Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3.

Acute lung injury (ALI) causes high mortality and lacks any pharmacological intervention. Here, we found that pazopanib ameliorated ALI manifestations and reduced mortality in mouse ALI models and reduced edema in human lung transplantation recipients. Pazopanib inhibits mitogen-activated protein kinase kinase kinase 2 (MAP3K2)- and MAP3K3-mediated phosphorylation of NADPH oxidase 2 subunit p47phox at Ser208 to increase reactive oxygen species (ROS) formation in myeloid cells. Genetic inactivation of MAP3K2 and MAP3K3 in myeloid cells or hematopoietic mutation of p47phox Ser208 to alanine attenuated ALI manifestations and abrogates anti-ALI effects of pazopanib. This myeloid MAP3K2/MAP3K3-p47phox pathway acted via paracrine H2O2 to enhance pulmonary vasculature integrity and promote lung epithelial cell survival and proliferation, leading to increased pulmonary barrier function and resistance to ALI. Thus, pazopanib has the potential to be effective for treating ALI. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Qianying Yuan, Abdul Basit, Wenhua Liang, Rihao Qu, Yi Luan, Chunguang Ren, Ao Li, Xin Xu, Xiaoqing Liu, Chun Yang, Andrew Kuo, Richard Pierce, Longbo Zhang, Benjamin Turk, Xin Hu, Fangyong Li, Weixue Cui, Run Li, Danxia Huang, Lili Mo, William C Sessa, Patty J Lee, Yuval Kluger, Bing Su, Wenwen Tang, Jianxing He, Dianqing Wu. Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3. Science translational medicine. 2021 Apr 28;13(591)

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PMID: 33910977

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