimulation of platelets, and inhibits the formation of platelet-neutrophil aggregates. These immuno-regulatory effects of C1q may have a crucial role in innate immunity and inflammation.

    Keywords
    AlfaIIbetaI integrin (αIIβI, GpIa/IIa), Blood platelet, C1q, C1qR, Complement, Platelet–neutrophil aggregates, P-selectin (CD62 P)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54665 (URN)10.1016/j.imbio.2009.11.004 (DOI)000285532100007 ()20163886 (PubMedID)
    Note
    Original Publication: Caroline Skoglund, Jonas Wetterö, Pentti Tengvall and Torbjörn Bengtsson, C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets, 2010, Immunobiology, (215), 12, 987-995. http://dx.doi.org/10.1016/j.imbio.2009.11.004 Copyright: Elsevier Science B. V., Amsterdam http://www.elsevier.com/ Available from: 2010-03-30 Created: 2010-03-30 Last updated: 2017-12-12
    3. C1q regulates collagendependentproduction of reactive oxygen species, formation of plateletleukocyteaggregates and levels of soluble Pselectinin whole blood
    Open this publication in new window or tab >>C1q regulates collagendependentproduction of reactive oxygen species, formation of plateletleukocyteaggregates and levels of soluble Pselectinin whole blood
    2010 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Blood platelets are nowadays recognized as cells with immuno‐modulatory properties as they express receptors involved in immunity (e.g. complement‐, toll‐like‐ and Fcγ‐receptors) and release inflammatory mediators. Furthermore, formation of plateletleukocyte aggregates has an important role during inflammatory conditions, e.g. coronary artery disease. We have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have continued by investigating the effect of C1q on collagen‐induced aggregation and production of reactive oxygen species (ROS), formation of plateletleukocyte aggregates and levels of soluble P‐selectin in whole blood. Impedance measurements showed that C1q, at physiological concentrations, inhibited collageninduced aggregation in whole blood, whereas it potentiated the collagen‐provoked production of ROS in a luminal‐dependent chemiluminescence assay. The potentiation was dependent on platelets, as the effect was not seen when the platelet fibrinogen binding receptor GpIIb/IIIa was blocked by Reopro. Moreover, the formation of large platelet‐leukocyte aggregates in collagen‐stimulated whole blood was inhibited by C1q. This may be explained by the finding that C1q antagonized the collagen‐induced activation, revealed by lowered levels of soluble P‐selectin. In conclusion, C1q may have an important role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury and thus be involved in inflammatory disorders such as coronary artery disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54666 (URN)
    Available from: 2010-03-30 Created: 2010-03-30 Last updated: 2015-06-29
    4. Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation
    Open this publication in new window or tab >>Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation
    Show others...
    2010 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 103, no 2, p. 398-407Article in journal (Refereed) Published
    Abstract [en]

    Toll-like receptor 2 (TLR2), which recognise and respond to conserved microbial pathogen-associated molecular patterns, is expressed on the platelet surface. Furthermore, it has recently been shown that the TLR2/1 agonist Pam(3)CSK(4) stimulates platelet activation. The aim of the present study was to clarify important signalling events in Pam(3)CSK(4)-induced platelet aggregation and secretion. Platelet interaction with Pam(3)CSK(4) and the TLR2/6 agonist MALP-2 was studied by analysing aggregation, ATP-secretion, [Ca2+](i) mobilisation and thromboxane B2 (TxB(2)) production. The results show that Pam(3)CSK(4) but not MALP-2 induces [Ca2+](i) increase, TxB(2) production, dense granule secretion and platelet aggregation. Preincubation of platelets with MALP-2 inhibited the Pam(3)CSK(4)-induced responses. The ATP-secretion and aggregation in Pam(3)CSK(4)-stimulated platelets was impeded by the purinergic P2X(1) inhibitor MRS 2159, the purinergic P2Y(1) and P2Y(12) antagonists MRS 2179 and cangrelor, the phospholipase C inhibitor U73122, the calcium chelator BAPT-AM and aspirin. The calcium mobilisation was lowered by MRS 2159, aspirin and U73122 whereas the TxB(2) production was antagonised by MRS 2159, aspirin and BAPT-AM. When investigating the involvement of the myeloid differentiation factor-88 (MyD88) -dependent pathway, we found that platelets express MyD88 and interleukin 1 receptor-associated kinase (IRAK-1), which are proteins important in TLR signalling. However, Pam(3)CSK(4) did not stimulate a rapid (within 10 minutes) phosphorylation of IRAK-1 in platelets. In conclusion, the results show that Pam(3)CSK(4)-induced platelet aggregation and secretion depends on a P2X(1)-mediated Ca2+ mobilisation, production of TxA(2) and ADP receptor activation. The findings in this study further support a role for platelets in sensing bacterial components.

    Keywords
    Infection, purinergic P2X(1) receptor, atherosclerosis, MALP-2, Pam(3)CSK(4), platelet, MyD88, IRAK-1
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54249 (URN)10.1160/TH09-07-0442 (DOI)000274734100022 ()
    Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2017-12-12Bibliographically approved
  • 177.
    Skoglund, Caroline
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjorn
    University of Örebro.
    C1q regulates collagen-dependent production of reactive oxygen species, aggregation and levels of soluble P-selectin in whole blood2012In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 142, no 1-2, p. 28-33Article in journal (Refereed)
    Abstract [en]

    Blood platelets express several receptors involved in immunity (e.g. complement-, toll-like- and Fc gamma-receptors) and release inflammatory mediators. Furthermore, formation of platelet-leukocyte aggregates has an important role during inflammatory conditions such as coronary artery disease. Thus, apart from their well-known role in haemostasis, platelets are today also recognized as cells with immunomodulatory properties. less thanbrgreater than less thanbrgreater thanWe have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have proceeded by investigating effects of C1q on collagen-induced aggregation, production of reactive oxygen species (ROS), formation of platelet-leukocyte aggregates and levels of soluble P-selectin in whole blood. less thanbrgreater than less thanbrgreater thanImpedance measurements showed that C1q inhibited collagen-induced aggregation whereas it potentiated the collagen-provoked production of ROS in a luminol-dependent chemiluminescence assay. The effects of C1q on aggregation and ROS-production were dependent upon platelets, as they were no longer observed in presence of the platelet (GpIIb/IIIa) inhibitor Reopro. Furthermore, the levels of soluble P-selectin were found to be lowered upon treatment with C1q prior to addition of collagen. There was also a trend towards a decreased formation of large platelet-leukocyte aggregates in collagen-stimulated whole blood following C1q treatment. In conclusion, our data indicate that C1q could have a role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury. This has implications for inflammatory disorders such as coronary artery disease.

  • 178.
    Skoglund, Caroline
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    C1q regulates collagendependentproduction of reactive oxygen species, formation of plateletleukocyteaggregates and levels of soluble Pselectinin whole blood2010Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Blood platelets are nowadays recognized as cells with immuno‐modulatory properties as they express receptors involved in immunity (e.g. complement‐, toll‐like‐ and Fcγ‐receptors) and release inflammatory mediators. Furthermore, formation of plateletleukocyte aggregates has an important role during inflammatory conditions, e.g. coronary artery disease. We have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have continued by investigating the effect of C1q on collagen‐induced aggregation and production of reactive oxygen species (ROS), formation of plateletleukocyte aggregates and levels of soluble P‐selectin in whole blood. Impedance measurements showed that C1q, at physiological concentrations, inhibited collageninduced aggregation in whole blood, whereas it potentiated the collagen‐provoked production of ROS in a luminal‐dependent chemiluminescence assay. The potentiation was dependent on platelets, as the effect was not seen when the platelet fibrinogen binding receptor GpIIb/IIIa was blocked by Reopro. Moreover, the formation of large platelet‐leukocyte aggregates in collagen‐stimulated whole blood was inhibited by C1q. This may be explained by the finding that C1q antagonized the collagen‐induced activation, revealed by lowered levels of soluble P‐selectin. In conclusion, C1q may have an important role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury and thus be involved in inflammatory disorders such as coronary artery disease.

  • 179.
    Skoglund, Caroline
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Pharmacology.
    Wetterö, Jonas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Sjöwall, Christopher
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Tengvall, Pentti
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    C-reactive protein and C1q regulate platelet adhesion and activation on adsorbed immunoglobulin G and albumin2008In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 86, no 5, p. 466-474Article in journal (Refereed)
    Abstract [en]

    Blood platelets and C-reactive protein (CRP) are both used clinically as markers of ongoing inflammation, and both participate actively in inflammatory responses, although the biological effects are still incompletely understood. Rapidly adhering platelets express receptors for complement factor 1q (C1q) and the Fc part of immunoglobulin G (IgG), and CRP is known to activate/regulate complement via C1q binding, and to ligate FcγRs. In the present study, we used normal human IgG pre-adsorbed to a well-characterized methylated surface as a model solid-phase immune complex when investigating the effects of CRP and C1q on platelet adhesion and activation. Protein adsorption was characterized using ellipsometry and polyclonal antibodies, and human serum albumin (HSA) and non-coated surfaces were used as reference surfaces. Platelet adhesion to IgG and HSA was inhibited by both C1q and CRP. Furthermore, CRP (moderately) and C1q (markedly) decreased the spreading of adhering platelets. The combination of C1q and CRP was slightly more potent in reducing cell adhesion to IgG, and also impaired the adhesion to HSA and non-coated surfaces. Platelet production of thromboxane B2 (TXB2) was also reduced by C1q both in the presence and absence of CRP, whereas CRP alone had no effect on TXB2 production. We conclude that CRP and C1q regulate the behaviour of platelets, and that this may be an important immunoregulatory mechanism during inflammatory conditions. © 2008 Australasian Society for Immunology Inc. All rights reserved.

  • 180.
    Skoglund, Caroline
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets2010In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 215, no 12, p. 987-995Article in journal (Refereed)
    Abstract [en]

    Blood platelets are emerging as important immunomodulatory cells, but complement interaction with platelets is not well understood. Several platelet structures have been described as complement protein 1q (C1q) binding receptors, such as C1qRp/CD93 and gC1qR. However, there are conflicting results whether these receptors are C1q binding structures, or even at all expressed on the cell surface. Recently, the collagen-binding integrin alphaIIbetaI was reported to bind C1q on mast cells, and this receptor is also present on platelets. The aim of this study was to further characterize the effects of C1q on platelets, by quantifying the platelet surface expression of P-selectin (CD62P) and monitoring the formation of platelet-neutrophil aggregates. Using flow cytometry, we found that C1q dose-dependently triggered a rapid but moderate and transient up-regulation of P-selectin already within 5s of C1q exposure. Pre-incubation with an antibody directed against gC1qR significantly inhibited (with 57% compared to control) the up-regulation, whereas an antibody towards the alphaIIbetaI-integrin showed no effect. Stimulation with C1q did not change the cytosolic calcium-levels, as measured with the fluorescent ratiometric probe Fura-2, however, a protein kinase C inhibitor (GF109203x) blocked the C1q-induced P-selectin expression. Furthermore, pre-incubation of platelets with C1q diminished both the collagen as well as the collagen-related peptide-induced up-regulation of P-selectin, most evident after 90s of stimulation. This indicates that C1q may regulate platelet activation via the GPVI receptor, which is a novel finding. Moreover, C1q antagonized the collagen-induced formation of platelet-neutrophil aggregates, indicating a reduced interaction between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1(PSGL-1/CD162). In summary, C1q induces a moderate rapid platelet P-selectin expression, modulates subsequent collagen and collagen-related peptide stimulation of platelets, and inhibits the formation of platelet-neutrophil aggregates. These immuno-regulatory effects of C1q may have a crucial role in innate immunity and inflammation.

  • 181.
    Solem, K
    et al.
    Gambro Lundia AB.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Olde, B
    Gambro Lundia AB.
    A VENOUS NEEDLE DISLODGEMENT METHODOLOGY BASED ON DETECTION OF HEART PULSES IN THE EXTRACORPOREAL CIRCUIT in INTERNATIONAL JOURNAL OF ARTIFICIAL ORGANS, vol 34, issue 8, pp 613-6132011In: INTERNATIONAL JOURNAL OF ARTIFICIAL ORGANS, Wichtig Editore , 2011, Vol. 34, no 8, p. 613-613Conference paper (Refereed)
    Abstract [en]

    n/a

  • 182.
    Solem, K
    et al.
    Gambro Lundia AB.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Olde, B
    Gambro Lundia AB.
    BIOMEDICAL ENGINEERING APPROACH FOR MECHANICAL CIRCULATORY ASSIST USING NOVEL SHAPE MEMORY ALLOY FIBRES in INTERNATIONAL JOURNAL OF ARTIFICIAL ORGANS, vol 34, issue 8, pp 613-6142011In: INTERNATIONAL JOURNAL OF ARTIFICIAL ORGANS, Wichtig Editore , 2011, Vol. 34, no 8, p. 613-614Conference paper (Refereed)
    Abstract [en]

    n/a

  • 183.
    Stroikin, Yuri
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Brunk, Ulf T.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Testing the “garbage” accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy2005In: Biogerontology, ISSN 1389-5729, Vol. 6, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    Imperfect autophagic degradation of oxidatively damaged macromolecules and organelles (so-called biological garbage) is considered an important contributor to ageing and consequent death of postmitotic (non-dividing) cells, such as neurons and cardiac myocytes. In contrast, proliferating cells apparently escape senescence by a continuous dilution and repair of damaged structures during division. Postmitotic ageing can be mimicked and studied in cultures of potentially dividing cells if their mitotic activity is inhibited. To test the garbage accumulation theory of ageing, we compared survival of density-dependent growth-arrested (confluent) and proliferating human fibroblasts and astrocytes following inhibition of autophagic sequestration with 3-methyladenine (3MA). Exposure of confluent fibroblast cultures to 3MA for two weeks resulted in a significantly increased proportion of dying cells compared to both untreated confluent cultures and dividing cells with 3MA-inhibited autophagy. Similar results were obtained when autophagic degradation was suppressed by the protease inhibitor leupeptin. In 3MA- or leupeptin-exposed cultures, dying cells were overloaded with undegraded autofluorescent material. The results support a key role of biological lysosomal garbage accumulation in the triggering of ageing and death of postmitotic cells, as well as the anti-ageing role of cell division.

  • 184.
    Sundelin, Staffan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology . Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Nilsson, SEG
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lipofuscin accumulation in cultured retinal pigment epithelial cells is dependent on the melanin content2000In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 41, no 4, p. 4472B419-Conference paper (Other academic)
  • 185.
    Svensson, Ann-Charlotte B.
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet-induced 5-LOX activity is associated with ROS-dependent ASMC proliferation2007Conference paper (Refereed)
  • 186.
    Svensson, Ann-Charlotte B.
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet fragments, like platelets, induce airway smooth muscle cell proliferation through mechanisms dependent on ros and 5-lox2007Conference paper (Refereed)
  • 187.
    Svensson Holm, Ann-Charlotte B.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelets and airway remodeling: Mechanisms involved in platelet-induced fibroblast and airway smooth muscle cell proliferation in vitro2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Airway remodeling is a contributing cause to the pathological structural changes, such as increased cell proliferation, observed in asthma. Platelets have been found in autopsy lungmaterial obtained from asthmatic patients and are well known to induce proliferation in vitro of a variety of cells. However, the role of platelets in airway remodeling is far from understood. This thesis aims to clarify the involvement of platelets in fibroblast and airway smooth muscle cell (ASMC) proliferation in vitro and to elucidate the importance of HA, FAK, eicosanoid and ROS dependent signaling. The results demonstrate that platelets induce ASMC proliferation through NADPH-oxidase and 5-LOX dependent mechanisms. In addition, platelets also induce a 5-LOX dependent fibroblast proliferation. Furthermore, morphological analysis demonstrates that platelets bind to the extracellular matrix component HA through its receptor CD44 and thereby induce a FAK dependent ASMC proliferation. Taken together, the results obtained in this thesis suggest that platelet/HA interaction mediated through CD44 is of importance for platelets ability to induce cell proliferation. Moreover, the results propose that platelet-induced fibroblast proliferation is 5-LOX dependent and that platelets induce a HA, CD44, FAK, 5-LOX, and ROSdependent ASMC proliferation. This action of platelets represents a potential important and novel mechanism that may have an impact on the remodeling process and in the development of new pharmacological strategies in the treatment of inflammatory respiratory disease such as asthma.

    List of papers
    1. Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase
    Open this publication in new window or tab >>Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase
    Show others...
    2006 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 96, no 5, p. 652-659Article in journal (Refereed) Published
    Abstract [en]

    Proliferation of fibroblasts is vital for adequate wound healing but is probably also involved in different hyperproliferative disorders such as atherosclerosis and cancer. The regeneration of tissue usually starts with coagulation, involving release of mitogenic and inflammatory factors from activated platelets. This study focuses on the role of eicosanoids in the proliferative effects of platelets on human fibroblasts. We show that the phospholipase A2 inhibitor 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), the combined cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) and the LOX inhibitor 5,8,11-eicosatriynoic acid (ETI) block the platelet-induced proliferation of serum starved subconfluent human fibroblasts. Anti-proliferative effects were also obtained by specific inhibition of 5-LOX with 5,6-dehydro arachidonic acid (5,6-dAA), whereas the 12-LOX inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) did not affect the platelet-stimulated growth of fibroblasts. The expression of 5-LOX was analyzed by reverse-transcriptase-mediated PCR (RT-PCR), Western blotting and HPLC. 5-LOX message and protein was detected in fibroblasts but not in platelets. Incubation with platelets markedly increased, already after one hour, the expression of 5-LOX in the fibroblast culture. The increased 5-LOX activity was associated with an elevated level of the 5-LOX metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) reaching its maximum after 1-2 hours of co-incubation of fibroblasts and platelets. The 5-HETE production was reduced by the inhibitors DMDA, ETYA and ETI. In conclusion, this study suggests that platelet-stimulated proliferation of fibroblasts is mediated by an increased 5-LOX activity, which supports recent findings indicating a crucial role for this enzyme in proliferative disorders such as atherosclerosis. © 2006 Schattauer GmbH, Stuttgart.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-36111 (URN)10.1160/TH06-02-0069 (DOI)000242168400016 ()29986 (Local ID)29986 (Archive number)29986 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    2. Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species
    Open this publication in new window or tab >>Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species
    2008 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 19, no 7, p. 528-536Article in journal (Refereed) Published
    Abstract [en]

    Continuous recruitment and inappropriate activity of platelets in the airways may contribute to airway remodeling, a characteristic feature of inflammatory airway diseases that includes increased proliferation of the smooth muscle.

    The aim of the present investigation was to examine the effect of platelets on proliferation of airway smooth muscle cells (ASMC) in culture and to determine the possible role of 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) in this context.

    ASMC obtained from guinea pigs were cultured and co-incubated with washed platelets for 24 hours. Thereafter, the proliferation was measured with the MTS-assay, the results were also verified by using thymidine incorporation, DNA measurements and manual counting. The interaction between platelets and ASMC was visualised with fluorescence microscopy.

    We found that platelets bind to the ASMC and the presence of platelets caused a significant dose-dependent increase in ASMC proliferation. Co-incubation of ASMC with platelets also increased ROS-production, detected by the fluorescent probe DCFDA. Furthermore, the platelet-induced proliferation was reduced in the presence of the NADPH-oxidase inhibitors DPI and apocynin.

    A possible role of 5-LOX in platelet-induced proliferation and ROS-generation was evaluated by using the 5-LOX inhibitor AA-861 and the PLA2-inhibitor ATK. The results showed that inhibition of these enzymes significantly reduced the platelet-induced proliferation. Moreover, Western blot analysis revealed that the ASMC but not the platelets express 5-LOX.

    In addition, our experiments revealed that the presence of AA-861 and ATK significantly inhibited the ROS-production generated upon coincubation of platelets and ASMC.

    In conclusion, we show that platelets have a marked capacity to induce ASMC proliferation. Furthermore, our study indicates that the interaction between platelets and ASMC leads to activation of 5-LOX in the ASMC followed by an increased ROS-production, events resulting in enhanced ASMC proliferation. The new findings are of importance in understanding possible mechanisms contributing to airway remodeling.

    Keywords
    platelet-induced proliferation, airway smooth muscle, 5-lipoxygenase, reactive oxygen species, airway remodeling
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-15607 (URN)10.1080/09537100802320300 (DOI)
    Note
    Original publication: Ann-Charlotte B. Svensson Holm, Torbjörn Bengtsson, Magnus Grenegård and Eva G. Lindström, Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species, 2008, Platelets, (19), 7, 528-536.http://dx.doi.org/10.1080/09537100802320300. Copyright © Taylor & Francis Group, an informa businessAvailable from: 2008-11-20 Created: 2008-11-20 Last updated: 2017-12-14Bibliographically approved
    3. Platelet membranes induce airway smooth muscle cellproliferation
    Open this publication in new window or tab >>Platelet membranes induce airway smooth muscle cellproliferation
    2011 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 1, p. 45-55Article in journal (Refereed) Published
    Abstract [en]

    The role of platelets in airway disease is poorly understood although they have been suggested to influence on proliferation of airway smooth muscle cells (ASMC). Platelets have been found localised in the airways in autopsy material from asthmatic patients and have been implicated in airway remodeling. The aim of the present study was to investigate the effects of various platelet fractions on proliferation of ASMC obtained from guinea pigs (GP-ASMC) and humans (H-ASMC). Proliferation of ASMC was measured by the MTS-assay and the results were confirmed by measurements of the DNA content. A key observation was that the platelet membrane preparations induced a significant increase in the proliferation of both GPASMC (129.9 ± 3.0 %) and H-ASMC (144.8 ± 12.2). However, neither supernatants obtained from lysed nor filtrate from thrombin stimulated platelets did induce ASMC proliferation to the same extent as the membrane preparation. We have previously shown the platelet-induced proliferation is dependent on the 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) pathways. In the present work we established that platelet membrane-induced ASMC proliferation was reduced in the presence of the NADPH oxidase inhibitor DPI and the 5-LOX inhibitor AA-861. In conclusion, our results showed that platelet  membranes significantly induced ASMC proliferation, demonstrating that the mitogenic effect of platelets and platelet membranes on ASMC is mainly due to membrane-associated factors. The effects of platelet membranes were evident on both GP-ASMC and H-ASMC and involved 5-LOX and ROS. These new findings are of importance in understanding the mechanisms contributing to airway remodeling and may contribute to the development of new pharmacological tools in the treatment of inflammatory airway diseases.

    Place, publisher, year, edition, pages
    Informa, 2011
    Keywords
    platelets; platelet membranes; airway smooth muscle cell; 5-lipoxygenase; reactive oxygen species; airway remodeling
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-61615 (URN)10.3109/09537104.2010.515696 (DOI)000286937800006 ()
    Note
    Original Publication: Ann-Charlotte B. Svensson Holm, Torbjörn Bengtsson, Magnus Grenegård and Eva G. Lindström, Platelet membranes induce airway smooth muscle cellproliferation, 2011, Platelets, (22), 1, 45-55. http://dx.doi.org/10.3109/09537104.2010.515696 Copyright: Informa Healthcare http://informahealthcare.com/ Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2017-12-12
    4. Platelets bind to hyaluronic acid through CD44 and induce a focal adhesion kinase dependent airway smooth muscle cell proliferation
    Open this publication in new window or tab >>Platelets bind to hyaluronic acid through CD44 and induce a focal adhesion kinase dependent airway smooth muscle cell proliferation
    2008 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Platelets have been implicated as important players in the remodeling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of the extracellular matrix component hyaluronic acid (HA), the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. The ability of ASMC to synthesize HA was investigated by fluorescent staining using biotinylated HA-binding protein and streptavidin conjugate. In addition, the interaction between ASMC and platelets was studied by fluorescent staining of the F-actin. We found that ASMC produced HA and that a CD44 blocking antibody and the hyaluronic acid synthase inhibitor 4-Methylumbelliferone (4-MU) inhibited platelet binding to the area surrounding the ASMC. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and 4-MU inhibited platelet-induced ASMC proliferation. We also found that co-culture of ASMC and platelets resulted in increased phosphorylation of FAK as detected by Western blot analysis. Furthermore, the FAKinhibitor PF 573228 inhibited platelet-induced ASMC proliferation. In conclusion, our findings demonstrate that HA, CD44 and FAK contribute to the increased ASMC proliferation caused by platelets. This event is initiated by an interaction between platelets CD44 and HA produced by the ASMC. These new findings may be important in understanding the interplay between ECM, platelets and ASMC in the remodeling process. In conclusion, our results demonstrate that FAK is phosphorylated and on that account activated during the CD44-dependent platelet/ASMC interaction and this contributes to proliferation of the ASMC. These new findings may be important in understanding the interplay between ECM, platelets and ASMC in the remodeling process.

    Keywords
    airway smooth muscle; airway remodeling, hyaluronic acid, CD44, focal adhesion kinase
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-61622 (URN)
    Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2010-11-17Bibliographically approved
  • 188.
    Svensson Holm, Ann-Charlotte B.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Department of Biomedicine, School of Health and Medical Sciences, Örebro University, Sweden.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lindström, Eva G.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species2008In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 19, no 7, p. 528-536Article in journal (Refereed)
    Abstract [en]

    Continuous recruitment and inappropriate activity of platelets in the airways may contribute to airway remodeling, a characteristic feature of inflammatory airway diseases that includes increased proliferation of the smooth muscle.

    The aim of the present investigation was to examine the effect of platelets on proliferation of airway smooth muscle cells (ASMC) in culture and to determine the possible role of 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) in this context.

    ASMC obtained from guinea pigs were cultured and co-incubated with washed platelets for 24 hours. Thereafter, the proliferation was measured with the MTS-assay, the results were also verified by using thymidine incorporation, DNA measurements and manual counting. The interaction between platelets and ASMC was visualised with fluorescence microscopy.

    We found that platelets bind to the ASMC and the presence of platelets caused a significant dose-dependent increase in ASMC proliferation. Co-incubation of ASMC with platelets also increased ROS-production, detected by the fluorescent probe DCFDA. Furthermore, the platelet-induced proliferation was reduced in the presence of the NADPH-oxidase inhibitors DPI and apocynin.

    A possible role of 5-LOX in platelet-induced proliferation and ROS-generation was evaluated by using the 5-LOX inhibitor AA-861 and the PLA2-inhibitor ATK. The results showed that inhibition of these enzymes significantly reduced the platelet-induced proliferation. Moreover, Western blot analysis revealed that the ASMC but not the platelets express 5-LOX.

    In addition, our experiments revealed that the presence of AA-861 and ATK significantly inhibited the ROS-production generated upon coincubation of platelets and ASMC.

    In conclusion, we show that platelets have a marked capacity to induce ASMC proliferation. Furthermore, our study indicates that the interaction between platelets and ASMC leads to activation of 5-LOX in the ASMC followed by an increased ROS-production, events resulting in enhanced ASMC proliferation. The new findings are of importance in understanding possible mechanisms contributing to airway remodeling.

  • 189.
    Svensson Holm, Ann-Charlotte B.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Department of Biomedicine, School of Health and Medical Sciences, Örebro University, Sweden.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva G.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet membranes induce airway smooth muscle cellproliferation2011In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 1, p. 45-55Article in journal (Refereed)
    Abstract [en]

    The role of platelets in airway disease is poorly understood although they have been suggested to influence on proliferation of airway smooth muscle cells (ASMC). Platelets have been found localised in the airways in autopsy material from asthmatic patients and have been implicated in airway remodeling. The aim of the present study was to investigate the effects of various platelet fractions on proliferation of ASMC obtained from guinea pigs (GP-ASMC) and humans (H-ASMC). Proliferation of ASMC was measured by the MTS-assay and the results were confirmed by measurements of the DNA content. A key observation was that the platelet membrane preparations induced a significant increase in the proliferation of both GPASMC (129.9 ± 3.0 %) and H-ASMC (144.8 ± 12.2). However, neither supernatants obtained from lysed nor filtrate from thrombin stimulated platelets did induce ASMC proliferation to the same extent as the membrane preparation. We have previously shown the platelet-induced proliferation is dependent on the 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) pathways. In the present work we established that platelet membrane-induced ASMC proliferation was reduced in the presence of the NADPH oxidase inhibitor DPI and the 5-LOX inhibitor AA-861. In conclusion, our results showed that platelet  membranes significantly induced ASMC proliferation, demonstrating that the mitogenic effect of platelets and platelet membranes on ASMC is mainly due to membrane-associated factors. The effects of platelet membranes were evident on both GP-ASMC and H-ASMC and involved 5-LOX and ROS. These new findings are of importance in understanding the mechanisms contributing to airway remodeling and may contribute to the development of new pharmacological tools in the treatment of inflammatory airway diseases.

  • 190.
    Svensson Holm, Ann-Charlotte B.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Department of Biomedicine, School of Health and Medical Sciences, Örebro University, Sweden.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lindström, Eva G.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Platelets bind to hyaluronic acid through CD44 and induce a focal adhesion kinase dependent airway smooth muscle cell proliferation2008Manuscript (preprint) (Other academic)
    Abstract [en]

    Platelets have been implicated as important players in the remodeling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of the extracellular matrix component hyaluronic acid (HA), the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. The ability of ASMC to synthesize HA was investigated by fluorescent staining using biotinylated HA-binding protein and streptavidin conjugate. In addition, the interaction between ASMC and platelets was studied by fluorescent staining of the F-actin. We found that ASMC produced HA and that a CD44 blocking antibody and the hyaluronic acid synthase inhibitor 4-Methylumbelliferone (4-MU) inhibited platelet binding to the area surrounding the ASMC. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and 4-MU inhibited platelet-induced ASMC proliferation. We also found that co-culture of ASMC and platelets resulted in increased phosphorylation of FAK as detected by Western blot analysis. Furthermore, the FAKinhibitor PF 573228 inhibited platelet-induced ASMC proliferation. In conclusion, our findings demonstrate that HA, CD44 and FAK contribute to the increased ASMC proliferation caused by platelets. This event is initiated by an interaction between platelets CD44 and HA produced by the ASMC. These new findings may be important in understanding the interplay between ECM, platelets and ASMC in the remodeling process. In conclusion, our results demonstrate that FAK is phosphorylated and on that account activated during the CD44-dependent platelet/ASMC interaction and this contributes to proliferation of the ASMC. These new findings may be important in understanding the interplay between ECM, platelets and ASMC in the remodeling process.

  • 191.
    Svensson Holm, Ann-Charlotte
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The role of reactive oxygen species and 5-lipoxygenase in platelet-induced airway smooth muscle cell proliferation2006Conference paper (Refereed)
  • 192.
    Svensson Holm, Ann-Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Örebro University.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva G
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation2012In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 318, no 5, p. 632-640Article in journal (Refereed)
    Abstract [en]

    Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodelling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation. The interaction between ASMC and platelets was studied by fluorescent staining of F-actin. In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

  • 193.
    Svensson Holm, Ann-Charlotte
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Berg, Cecilia
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Herbertsson, Helena
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Söderström, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    5-Lipoxygenase activity is involved in platelet-induced fibroblast proliferation2006Conference paper (Refereed)
  • 194.
    Svensson Holm, Ann-Charlotte
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Berg, Cecilia
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Herbertsson, Helena
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Söderström, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    5-Lipoxygenase activity is involved in platelet-induced fibroblast proliferation2006Conference paper (Refereed)
  • 195.
    Szabó, Zoltan
    et al.
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Intraoperative muscle and fat metabolism in diabetic patients during coronary artery bypass grafting surgery: a parallel microdialysis and organ balance study2009In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 103, no 2, p. 166-172Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Surgical trauma causes stress and inflammatory reactions with elevated serum free fatty acids (FFA) and glucose levels characteristic of intraoperative insulin resistance. Our aim was to compare microdialysis findings with those using the classical organ balance technique and to test the clinical feasibility of microdialysis during cardiac surgery. METHODS: Nine diabetic and nine non-diabetic patients, undergoing routine coronary artery bypass grafting surgery, were studied using both microdialysis and the organ balance technique in the brachio-radial muscle of the forearm, and microdialysis in the pre-pectoral fat tissue. Glucose, lactate, and glycerol were measured in arterial and venous plasma and in the microdialysate before administration of heparin, at the release of the aortic cross-clamp, and before transfer to the intensive care unit. RESULTS: Glucose release from the diabetic muscle at the last sampling time was detected. This was confirmed by a negative glucose A-I (arterial-interstitial difference) in the muscle. No differences were observed regarding lipolysis in the fat tissue in terms of A-I of glycerol. Intergroup differences were detected at the first sampling time, where arterial plasma glucose and plasma insulin levels were higher and muscle interstitial glucose lower in the diabetic patients. Plasma insulin was higher in the diabetic patients even at the final measurement time. CONCLUSIONS: In terms of lipolysis in the fat tissue and glucose transport in the muscle, the non-diabetic patients were metabolically 'diabetics' during surgery. Despite strict blood glucose control, disturbances in glucose homeostasis in the diabetic muscle persist. Microdialysis was easy to use during cardiac surgery.

  • 196.
    Szabó, Zoltán
    et al.
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Katkits, Kristofer
    Östergötlands Läns Landsting.
    Gabro, George
    Östergötlands Läns Landsting.
    Andersson, Rolf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    The Contractility of Isolated Rat Atrial Tissue during Hypoxia is Better Preserved in a High- or Zero-glucose Environment than in a Normal Glucose Environment2009In: International Journal of Biomedical Sciences, ISSN 1306-1216, Vol. 5, no 1, p. 12-16Article in journal (Refereed)
    Abstract [en]

    Aim: Hyperglycemia is known to be associated with an increase in mortality in myocardial infarction and intensive care patients despite the fact that glucose metabolism plays a central role in myocardial protection. We studied the effect of different glucose levels (22 Mm L-1; 5.5 mM L-1; and 0 mM L-1) on the contractile reserve of isolated rat atrial myocardium during and after hypoxia.Methods: We observed the contraction ofisolated rat atrium strips caused by electrical-field stimulation in a modified Krebs-Henseleit Buffer (KHB) organ bath oxygenated with 95% O2 + 5% CO2 at 37°C. We applied two periods of hypoxia and two periods of reoxygenation. Three glucose concentrations were used in the buffer to study the effect of glucose (high- n=6; normal- n=7; and zero-glucose n=6). The effect of isoproterenol 1 µM L-1 was tested during the second ischemic period.Results: The main finding was that both a zero-glucose (27.8 ± 5.9 vs. 14.7 ± 3 % of baseline tension) and a high-glucose environment (38.5 ± 14 vs. 14.7 ± 3 % of baseline tension) had a positive effect in terms of better contractility than the normal-glucose buffer during both the first (p=0.00062) and the second ischemic period (31.2 ± 5.9 % zero-glucose vs 14.7 ± 4.2 normal-glucose vs. 35.3 ± 15.9% high-glucose p=0.0038).Conclusion: Both zero-glucose and high-glucose environments resulted in a better contractile reserve in isolated rat atrial myocardium during hypoxia than in a normal one. The exact clinical relevance of this observation is, at present, unclear.

  • 197.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Aging as a catabolic malfunction2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, no 12, p. 2365-2375Article, review/survey (Refereed)
    Abstract [en]

    Cellular degradative processes, which include lysosomal (autophagic) and proteasomal degradation, as well as catabolism of proteins by cytosolic and mitochondrial proteases, provide for a continuous turnover of cellular components, such as damaged or obsolete biomolecules and organelles. Inherent insufficiency of these degradative processes results in progressive accumulation within long-lived postmitotic cells of biological 'garbage' (waste material), such as various oxidized proteins, functionally effete mitochondria, and lipofuscin (age pigment), an intralysosomal, polymeric, undegradable material. There is increasing evidence that lipofuscin hampers lysosomal degradative capacity, thus promoting the aggravation of accumulated damage at old age. Being rich in redox-active iron, lipofuscin granules also may exacerbate oxidative stress levels in senescent cells. Thus, increasing the efficiency of cellular degradative pathways and preventing involvement of iron in oxidant-induced lysosomal and cellular damage may be potential strategies for anti-aging interventions. © 2004 Elsevier Ltd. All rights reserved.

  • 198.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lipofuscin2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, no 8, p. 1400-1404Article, review/survey (Refereed)
    Abstract [en]

    Over time, postmitotic cells accumulate a non-degradable intralysosomal substance, lipofuscin, which forms due to iron-catalyzed oxidation/ polymerization of protein and lipid residues. Lipofuscin is often considered a hallmark of aging, showing an accumulation rate that inversely correlates with longevity. There is an emerging impression that lipofuscin, although still typically considered a harmless wear-and-tear product, may have multiple negative effects. By interfering with the important autophagic process, by which most worn out cellular components are degraded, it may prevent cellular renewal and advance the accumulation of damaged cellular constituents. Due to binding of transition metals, such as iron and copper, lipofuscin also seems to sensitize lysosomes and cells to oxidative stress. Of importance for the pathogenesis of age-related macular degeneration, lipofuscin deposition interferes with the phagocytic activity of retinal pigment epithelial cells and also sensitizes their lysosomes to blue light. © 2003 Published by Elsevier Ltd.

  • 199.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Myocyte aging and mitochondrial turnover2004In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 39, no 5, p. 701-705Article, review/survey (Refereed)
    Abstract [en]

    Cardiac myocytes, skeletal muscle fibers, and other long-lived postmitotic cells show dramatic age-related alterations that mainly affect mitochondria and the lysosomal compartment. Mitochondria are primary sites of reactive oxygen species formation that causes progressive damage to mitochondrial DNA and proteins in parallel to intralysosomal lipofuscin accumulation. There is amassing evidence that several various mechanisms may contribute to age-related accumulation of damaged mitochondria following initial oxidative injury. Such mechanisms may include clonal expansion of defective mitochondria, decreased propensity of altered mitochondria to become autophagocytosed (due to mitochondrial enlargement or decreased membrane damage associated with weakened respiration), suppressed autophagy because of heavy lipofuscin loading of lysosomes, and decreased efficiency of Lon protease. © 2004 Elsevier Inc. All rights reserved.

  • 200.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. 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 .
    Autophagy, organelles and ageing2007In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 211, no 2, p. 134-143Article, review/survey (Refereed)
    Abstract [en]

    As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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