Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase

Am J Respir Crit Care Med. 2004 Feb 15;169(4):518-24. doi: 10.1164/rccm.200305-660OC. Epub 2003 Nov 25.

Abstract

Positive pressure ventilation with large VTs has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human interleukin-8. The mechanisms regulating ventilation-induced cytokine production are unclear. Based on our previous in vitro model of lung cell stretch, we hypothesized that high VT ventilation-induced MIP-2 production is dependent on the activation of the c-Jun N-terminal kinase (JNK). We exposed C57BL/6 mice to high VT (30 ml/kg) or low VT (6 ml/kg) mechanical ventilation for 5 hours. High VT ventilation-induced neutrophil migration into the lung, MIP-2 protein production, MIP-2 messenger RNA expression, and JNK activation. Large VT ventilation of JNK knockout mice and pharmacologic JNK inhibition with SP600125 attenuated neutrophil sequestration and blocked MIP-2 messenger RNA expression and MIP-2 production. We conclude that lung cell stretch in vivo results in increased lung neutrophil sequestration and increased MIP-2 production, which was, at least in part, dependent upon the JNK pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • Cell Count
  • Chemokine CXCL2
  • Chemokines / genetics
  • Chemokines / metabolism
  • Enzyme Activation
  • JNK Mitogen-Activated Protein Kinases
  • Lung / pathology*
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Neutrophils / pathology*
  • RNA, Messenger / metabolism
  • Respiration, Artificial / adverse effects*
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / pathology
  • Respiratory Distress Syndrome / physiopathology*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Anthracenes
  • Chemokine CXCL2
  • Chemokines
  • Cxcl2 protein, mouse
  • RNA, Messenger
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • MAP3K3 protein, human
  • Map3k3 protein, mouse