Sepsis syndrome is the potentially lethal response to a systemic bacterial infection. A principal complication of sepsis is secondary lung infection, most notably nosocomial pneumonia, estimated to directly relate to as many as 15% of all hospital deaths. Macrophages play an essential role in the resolution phase of pulmonary infection. Recruitment of macrophages to the infected lung is regulated by a class of cytokines called p-chemokines, which mediate their chemotactic activity via binding to specific p-chemokine receptors. Work by us and others has shown that exposure of macrophages to bacterial IPS results in sustained downregulation of three p-chemokine receptors (CCR1, CCR2, and CCR5), markedly impairing the ability of affected cells to migrate in response to p-chemokine signals. These data raise the possibility that LPS- triggered defects in p-chemokine receptor expression interfere with normal macrophage trafficking in septic patients, and contribute to the immunocompromised state that permits secondary lung infection to flourish in these patients. The molecular mechanisms that mediate sustained downregulation of p-chemokine receptors in LPS-treated macrophages are not known. Also, the potential link between chemokine receptor dysregulation in sepsis patients and increased susceptibility to secondary infection has yet to be explored. Our long-term goal is to overcome mechanisms that subvert effective pulmonary defense in septic patients. The objectives of the current application are to identify the mechanisms and clinical consequences of macrophage p-chemokine receptor loss within the context of sepsis.
In Specific Aim 1, we will use a combination of biochemical, gene knockout, dominant-negative mutant, and RNAi techniques to test our working hypothesis that LPS-induced defects in p-chemokine receptor expression and function are mediated via activation of a Src family kinase and subsequent activation of the small GTPase, Rac, via its guanine nucleotide exchange factor, Vav.
In Specific Aim 2, we will test our working hypothesis that p-chemokine receptor expression and function are impaired in murine endotoxemia and in patients with sepsis, and that these receptor defects correlate with increased susceptibility to lung infections. The rationale that underlies the proposed research is that knowledge of the mechanisms and clinical consequences of macrophage B-chemokine receptor loss and/or dysfunction in sepsis will offer new targets for therapeutic intervention.
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