Mechanisms of asthma and allergic inflammationSecretory phospholipases A2 in inflammatory and allergic diseases: Not just enzymes
Section snippets
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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2022, Brain Research BulletinCitation Excerpt :Two main classes of mammalian sPLA2 receptors have been discovered; muscular (M)-type and neural (N)-type receptors, both of which are capable of binding human sPLA2-IIA and other neurotoxic sPLA2 such as ammodytoxin C present in viper venom, sPLA2-OS2 from Australian taipan snakes, and bee venom PLA2s (Čopič et al., 1999; Lambeau and Lazdunski, 1999; Quach et al., 2014). Although the N-type receptors have not yet been cloned and their physiological roles and ligand binding affinities are currently under investigation, these receptors are highly expressed in mammalian brains and display a high affinity for neurotoxic sPLA2s (Cupillard et al., 1999; Quach et al., 2014; Rouault et al., 2006; Triggiani et al., 2005). Several other neuronal receptors have been suggested as targets of cytotoxic sPLA2s, including vascular endothelial growth factor receptor (VEGFR) 1 and 2, and heparan sulfate proteoglycan (HSPG) (Boilard et al., 2003; Lambeau and Gelb, 2008; Montecucco et al., 2008; Triggiani et al., 2005).
sPLA<inf>2</inf>-IIa participates in ocular surface inflammation in humans with dry eye disease
2020, Experimental Eye ResearchCitation Excerpt :The purported function of sPLA2-IIa is as a bactericidal agent to protect the ocular surface from Gram-positive infection (Qu and Lehrer, 1998). However, although sPLA2-IIa is produced in the course of the innate immune response to bacterial infection, it has also been found in high concentrations in the synovia and tears in the setting of systemic inflammation, such as autoimmune disease or allergic response (Qu and Lehrer, 1998; Nevalainen et al., 1994; Saari et al., 2001) (Triggiani et al., 2005; Murakami et al., 2016). In addition to the immune cells which mediate innate immunity and secrete sPLA2-IIa, human conjunctival epithelial and goblet cells have been shown to accumulate large amounts of sPLA2-IIa and its isoforms in response to signals of degranulation and/or cell activation (Capper and Marshall, 2001; Turner et al., 2007).
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).