Regulation of Neutrophil Responses by p38 MAP Kinase in Acute Lung Injury

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): In the setting of severe infection or shock, a percentage of patients will develop Acute Lung Injury (ALI). Other individuals, despite equal or greater insults and similar risk factors appear protected from the syndrome. A central feature of ALI is rapid and massive accumulation of neutrophils to the lung. Considerable heterogeneity in the magnitude of neutrophil response exists within the normal population. Thus, in the setting of systemic inflammation, variability in the neutrophil response could contribute to variability in predisposition to ALI. Many responses by the neutrophil that have been linked to the pathogenesis of ALI are now known to be regulated by p38 mitogen-activated protein kinase (MAPk). The proposed studies are designed to characterize the spectrum of p38 MAPk-mediated neutrophil response in both health and disease, emphasizing the variability in neutrophil inflammatory potential as a mechanism for heterogeneity in ALI. A functional neutrophil phenotype is proposed that demonstrates a high inflammatory potential based on increased activation of p38 MAPk. Specific Aims for this projects are: 1) Identify response phenotypes in normal neutrophils based on inflammatory potential. 2) Test if functional phenotypes identified in neutrophils predict clinical features of ALI. 3) Define patterns of p38 MAPk-regulated gene and protein expression in neutrophils with divergent inflammatory potential. Through simultaneous quantification of p38 MAPk activation and a series of p38 MAPk-regulated responses, combined with genomic analysis, neutrophils with high or low inflammatory potential will be identified. The effect of divergent inflammatory phenotypes on lung inflammation will be tested in vivo through bronchoscopic installation of endotoxin. Parallel studies of neutrophils from survivors of severe ARDS are expected to demonstrate a similar pattern of high inflammatory potential, while patients ?at risk? who did not develop the syndrome are expected to possess a low inflammatory phenotype. The spectrum of p38 MAPk-regulated protein release will be described, and gene expression mediated by activation of p38 MAPk will be examined in both human neutrophils and in a murine model of pulmonary inflammation. These studies will be coordinated with all of the Projects in the Program to achieve the broadest possible analysis of neutrophil signaling and function.