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Inhibition of c-Jun N-Terminal Kinase Limits Lipopolysaccharide-induced Pulmonary Neutrophil Influx

Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center; and Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Patrick G. Arndt, M.D., Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80206. E-mail: patrick.arndt{at}uchsc.edu

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 (TNF-–)–induced neutrophil actin assembly and retention were examined. Neutrophil actin assembly was decreased after LPS and TNF- 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- stimulation, thereby providing one mechanism by which c-Jun N-terminal kinase inhibition decreased actin assembly, and thereby pulmonary neutrophil accumulation.

Key Words: inflammation • lipopolysaccharide • lung • neutrophil

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