• Wei Shi, Chengyun Xu, Musaddique Hussain, Fugen Wu, Meiping Lu, Xiling Wu, Lanfang Tang, Ximei Wu, and Junsong Wu.
• *Department of Critical Care Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou City, China †Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou City, China ‡Department of Paediatrics, The First People's Hospital of Wenling City, Wenling City, China §Department of Respiratory Medicine, The Affiliated Children's Hospital, Zhejiang University School of Medicine, Hangzhou City, China.
• Shock. 2017 Sep 1; 48 (3): 377-386.

AbstractNeutrophils are a population of inflammatory cells involved in acute lung injury (ALI), and lipopolysaccharide (LPS)-induced prolonged neutrophil survival and delayed neutrophil apoptosis hinder the alleviation of lung inflammation. Myosin light-chain kinase (MLCK) involved the RhoA/Rho kinase signaling pathway responsible for the cytoskeletal arrangement, and previous studies have revealed that inhibition of MLCK induces apoptosis in vitro and in vivo. In this study, glycogen-induced neutrophils isolated from rats or mice were incubated with ML-7, a MLCK-specific inhibitor, and LPS-induced ALI mice administrated with ML-7 were investigated, to demonstrate the roles of MLCK in neutrophil apoptosis as well as its possibility of contributing to the clearance of inflammation. We found that ML-7 dramatically promoted neutrophil apoptosis that possibly signal through the p38 to upregulate the expression of the apoptotic proteins caspase-9 and B-cell lymphoma 2 and to downregulate the expression of the antiapoptotic protein Bcl-2-associated X protein and myeloid cell leukemia-1. In mice, ML-7 accelerated the clearance of inflammation in LPS-induced ALI through attenuating neutrophil accumulation, histopathological changes, and pulmonary edema. ML-7 promoted elimination of inflammation possibly by accelerating neutrophil apoptosis and macrophage-mediated clearance. Moreover, ML-7 also reduced the LPS-induced production of proinflammatory cytokines interleukin-1β and tumor necrosis factor-α, and the activity of myeloperoxidase. Taken together, the present study uncovers a hitherto uncharacterized role of MLCK in neutrophil apoptosis that contributes to the alleviation of inflammation in response to LPS.

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