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

¹ Pediatric Department, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel
² Pediatric Pulmonology Clinic, Barzilai Hospital, Ashkelon, Israel
³ Institute of Biochemistry, Faculty of Agriculture, Hebrew University, Jerusalem, Rehovot, Israel
⁴ Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel

Correspondence to:
Correspondence to:
Professor S Yedgar
Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120; Yedgar{at}md.huji.ac.il

Background: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A₂ (PLA₂). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA₂ (sPLA₂) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA₂ and prostaglandin E₂. These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA₂ inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA₂ 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 sPLA₂ 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 µg) 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 (TNF) 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 TNF 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 sPLA₂ in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA₂ may be a new therapeutic approach to the treatment of asthma.

Abbreviations: ASM, airway smooth muscle; CysLT, cysteinyl leukotriene; ExPLI, extracellular sPLA₂ inhibitor; GAG, glycosaminoglycans; HyPE, hyaluronic acid-linked phosphatidyl ethanolamine; IL, interleukin; LT, leukotriene; NO, nitric oxide; OVA, ovalbumin; PG, prostaglandin; PLA₂, phospholipase A₂; TNF, tumour necrosis factor

Keywords: asthma; experimental allergic bronchitis; phospholipase A2; glycosaminoglycans

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