Mechanisms of asthma and allergic inflammation
Secretory phospholipases A2 in inflammatory and allergic diseases: Not just enzymes

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Secretory phospholipases A2 (sPLA2s) are molecules released in plasma and biologic fluids of patients with systemic inflammatory, autoimmune, and allergic diseases. Several sPLA2 isoforms are expressed and released by such human inflammatory cells as neutrophils, eosinophils, basophils, T cells, monocytes, macrophages, and mast cells. Certain sPLA2s release arachidonic acid, thereby providing the substrate for the biosynthesis of proinflammatory eicosanoids. However, there are other mechanisms by which sPLA2s might participate in the synthesis of lipid mediators. Interestingly, sPLA2s activate inflammatory cells through mechanisms unrelated to their enzymatic activity. Several sPLA2s induce degranulation of mast cells and eosinophils and activate exocytosis in macrophages. Furthermore, sPLA2s promote cytokine and chemokine production from macrophages, neutrophils, eosinophils, monocytes, and endothelial cells. Some of these effects are mediated by the binding of sPLA2s to specific receptors expressed on effector cells. Thus sPLA2s might play important roles in the initiation and amplification of the inflammatory reaction. Selective inhibitors of sPLA2s and specific antagonists of sPLA2 receptors might prove useful in the treatment of allergic and autoimmune diseases, such as bronchial asthma and rheumatoid arthritis.

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Expression and release of sPLA2s in allergic inflammation

Stadel et al10 were the first to report sPLA2 activity in the nasal lavage fluid of patients with allergic rhinitis on specific antigen challenge. sPLA2s were later found in the bronchoalveolar lavage fluid of patients with bronchial asthma in which bronchial antigen challenge increased sPLA2 activity 3- to 5-fold during the late-phase reaction (ie, 4-20 hours after challenge).11, 12 This increase was associated with the appearance of AA and lysophospholipids, which are major enzymatic products

Role of sPLA2s in AA generation and eicosanoid synthesis

In most inflammatory cells, the majority of intracellular AA converted to eicosanoids is provided by the major cPLA2 (GIV).1 However, sPLA2s also could contribute to the generation of AA. Earlier studies performed with nonspecific inhibitors were unable to discriminate the effects of different sPLA2 isoforms. Transfection technology is now being used to evaluate the role of individual sPLA2s in the mobilization of AA. For example, Satake et al26 showed that zymosan-induced generation of

Biologic effects of sPLA2s relevant to asthma and allergic disorders

Inflammation induced by sPLA2s in vivo is characterized by the following: (1) vasodilation and increased vascular permeability; (2) recruitment of inflammatory cells; (3) severe tissue damage; and (4) proliferation of resident cells (eg, fibroblasts in the lung or keratinocytes in the skin).2 These effects are partially explained by the contribution of sPLA2s to the generation of lipid mediators. Other mechanisms by which sPLA2s might induce biologic responses are based on the ability of

Therapeutic implications of sPLA2 inhibitors in inflammatory and allergic diseases

The multivalent proinflammatory activities of sPLA2s led many research groups to develop selective inhibitors to be tested in in vitro and in vivo models of inflammation. Recently, using an extracellular inhibitor of sPLA2s in a murine model of asthma, Offer et al50 showed that sPLA2s induce primarily cysteinyl leukotriene generation, whereas cPLA2 is mainly responsible for prostaglandin E2 production. These results suggest that cPLA2s and sPLA2s might have opposing roles in asthma and that

Concluding remarks and future directions

sPLA2s are emerging as a novel class of mediators of inflammation and immune responses. These molecules are found in biologic fluids in a variety of systemic inflammatory, allergic, and autoimmune disorders. The biologic effects of sPLA2s relevant to the pathogenesis of bronchial asthma are schematically summarized in Fig 1. These effects are mediated by various mechanisms that involve the enzymatic activity of sPLA2s and their capacity to interact with membrane targets (HSPG, M-type, N-type,

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    Supported by grants from the Ministero dell'Istruzione, dell'Università e della Ricerca, the Istituto Superiore di Sanità (AIDS Project 40D.57), and the Ministero della Salute “Alzheimer Project” (Rome, Italy).

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