The p38 MAPK signaling pathway plays a key role in lung inflammation and the development of acute lung injury (ALI). We previously reported that the phenolic compound procyanidin B1 inhibits inflammation by suppressing the p38 MAPK signaling pathway. Here, we asked whether the monomer of procyanidin B1, epicatechin (EC), can alleviate LPS-induced ALI in mice, and if so, whether EC acts by inhibiting p38 MAPK. C57BL/6 mice were randomly divided into four groups (n = 8) and received EC alone, vehicle (sham group), LPS alone, or LPS and EC. LPS was administered via intraperitoneal injection and EC via nasogastric feeding. Lung histopathology, alveolocapillary membrane permeability, inflammation, and p38 MAPK pathway activation were assessed by immunohistochemistry, tissue wet/dry weight analysis, quantitative PCR, protein assays, ELISA, and western blot analysis using lung tissue and/or bronchoalveolar fluid. We also performed molecular modeling and in vitro enzymatic assays to examine the potential interaction between EC and p38 MAPK at the molecular level. We found that LPS caused an increase in ALI-associated lung pathology accompanied by activation of p-p38 pathway components and the transcription factor AP1. All of these effects were substantially reduced by treatment with EC. Furthermore, molecular modeling suggested that EC suppressed p38 MAPK signaling by hydrogen bonding with Glu71, Ala 111, Asp112, and Leu171 in the active site of p38α. In vitro kinase assays confirmed the ability of EC to directly inhibit purified p38 MAPK. Collectively, our data suggest that the naturally occurring compound EC could be a new therapeutic option for ALI.
Keywords: ALI; AP1; Epicatechin; LPS; p38.
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