Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3

Sci Transl Med. 2021 Apr 28;13(591):eabc2499. doi: 10.1126/scitranslmed.abc2499.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury* / drug therapy
  • Animals
  • Humans
  • Hydrogen Peroxide
  • Indazoles / pharmacology*
  • MAP Kinase Kinase Kinase 2 / antagonists & inhibitors*
  • MAP Kinase Kinase Kinase 3 / antagonists & inhibitors*
  • Mice
  • NADPH Oxidases / metabolism
  • Phosphorylation
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species
  • Sulfonamides / pharmacology*

Substances

  • Indazoles
  • Pyrimidines
  • Reactive Oxygen Species
  • Sulfonamides
  • pazopanib
  • Hydrogen Peroxide
  • NADPH Oxidases
  • MAP Kinase Kinase Kinase 2
  • MAP Kinase Kinase Kinase 3
  • MAP3K2 protein, human
  • MAP3K3 protein, human