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Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
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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.

Place, publisher, year, edition, pages
2006. Vol. 96, no 5, 652-659 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-36111DOI: 10.1160/TH06-02-0069ISI: 000242168400016Local ID: 29986OAI: oai:DiVA.org:liu-36111DiVA: diva2:256959
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
In thesis
1. Platelets and airway remodeling: Mechanisms involved in platelet-induced fibroblast and airway smooth muscle cell proliferation in vitro
Open this publication in new window or tab >>Platelets and airway remodeling: Mechanisms involved in platelet-induced fibroblast and airway smooth muscle cell proliferation in vitro
2010 (English)Doctoral 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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1203
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61623 (URN)978-91-7393-324-7 (ISBN)
Public defence
2010-12-03, Berzeliussalen, Universitetssjukhuset, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2012-01-30Bibliographically approved
2. 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, CeciliaHammarström, SvenHerbertsson, HelenaLindström, EvaSvensson, Ann-CharlotteSöderström, MatsTengvall, PenttiBengtsson, Torbjörn

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Berg, CeciliaHammarström, SvenHerbertsson, HelenaLindström, EvaSvensson, Ann-CharlotteSöderström, MatsTengvall, PenttiBengtsson, Torbjörn
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