EFFECT OF ACUTE LUNG INJURY ON PULMONARY HOST DEFENSE

脓毒症并发急性肺损伤（ALI）使宿主易于发生 感染并发症（如革兰氏阴性医院感染）的数量 肺炎）。脓毒症/ALI导致肺损伤的机制 抗菌宿主防御尚未确定。最近的证据 表明特异性细胞因子，包括T1-表型[白细胞介素-12 （IL-12）和干扰素-γ（IFN-γ）]和T2-表型[白细胞介素-10 （IL-10）]细胞因子以及趋化因子单核细胞趋化因子 蛋白-1（MCP-1）在调节脓毒症反应中起重要作用 并且是抵抗细菌的先天免疫的关键成分 病原体本提案的重点是确定以下方面的影响： 脓毒症/ALI对奎宁介导的肺抗菌宿主防御的影响。的 项目2假设是脓毒症诱导肺抑制 抗菌宿主防御是改变平衡的结果， 重要的促炎和抗炎细胞因子的表达，有利于 产生T2-而不是T1-表型细胞因子。人类受试者和 鼠模型将用于执行以下特定目的：I） 为了a）评估腹腔内脓毒症（实验性盲肠炎）的影响， 结扎和穿刺）对小鼠肺泡巨噬细胞细胞因子表达的影响 和体外抗微生物活性，和B）测定体内 腹腔脓毒症对促炎和抗炎细胞因子表达的影响，肺 小鼠中炎性细胞流入、细菌清除和存活 铜绿假单胞菌肺炎模型; III）确定 内源性产生的MCP-1和IL-10对脓毒症诱导的 通过中和MCP-1或 腹腔脓毒症小鼠IL-10在脓毒症发病过程中的变化 假单胞菌肺炎; IV）以确定是否受损的IL-1产生。 12和IFN-γ有助于脓毒症诱导的肺抑制 通过瞬时过表达IL-12和IFN-γ的抗菌宿主防御 腹腔内脓毒症小鼠肺内的γ 假单胞菌肺炎的发展;和V）a）评估以下的作用： 急性肺损伤对人肺泡巨噬细胞细胞因子表达及抗菌活性的影响 B）测定离体IL-10和MCP-1的作用 中和或IFN-γ给药对逆转 脓毒症诱导的巨噬细胞失活。这些研究将提供洞察力 开发新的治疗策略， ALI合并医院获得性肺炎患者。

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.