Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation

Pitchford, Simon; Riffo‐Vasquez, Yanira; Sousa, Ana R.; Momi, Stefania; Gresele, Paolo; Spina, Domenico; Page, Clive

doi:10.1182/blood-2003-05-1707

Cited by 133 publications

(119 citation statements)

References 59 publications

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“…Some of these processes may be independent of the separate requirement of platelets for leukocyte recruitment, since platelets may release a number of mitogens and enzymes that may contribute to tissue remodelling directly. As an example, airway remodelling occurs in experimental models where leukocyte recruitment has been inhibited by glucocorticosteroid administration, but not in animals depleted of platelets (Pitchford et al, 2004a). Thus, platelets may directly affect chronic inflammatory events that lead to smooth muscle proliferation, angiogenesis, myofibroblast proliferation and fibrosis (Tutluoglu et al, 2005; Zernecke et al, Anti-platelet agents as anti-inflammatory drugs SC Pitchford 2005).…”

Section: Platelets and Tissue Remodelling Eventsmentioning

confidence: 99%

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

Pitchford

2007

British J Pharmacology

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An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations have been dissociated from the well‐characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of inflammation. The mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention. There is now acceptance that platelets act as innate inflammatory cells in immune responses, with roles as sentinel cells undergoing surveillance, responding to microbial invasion, orchestrating leukocyte recruitment, and migrating through tissue, causing damage and influencing repair processes in chronic disease. Some of these processes are targeted by drugs that are being developed to target platelet participation in atherosclerosis. The actions of platelets therefore influence the pathogenesis of diverse inflammatory diseases in various body compartments, encompassing parasitic and bacterial infection, allergic inflammation (especially asthma and rhinitis), and non‐atopic inflammatory conditions, for example, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and atherosclerosis. This review will first discuss the evidence for platelet activation in these various inflammatory diseases, and secondly discuss the mechanisms by which this pathogenesis occurs and the various anti‐platelet agents which have been developed to combat platelet activation in atherosclerosis and their potential future use for the treatment of other inflammatory diseases.British Journal of Pharmacology (2007) 152, 987–1002; doi:10.1038/sj.bjp.0707364; published online 2 July 2007

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Section: Platelets and Tissue Remodelling Eventsmentioning

confidence: 99%

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

Pitchford

2007

British J Pharmacology

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“…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. In the present study, we demonstrate by using different cell proliferation assays (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have investigated the role of platelets in asthma and indicate that platelets from asthmatics express a different behaviour for example regarding aggregation response, cytosolic calcium mobilization and arachidonic acid metabolism [10,11]. In addition, depletion of platelets in a murine model of chronic allergic inflammation markedly reduced airway remodeling [12].…”

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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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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“…guinea pig e.g. guinea pig [2,3], murine [4,5] and human models [6]. We have previously found that platelets have the ability to induce proliferation of airway smooth muscle cells (ASMC) obtained from guinea pigs (GP-ASMC) [13].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, different animal models are used within respiratory research to study airway remodelling, e.g. 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].…”

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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Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation

Cited by 133 publications

References 59 publications

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

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

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

Platelet membranes induce airway smooth muscle cell proliferation

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