Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Pitchford, Simon

doi:10.1038/sj.bjp.0707364

Cited by 64 publications

(59 citation statements)

References 212 publications

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“…The interest in platelets as important players in inflammatory airway diseases has increased during recent years [2,3]. Platelets may play a vital role in asthma through their possible impact on airway remodeling [12] where increased growth of ASMC is a main feature.…”

Section: Discussionmentioning

confidence: 99%

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Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

et al. 2008

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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.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 busines

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Section: Discussionmentioning

confidence: 99%

“…Several cell types and inflammatory mediators have been suggested to contribute to airway remodeling. A growing amount of evidence support a role of platelets as important players in inflammatory airway diseases [2,3].…”

Section: Introductionmentioning

confidence: 99%

Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

et al. 2008

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“…Platelets contribute to airway inflammation and facilitate structural changes, such as increased cell proliferation, observed during the remodeling process [25,26]. We have previously found that platelets as well as platelet-derived membrane preparations stimulate ASMC proliferation measured using the MTS-assay, thymidine incorporation, measurement of DNA content and manual cell counting [3,4].…”

Section: Discussionmentioning

confidence: 99%

Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation

Holm

Bengtsson

Grenegård

et al. 2012

Experimental Cell Research

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Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway 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 HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in plateletinduced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation.The interaction between ASMC and platelets was studied by fluorescent staining of F-actin.In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

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“…guinea pig [2,3], murine [4,5] and human models [6]. Platelets possess both inflammatory and proliferative qualities [7][8][9][10] and are suggested to play a role in airway inflammation [11,12]. Platelets release different growth factors upon activation e.g.…”

Section: Introductionmentioning

confidence: 99%

Platelet membranes induce airway smooth muscle cell proliferation

et al. 2011

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The role of platelets in airway disease is poorly understood although they have been suggested to influence on proliferation of airway smooth muscle cells (ASMC). Platelets have been found localised in the airways in autopsy material from asthmatic patients and have been implicated in airway remodeling. The aim of the present study was to investigate the effects of various platelet fractions on proliferation of ASMC obtained from guinea pigs (GP-ASMC) and humans (H-ASMC). Proliferation of ASMC was measured by the MTS-assay and the results were confirmed by measurements of the DNA content. A key observation was that the platelet membrane preparations induced a significant increase in the proliferation of both GP-ASMC (129.9 ± 3.0 %) and H-ASMC (144.8 ± 12.2). However, neither supernatants obtained from lysed nor filtrate from thrombin stimulated platelets did induce ASMC proliferation to the same extent as the membrane preparation. We have previously shown the platelet-induced proliferation is dependent on the 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) pathways. In the present work we established that platelet membrane-induced ASMC proliferation was reduced in the presence of the NADPH oxidase inhibitor DPI and the 5-LOX inhibitor AA-861. In conclusion, our results showed that platelet membranes significantly induced ASMC proliferation, demonstrating that the mitogenic effect of platelets and platelet membranes on ASMC is mainly due to membrane-associated factors. The effects of platelet membranes were evident on both GP-ASMC and H-ASMC and involved 5-LOX and ROS. These new findings are of importance in understanding the mechanisms contributing to airway remodeling and may contribute to the development of new pharmacological tools in the treatment of inflammatory airway diseases.

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Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Cited by 64 publications

References 212 publications

Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation

Platelet membranes induce airway smooth muscle cell proliferation

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