Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation

Jerry A. Nick, Scott K. Young, Kevin K. Brown, Natalie J. Avdi, Patrick G. Arndt, Benjamin T. Suratt, Michael S. Janes, Peter M. Henson, G. Scott Worthen

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228 Scopus citations


Early inflammatory events include cytokine release, activation, and rapid accumulation of neutrophils, with subsequent recruitment of mononuclear cells. The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory responses in many different cells. A murine model of mild LPS- induced lung inflammation was developed to investigate the role of the p38 MAPK pathway in the initiation of pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine the functional consequences of p38 MAPK activation. In vitro exposure to M39 inhibited p38 MAPK activity in LPS- stimulated murine and human neutrophils and macrophages, blocked TNF-α and macrophage inflammatory protein-2 (MIP-2) release, and eliminated migration of murine neutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrophages required a 1000-fold greater concentration of M39 to block release of TNF-α and MIP-2. Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-α and neutrophil accumulation in the airspaces following intratracheal administration of LPS. Recovery of MIP-2 and KC from the airspaces was not affected by inhibition of p38 MAPK, and accumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was significantly decreased by p38 MAPK inhibition independent of TNF-α or LPS. Together, these results demonstrate a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes, and suggest a means of selectively studying and potentially modulating early inflammation in the lung.

Original languageEnglish (US)
Pages (from-to)2151-2159
Number of pages9
JournalJournal of Immunology
Issue number4
StatePublished - Feb 15 2000


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