Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury

J Immunol. 2013 Feb 1;190(3):1264-75. doi: 10.4049/jimmunol.1202012. Epub 2012 Dec 28.

Abstract

Sepsis is a leading cause of intensive care unit admissions, with high mortality and morbidity. Although outcomes have improved with better supportive care, specific therapies are limited. Endothelial activation and oxidant injury are key events in the pathogenesis of sepsis-induced lung injury. The signaling pathways leading to these events remain poorly defined. We sought to determine the role of MAPK kinase 3 (MKK3), a kinase of the p38 group, in the pathogenesis of sepsis. We used a murine i.p. LPS model of systemic inflammation to mimic sepsis. Lung injury parameters were assessed in lung tissue and bronchoalveolar lavage specimens. Primary lung endothelial cells were cultured and assessed for mediators of inflammation and injury, such as ICAM-1, AP-1, NF-κB, and mitochondrial reactive oxygen species. Our studies demonstrate that MKK3 deficiency confers virtually complete protection against organ injury after i.p. LPS. Specifically, MKK3(-/-) mice were protected against acute lung injury, as assessed by reduced inflammation, mitochondrial reactive oxygen species generation, endothelial injury, and ICAM-1 expression after LPS administration. Our results show that endothelial MKK3 is required for inflammatory cell recruitment to the lungs, mitochondrial oxidant-mediated AP-1, NF-κB activation, and ICAM-1 expression during LPS challenge. Collectively, these studies identify a novel role for MKK3 in lethal LPS responses and provide new therapeutic targets against sepsis and acute lung injury.

Publication types

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

MeSH terms

  • Acute Lung Injury / enzymology*
  • Acute Lung Injury / pathology
  • Acute Lung Injury / prevention & control
  • Animals
  • Apoptosis
  • Bronchoalveolar Lavage Fluid
  • Chemotaxis, Leukocyte / physiology
  • Disease Models, Animal
  • Endothelial Cells / enzymology*
  • Endothelial Cells / pathology
  • Endotoxemia / enzymology*
  • Endotoxemia / pathology
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Lipopolysaccharides / toxicity
  • Lung / pathology
  • MAP Kinase Kinase 3 / antagonists & inhibitors
  • MAP Kinase Kinase 3 / deficiency
  • MAP Kinase Kinase 3 / genetics
  • MAP Kinase Kinase 3 / physiology*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • NF-kappa B / metabolism
  • Neutrophil Activation
  • Peritonitis / chemically induced
  • Peritonitis / enzymology
  • RNA, Small Interfering / pharmacology
  • Radiation Chimera
  • Reactive Oxygen Species / metabolism
  • Sepsis / enzymology
  • Transcription Factor AP-1 / metabolism

Substances

  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • lipopolysaccharide, E coli O55-B5
  • Intercellular Adhesion Molecule-1
  • MAP Kinase Kinase 3
  • Map2k3 protein, mouse