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bioRxiv · 10.1101/2023.09.27.559864

Inhibiting endothelial cell Mst1 attenuates acute lung injury in mice

Guo, Z.-F.·Tongmuang, N.·Li, C.·Zhang, C.·Hu, L.·Capreri, C.·Zuo, M.-X.·Summer, R.·Sun, J.
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Abstract

BackgroundLung endothelium plays a pivotal role in the orchestration of inflammatory and injury responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1), a mammalian homolog of Hippo, is a serine/threonine kinase that is ubiquitously expressed in many tissues and has been shown to play an important role in the regulation of apoptosis, inflammation, stress responses, and organ growth. While Mst1 exhibits high expression in the lung, its involvement in the endothelial response to pulmonary insults remains largely unexplored. MethodsMst1 activity was assessed in lung endothelium by western blot. Mst1 endothelial specific knockout mice and a pharmacological inhibitor were employed to assess the effects of Mst1 on homeostatic and lipopolysaccharide (LPS)-induced endothelial responses. Readouts for these studies included various assays, including NF-{kappa}B activation and levels of various inflammatory cytokines and adhesion molecules. The role of Mst1 in lung injury was evaluated in a LPS-induced murine model of acute lung injury (ALI). ResultsMst1 phosphorylation was significantly increased in lung endothelial cells after exposure to tumor necrosis factor (TNF)-alpha (TNF-) and mouse lung tissues after LPS exposure. Overexpression of full length Mst1 or its kinase domain promoted nuclear factor kappaB (NF-{kappa}B) activation through promoting JNK and p38 activation, whereas dominant negative forms of Mst1 (DN-Mst1) attenuated endothelial responses to TNF- and interleukin-1{beta}. Consistent with this, targeted deletion of Mst1 in lung endothelium reduced lung injury to LPS in mice. Similarly, wild-type mice were protected from LPS-induced lung injury following treatment with a pharmacological inhibitor of Mst1/2. ConclusionsOur findings identified Mst1 kinase as a key regulator in the control of lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of lung injury to inflammatory insults.

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Guo, Z.-F., Tongmuang, N., Li, C., Zhang, C., Hu, L., Capreri, C., Zuo, M.-X., Summer, R., Sun, J.. 2023-09-29. Inhibiting endothelial cell Mst1 attenuates acute lung injury in mice. https://doi.org/10.1101/2023.09.27.559864

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