sPLA2-IIA inhibitor Tricyclic Dipyrido Diazepinone derivative 6 f suppresses poultry organic dust-induced pulmonary inflammation by downregulating ERK1/2-cPLA2 pathway

Poultry farm workers are highly susceptible to developing lung inflammatory diseases (asthma, COPD, ARDS, and ALI) due to prolonged exposure to organic dust and other airborne irritants in confined poultry facilities. Secretory phospholipase A2 (sPLA₂-IIA) is a vital proinflammatory enzyme play an important role in the production of inflammatory mediators. Hence, this study examined the regulatory role of secretory phospholipase A2 enzyme in poultry dust induced lung inflammation in in vitro and in vivo models. Lung epithelial A549 cells and BALB/c mice treated with poultry dust increased the sPLA₂-IIA mRNA expression and stimulated the induction of inflammatory symptoms. Inhibition of sPLA₂ enzyme activity by Tricyclic Dipyrido Diazepinone derivative 6 f (sPLA₂ inhibitor) markedly ameliorated ODE-induced lung histopathological conditions, decreased lung edema, cellular infiltration, and protein secretion. Further, downregulated activation of cPLA₂ via decreasing phosphorylation of ERK1/2 and p38. Suppressing cPLA₂ signalling cascade significantly reduced the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) and chemokines (MIP-1, MCP, and RANTES). Consequently, the activation of COX-2 and the production of prostaglandin E2 and thromboxane B2 were significantly decreased. Conclusively, these findings indicated that sPLA₂-IIA could potentially serve as a novel therapeutic target for treating lung inflammation in disease conditions.