Abstract
Acute respiratory distress syndrome (ARDS), a common and fatal clinical condition, is characterized by the destruction of epithelium and augmented permeability of the alveolar-capillary barrier. Resolvin conjugates in tissue regeneration (RCTR1) is an endogenous lipid mediator derived from DHA, exerting pro-resolution effects in the process of inflammation. In our research, we evaluated the role of RCTR1 in alveolar fluid clearance (AFC) in Lipopolysaccharide-induced ARDS/ALI rat model. Rats were injected with RCTR1 (5 μg/kg) via caudal veins 8h after LPS (14 mg/kg) treatment, then AFC was estimated after 1h of ventilation. Primary type II alveolar epithelial cells (AEC II) were incubated with LPS (1 ug/ml) with or without RCTR1 (10 nM) for 8 h. Our results showed that RCTR1 significantly enhanced the survival rate, promoted the AFC, and alleviated LPS-induced ARDS/ALI in vivo. Furthermore, RCTR1 remarkably elevated the protein expression of sodium channels and Na, K-ATPase, and the activity of Na, K-ATPase in vivo and in vitro. Additionally, RCTR1 also decreased Nedd4-2 level via up-regulating P-Akt expression. Besides, inhibitors of ALX, cAMP, and PI3K (BOC‐2, KH-7, and LY294002) notably inhibited the effects of RCTR1 on AFC. In summary, RCTR1 enhances the protein levels of sodium channels and Na, K-ATPase, and the Na, K-ATPase activity to improve AFC in ALI through ALX/cAMP/PI3K/Nedd4-2 pathway, suggesting that RCTR1 may become a therapeutic drug for ARDS/ALI.
Significance Statement 1.RCTR1, an endogenous lipid mediator, enhanced the rate of AFC to accelerate the resolution of inflammation in the LPS-induced murine lung injury model. 2. RCTR1 up-regulates the expression of ENaC and Na, K-ATPase in vivo and in vitro to accelerate the AFC. 3. The efficacy of RCTR1 on the ENaC and Na, K-ATPase level was in an ALX/cAMP/PI3K/Nedd4-2-dependent
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