EFFECT OF ACUTE LUNG INJURY ON PULMONARY HOST DEFENSE

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Sepsis complicated by acute lung injury (ALI) predisposes the host to a number of infectious complications (e.g. gram-negative nosocomial pneumonia). Mechanisms by which sepsis/ALI results in impairment in lung antibacterial host defenses have not been defined. Recent evidence indicates that specific cytokines, including T1-phenotype [interleukin-12 (IL-12) and interferon-gamma (IFN-gamma)] and T2-phenotype [interleukin-10 (IL-10)] cytokines, as well as the chemokine monocyte chemoattractant protein-1 (MCP-1), play an important role in modulating septic responses and are critical components of the innate immunity against bacterial pathogens. The focus of this proposal is to determine the effects of sepsis/ALI on cytokine-mediated lung antibacterial host defense. The hypothesis of Project 2 is that sepsis induced suppression of lung antibacterial host defense is the result of an altered balance in the expression of important pro- and anti-inflammatory cytokines, favoring the production of T2-, rather than T1-phenotype cytokines. Human subjects and murine models will be utilized to perform the following Specific Aims: I) To a) assess the effect of intra-abdominal sepsis (experimental cecal ligation and puncture) on murine alveolar macrophage cytokine expression and antimicrobial activity ex-vivo, and b) determine the effect of intra- abdominal sepsis on pro- and anti-inflammatory cytokine expression, lung inflammatory cell influx, bacterial clearance, and survival in a murine model of Pseudomonas aeruginosa pneumonia; III) to determine the contribution of endogenously-produced MCP-1 and IL-10 to sepsis-induced suppression of lung antibacterial host defense by neutralizing MCP-1 or IL-10 in mice with intra-abdominal sepsis during the development of Pseudomonas pneumonia; IV) to determine whether impaired production of IL- 12 and IFN-gamma contributes to sepsis induced suppression of lung antibacterial host defense by transiently over-expressing IL-12 and IFN- gamma within the lung in mice with intra-abdominal sepsis during the development of Pseudomonas pneumonia; and V) to a) assess the effect of ALI on human alveolar macrophage cytokine expression and antimicrobial activity ex vivo, and b) determine the effect of ex-vivo IL-10 and MCP-1 neutralization, or IFN-gamma administration on the ability to reverse sepsis-induced macrophage deactivation. These studies will provide insight into the development of novel treatment strategies to be employed in patients with ALI complicated by nosocomial pneumonia.