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

Early inflammatory events include cytokine release, activation, and rapid a ccumulation of neutrophils, with subsequent recruitment of mononuclear cell s, The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory res ponses in many different cells. A murine model of mild LPS-induced lung inf lammation 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. I n vitro exposure to M39 inhibited p38 MAPK activity in LPS-stimulated murin e and human neutrophils and macrophages, blocked TNF-alpha and macrophage i nflammatory protein-2 (MIP-2) release, and eliminated migration of murine n eutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrop hages required a 1000-fold greater concentration of M39 to block release of TNF-alpha and MIP-2 Systemic inhibition of p38 MAPK resulted in significan t decreases in the release of TNF-alpha 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 a ccumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was signi ficantly decreased by p38 MAPK inhibition independent of TNF-alpha or LPS, Together, these results demonstrate a much greater dependence on the p38 MA PK cascade in the neutrophil when compared with other leukocytes, and sugge st a means of selectively studying and potentially modulating early inflamm ation in the lung.