Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening condition involving severe lung inflammation. The excessive oxidative stress and persistent inflammation that occur in ARDS lead to decreased epithelial integrity and hypoxemia due to pulmonary edema via increased vascular permeability. Resolvin D4 (RvD4) is one of the lipid mediators that is biosynthesized from omega-3 polyunsaturated fatty acids. It plays a role in the resolution of inflammation and reduces oxidative stress and cell death. We investigated the therapeutic potential of the administration of RvD4 in a murine model of lipopolysaccharide (LPS)-induced ARDS. Concurrent with the intratracheal administration of LPS, RvD4 or saline was administered to mice via the caudal vein every 12 h. This treatment with RvD4 alleviated the LPS-induced infiltration of inflammatory cells in lungs, inhibited increased pulmonary vascular permeability, decreased the levels of IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF), and suppressed the reduction of the expression levels of the tight junction protein, Zonula occludens-1 (Zo-1) and the NAD+-dependent deacetylase, Sirtuin-3 (Sirt3). In vitro experiments revealed that in LPS-stimulated BEAS-2B cells, treatment with RvD4 suppressed the increases in the expressions of pro-inflammatory cytokines and maintained the epithelial cell barrier function and cell viability. The silencing of SIRT3 abolished both the anti-inflammatory effect and the retention of cell integrity in BEAS-2B cells. Together these results indicate that treatment with RvD4 can (i) protect against LPS-induced lung injury by inhibiting inflammation, and (ii) maintain epithelial barrier function via a reduction in the downregulation of SIRT3.
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