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Platelets bind to hyaluronic acid through CD44 and induce a focal adhesion kinase dependent airway smooth muscle cell proliferation
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Department of Biomedicine, School of Health and Medical Sciences, Örebro University, Sweden.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
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.

Place, publisher, year, edition, pages
2008. Vol. 19, no 7, 528-536 p.
Keyword [en]
airway smooth muscle; airway remodeling, hyaluronic acid, CD44, focal adhesion kinase
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-61622OAI: oai:DiVA.org:liu-61622DiVA: diva2:370613
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2010-11-17Bibliographically approved
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

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Svensson Holm, Ann-Charlotte B.Grenegård, MagnusLindström, Eva G.

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