Inhibition of c-Jun N-terminal kinase limits lipopolysaccharide-induced pulmonary neutrophil influx.
The influx of neutrophils into the lung is a sentinel event in LPS-induced acute lung inflammation. Previous studies have shown that systemic inhibition of p38 decreases LPS-induced neutrophil influx into the alveolar space but has no effect on pulmonary parenchymal neutrophil accumulation or on microvascular leak, indicating other pathways are important in LPS-induced acute lung inflammation. This study examined the role of c-Jun N-terminal kinase in LPS-induced acute lung inflammation. Systemic inhibition of c-Jun N-terminal kinase, with the specific c-Jun N-terminal kinase inhibitor SP600125, decreased the LPS-induced accumulation of neutrophils into the lung parenchyma and alveolar space. In addition, increases in microvascular leak after LPS exposure were diminished by c-Jun N-terminal kinase inhibition. To determine mechanisms by which systemic c-Jun N-terminal kinase inhibition decreased pulmonary neutrophil influx, LPS and tumor necrosis factor alpha (TNF-alpha-)-induced neutrophil actin assembly and retention were examined. Neutrophil actin assembly was decreased after LPS and TNF-alpha stimulation with SP600125 pretreatment, as well as LPS-induced neutrophil retention. Finally, c-Jun N-terminal kinase inhibition decreased Cdc42 activation after LPS or TNF-alpha stimulation, thereby providing one mechanism by which c-Jun N-terminal kinase inhibition decreased actin assembly, and thereby pulmonary neutrophil accumulation.
Arndt
Patrick G
PG
Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80206, USA. patrick.arndt@uchsc.edu
Young
Scott K
SK
Lieber
Jonathan G
JG
Fessler
Michael B
MB
Nick
Jerry A
JA
Worthen
G Scott
GS
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology*; D011650:Pulmonary Alveoli; D015398:Signal Transduction / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology
D000873:Anthracenes; D008070:Lipopolysaccharides; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein