Acute lung injury (ALI) is a major clinical problem, affecting more than 50,000 patients per year in the United States. Recent studies have shown that the mortality of ALI remains high, generally being greater than 30%. Acute lung injury (ALI) is characterized by the accumulation of activated neutrophils in the lungs. However, even though pathways leading to neutrophil activation are well known, their control mechanisms in the context of ALI are poorly understood. We propose that phenotypic patterns exist that determine the nature of the neutrophil response to proinflammatory stimuli, thereby contributing not only to the development of ALI, but to its severity and persistence as well. The goal of the proposed work is to define the critical genetic and cellular risk factors that lead to ALI in certain individuals and not others. Our hypothesis is that a proinflammatory neutrophil phenotype is associated with increased pulmonary inflammation, a greater likelihood of developing acute lung injury, and worse outcome from acute lung injury. We also hypothesize that this proinflammatory neutrophil phenotype is characterized by increased production of proinflammatory cytokines, enhanced activation of p38 and PI3K/Akt kinases, increased NF-kB activation, and resistance to glucocorticoids. This hypothesis will be explored by the four Projects and three Cores included in this Program. The first Specific Aim of each Project is to define high and low inflammatory phenotypes in human neutrophils, as defined by a) activation of PI3-K, Akt, and NF-kB (Project One); b) activation of p38 (Project Two); c) expression of proinflammatory cytokines (Project Three); and d) resistance to steroid induced cell death and inhibition of cytokine production (Project Four). The second Specific Aim of each project is to determine if high and low inflammatory phenotypes among neutrophils, as defined in the first Specific Aim, predict a) the intensity of in vivo pulmonary inflammatory responses in humans given endotoxin into the lungs, and b) the severity of lung injury in patients at risk for or with ALI. The third Specific Aim of each project is to determine the mechanisms by which a) PI3-K, Akt, and NF-kB activation (Project One); b) p38 activation (Project Two); c) proinflammatory cytokine production (Project Three); and d) glucocorticoid resistance (Project Four) lead to proinflammatory neutrophil phenotypes. The integrated approach proposed in this PPG application will provide insight not only into cellular pathways that initiate and contribute to the severity of ALI, but also into the critical genetic, immunologic, and environmental risk factors that lead to ALI in certain individuals, but not others.
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