PI3-K and Akt in Acute Lung Injury

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by the applicant): Acute lung injury (ALI) is characterized by the accumulation of activated neutrophils in the lungs. These pulmonary neutrophils express proinflammatory cytokines and show increased activation of the transcriptional regulatory factor NF-kB. NF-kB is activated in the lungs of patients with ARDS and, in experimental models, inhibition of NF-kB prevents the development of ALI. The serine/threonine kinase Akt/protein kinase B and the immediate upstream kinase, phosphoinositide 3-kinase (PI3-K), occupy central roles in pathways regulating activation of NFkB as well as expression of proinflammatory mediators, including cytokines. Because of the pivotal position that NF-kB has in modulating inflammatory processes, the degree of activation of PI3-K, Akt, and NF-kB in lung neutrophils may be important in determining the intensity of acute inflammatory responses in the lungs after exposure to relevant clinical stimuli, such as endotoxin and proinflammatory cytokines. Our hypothesis is that neutrophil phenotypes characterized by enhanced activation of PI3-K, Akt, and NF-kB in response to proinflammatory stimuli are associated with increased pulmonary inflammation, a greater likelihood of developing acute lung injury, and worse outcome from acute lung injury. Patients whose neutrophils are of a high responder phenotype, as defined by increased levels of PI3-K, Akt, and NF-kB activation in response to relevant stimuli, such as LPS or cytokines, would be hypothesized not only to be at higher risk of developing ALI, but also to have more severe ALI than patients with low responder phenotypes. The specific aims of this project are: 1) To define high and low responder neutrophil phenotypes in humans as determined by the activation of NF-kB, Akt, and related genes, in human peripheral blood neutrophils exposed to proinflammatory stimuli; 2) To determine if the degree of activation of NF-kB, Akt, and related genes in neutrophils stimulated in vitro by proinflammatory stimuli or under basal unstimulated conditions predicts a) the intensity of the in vivo pulmonary inflammatory response in humans given endotoxin into the lungs; b) the development and severity of acute lung injury in at risk patients; c) the severity of pulmonary dysfunction in patients with ALI; 3) To examine the roles that PI3-K and Akt play in modulating activation of NF-kB in neutrophils as well as the intensity and duration of acute in vivo pulmonary inflammatory responses. The overall goal of the proposed experiments is to define genetic, signaling, and transcriptional regulatory mechanisms induced in neutrophils and involving PI3-K, Akt and NF-kB that contribute to and/or predict the development and severity of acute lung injury. The elucidation of fundamental mechanisms that modulate neutrophil function and that involve PI3-K, Akt, and NF-kB should advance understanding of the causes, treatment, and prevention of ALI and ARDS.