Research ArticleAcute Lung Injury

Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3

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Science Translational Medicine  28 Apr 2021:
Vol. 13, Issue 591, eabc2499
DOI: 10.1126/scitranslmed.abc2499

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ROS-mediated lung protection

Neutrophils accumulate in the lung after acute lung injury (ALI) where they play a role in the innate immune response through multiple mechanisms, including the production of reactive oxygen species (ROS). Here, Yuan et al. investigated the mechanisms regulating ROS production during ALI and developed a therapeutic intervention. The authors found that MAP3K2 and MAP3K3 inhibited ROS production from neutrophils. Pazopanib, a specific MAP3K2/3 inhibitor, ameliorated ALI in mice by modulating phosphorylation of p47, a subunit of Nox2. The treatment was effective in reducing pulmonary edema in a pilot study in patients who underwent lung transplantation, suggesting that targeting MAP3K2/3 might be effective for treating ALI of multiple etiologies.

Abstract

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.

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