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Mechanisms of platelet-mediated fibroblast proliferation
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-26679Local ID: 11246ISBN: 91-7373-515-9 (print)OAI: oai:DiVA.org:liu-26679DiVA: diva2:247228
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
List of papers
1. Platelets induce reactive oxygen species-dependent growth of human skin fibroblasts
Open this publication in new window or tab >>Platelets induce reactive oxygen species-dependent growth of human skin fibroblasts
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26383 (URN)10.1078/0171-9335-00344 (DOI)000187637800004 ()10917 (Local ID)10917 (Archive number)10917 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13
2. 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, 652-659 p.Article 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

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