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Platelets induce reactive oxygen species-dependent growth of human skin fibroblasts
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
2003 (English)In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 82, no 11, 565-571 p.Article in journal (Refereed) Published
Abstract [en]

A growing amount of evidence suggests that reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, regulate intracellular signalling and have a role in cell proliferation. In the present study, we show that platelets increase the mitogenic rate in human fibroblasts and that this effect was inhibited by the intracellular antioxidant N-acetyl-L-cysteine (NAC) and the NADPH-oxidase inhibitor diphenyleneiodonium chloride (DPI). The mitogenic effects of platelets were mimicked by the platelet factors platelet-derived growth factor BB-isoform (PDGF-BB), transforming growth factor β1 (TGF-β1) and sphingosine-1-phosphate (S1P). The sphingosine kinase inhibitor DL-threo-dihydrosphingosine (DL-dihydro) abrogated the platelet-induced growth, while antibodies directed against PDGF or TGF-β had modest effects. Exposure of fibroblasts to platelets, PDGF-BB, TGF-β1 or S1P caused an extensive intracellular ROS production, measured as changes in dichlorofluorescein fluorescence. This ROS production was totally inhibited by NAC, pyrrolidinethiocarbamate (PDTC), DPI and apocynin. In conclusion, the results presented are indicative of a crucial role of ROS in the platelet-mediated regulation of fibroblast proliferation.

Place, publisher, year, edition, pages
2003. Vol. 82, no 11, 565-571 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26383DOI: 10.1078/0171-9335-00344ISI: 000187637800004Local ID: 10917OAI: oai:DiVA.org:liu-26383DiVA: diva2:246932
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13
In thesis
1. Mechanisms of platelet-mediated fibroblast proliferation
Open this publication in new window or tab >>Mechanisms of platelet-mediated fibroblast proliferation
2003 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Wound healing is a multicomponent event that involves a network of molecular and cellular crosstalk between cells, including leukocytes, platelets and fibroblasts. Despite increased knowledge over the past decades regarding the regulation of cell and tissue growth, the inter- and intracellular systems that control wound healing are incompletely understood. The platelet is a rich source of growth factors essential to natural tissue repair. In the present thesis, the role of platelets and platelet-derived factors on fibroblast proliferation was evaluated, and related to the generation of reactive oxygen species (ROS) and eicosanoids.

We found that whole platelets, platelet-derived growth factor (PDGF), transforming growth factor-ß (TGF-ß) and sphingosine-1-phosphate (S1P) induce fibroblast proliferation. Exposure of fibroblasts to these stimuli caused an extensive intracellular production of ROS, measured as increase in dichlorofluorescein fluorescence. Both fibroblast growth and the associated ROS production were inhibited by intracellular antioxidants (N-acetyl-L-cysteine (NAC) and pyrrolidinethiocarbamate (PDTC)) and NADPH-oxidase inhibitors (diphenyleneiodonium chloride (DPI) and apocynin). Moreover, platelet-mediated fibroblast proliferation was abrogated in the presence of the sphingosine kinase inhibitor DL-threo-dihydrosphingosine, but only slightly affected by antibodies directed against PDGF and TGF-ß.

The production of the arachidonic acid metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) in fibroblasts, analysed by HPLC, was markedly elevated in the presence of platelets. Furthermore, inhibition of phospholipase A2, by 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), or 5-lipoxygenase, by 5,8,11-eicosatriynoic acid (ETI) or 5,6-dehydro arachidonic acid (5,6-dAA), decreased the platelet-induced fibroblast proliferation and formation of 5-HETE. This indicate a role for transcellular metabolism of arachidonic acid during platelet-fibroblast interaction.

We conclude that the production of ROS and 5-HETE is crucial in the plateletmediated stimulation of fibroblast growth. These findings may represent new targets in the future therapy for a successful wound healing.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 48 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 63
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26679 (URN)11246 (Local ID)91-7373-515-9 (ISBN)11246 (Archive number)11246 (OAI)
Presentation
2003-11-28, Elsa Brändströmsalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-09-12

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Berg, CeciliaTrofast, CatarinaBengtsson, Torbjörn

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