Platelets and Aspirin-Induced Asthma: Pathogenesis and Melatonin

Book Preface

One of the most amazing observations brought out by the research in cellular immunity during the last three decades was the promotion of blood platelets to the status of effectors in the destruction of several pathogens and their involvement in the mechanisms of various inflammatory disorders. It is now widely accepted that, besides their classical role in thrombosis and hemostasis, blood platelets participate in other physiological processes, such as the initiation of tissue repair after injury, or the defense against bacteria, tumors, and parasites. These properties have led to the concept that platelets themselves can be considered as inflammatory cells [247]. Initially, it was suggested that the thrombocyte involvement in inflammatory reactions was a consequence of their passive role of targets for leukocyte mediators released in various circumstances of cell activation. Among these mediators, platelet-activating factor, interferon-γ, tumor necrosis factors, interleukin 6, C-reactive protein, or substance P were proposed as agents with stimulating properties for platelets. However, it appeared that these blood elements had an active role on their own by excreting specific factors in vitro and in vivo, such as platelet factor 4, β-thromboglobulin, platelet-derived growth factor, or histamine release-inducing factors, all with potent amplifying functions for basophils, mast cells, and other inflammatory cells. Finally, in the context of allergies, it was shown that platelets could also be seen as directly involved in the immunological mechanisms of immediate hypersensitivity reactions, and thus in the inflammation associated with allergy, partly as a consequence of the presence of receptors on their surface for IgE (FcεRI [248] and CD23 [246]).

In fact and unexpectedly, the demonstration of the binding of IgE to platelets led to the observation of a participation of platelets to aspirin-induced asthma (AIA). When analyzing cytotoxic functions of various cells against the parasite Schistosoma mansoni, we observed that the larvae of this pathogen were efficiently killed in vitro by blood platelets, either passively sensitized by IgE-specific antibodies when isolated from healthy donors or purified from the blood of patients infected with the parasite. Catalase and superoxide dismutase were good inhibitors of the platelet cytocidal activity against the parasite, focusing on a potential generation of oxygen-dependent free radicals among the mediators produced by platelets in these effects. When using platelets from healthy donors or from aspirin-tolerant asthmatics, aspirin and nonsteroid anti-inflammatory drugs (NSAIDs)—inhibitors of cyclooxygenase— inhibited the IgE-mediated cytocidal stimulation of platelets. With platelets from aspirin-intolerant patients, not only aspirin and NSAIDs were unable to inhibit the IgE-dependent cytotoxicity but they also increased the cytocidal effect. It appeared that these drugs induced directly the generation of cytotoxic mediators by AIA platelets [12]. Conversely, no other leukocyte population from aspirin-intolerant asthmatics could kill parasite larvae in vitro in the presence of acetylsalicylic acid or NSAID.