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Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species
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)In: Platelets, ISSN 0953-7104, Vol. 19, no 7, 528-536 p.Article 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.

Place, publisher, year, edition, pages
2008. Vol. 19, no 7, 528-536 p.
Keyword [en]
platelet-induced proliferation, airway smooth muscle, 5-lipoxygenase, reactive oxygen species, airway remodeling
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-15607DOI: 10.1080/09537100802320300OAI: oai:DiVA.org:liu-15607DiVA: diva2:126752
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: 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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