Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

Abstract

Background: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A 2 (PLA 2 ). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA 2 (sPLA 2 ) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA 2 and prostaglandin E 2 . These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA 2 inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA 2 inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways. Methods: Rats sensitised with OVA were treated with the sPLA 2 inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mg) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor a (TNFa) by BAL macrophages were determined. Results: Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFa and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge. Conclusions: These findings confirm the pivotal role of sPLA 2 in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA 2 may be a new therapeutic approach to the treatment of asthma.

Phospholipase A2-dependent Release of Inflammatory Cytokines by Superantigen-Stimulated Nasal Polyps of Patients with Chronic Rhinosinusitis

“…8,52,53 Similarly, in the study of EAB in rats, we found that the disease induction is associated with increased sPLA 2 expression and Cys-LTs production, whereas cPLA 2 expression and PGE 2 production were decreased. 11,35 This concurs with other studies that indicate that, by acting on different AA pools, sPLA 2 types were responsible for Leukotriene production, whereas PGE 2 was produced by cPLA 2 . 11,35 This indeed makes physiologic sense in airway conditions because Cys-LTs are bronchoconstrictors, whereas PGE 2 is a bronchodilator.…”

“…11,35 This concurs with other studies that indicate that, by acting on different AA pools, sPLA 2 types were responsible for Leukotriene production, whereas PGE 2 was produced by cPLA 2 . 11,35 This indeed makes physiologic sense in airway conditions because Cys-LTs are bronchoconstrictors, whereas PGE 2 is a bronchodilator. 11,35,40 However, the eicosanoids, as metabolites of AA, are downstream products of the cascade of inflammatory lipid mediators, whereas the upstream PLA 2 action produces both AA and lysophospholipids (Lyso-PL).…”

“…However, our study with the rat EAB model 11,35 assigned opposing roles to sPLA 2 and cPLA 2 . Although EAB induction was associated with enhanced sPLA 2 expression, cPLA 2 expression was suppressed, and both effects were reversed on amelioration of the disease, 11,35 similar to the findings of the present study, which indicate that sPLA 2 is involved in the disease induction, whereas cPLA 2 takes part in the disease resolution. 11,35 Additional insight into the role of PLA 2 in airway pathologies can be provided by previous studies of eicosanoid production.…”

Phospholipase A2 in Experimental Allergic Bronchitis: A Lesson from Mouse and Rat Models

“…In a previous study, we investigated the involvement of PLA 2 s and eicosanoids in asthma pathophysiology using a rat model of ovalbumin (OVA)-induced experimental allergic bronchitis (EAB) [4], [11], as expressed by broncho-constriction, airway remodeling, the levels of the broncho-dilator PGE 2 and the broncho-constrictor Cysteinyl-LTs (CysLTs) in bronchoalveolar lavage (BAL). Upon induction of EAB these indices were up-regulated, except for PGE 2 which was markedly reduced.…”

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

“…7 Gene silencing of either group V or X sPLA 2 in mice with ovalbumin-induced asthma attenuates T-helper cell type 2 infl ammation. [8][9][10] We have reported that sPLA 2 stimulate mucus hypersecretion in the ferret trachea through activation of the lipoxygenase (LO) pathway. 11 Mucus obstruction of airways and goblet cell hyperplasia are characteristic of severe asthma.…”