EFFECT OF ACUTE LUNG INJURY ON PULMONARY HOST DEFENSE

脓毒症并发急性肺损伤(ALI)使宿主易患 感染并发症的数量(例如革兰氏阴性医院 肺炎)。脓毒症/ALI致肺损伤的机制 抗菌宿主防御机制尚未定义。最近的证据 提示特定的细胞因子，包括T1表型[白介素12 (IL-12和干扰素-γ)和T2-表型[白介素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发挥重要作用 是抵抗细菌的先天免疫力的重要组成部分 病原体。这项提案的重点是确定 脓毒症/ALI对细胞因子介导的肺抗菌宿主防御的影响。这个 项目2的假设是脓毒症导致肺抑制 抗菌宿主防御是体内平衡改变的结果 重要的促炎和抗炎细胞因子的表达，有利于 产生T2表型细胞因子，而不是T1表型细胞因子。人类受试者和 将利用小鼠模型来实现以下特定目标：i) 评估腹内脓毒症的影响(实验性盲肠 结扎和穿孔)对小鼠肺泡巨噬细胞细胞因子表达的影响 和体外抗菌活性，以及b)决定体内的效果 腹部脓毒症对肺组织促炎和抗炎细胞因子表达的影响 小鼠体内炎症细胞的流入、细菌的清除和存活 铜绿假单胞菌肺炎模型的建立 内源性MCP-1和IL-10在脓毒症中的作用 中和MCP-1或MCP-1抑制肺抗菌宿主防御 IL-10在腹内脓毒症小鼠发病过程中的作用 肺炎假单胞菌；IV)确定IL-1的产生是否受损 12和干扰素-γ参与脓毒症所致的肺抑制 瞬时过表达IL-12和干扰素-1的抗菌宿主防御 腹腔型脓毒症小鼠肺组织中的伽马射线 肺炎假单胞菌的发展；以及v)评估 ALI对人肺泡巨噬细胞细胞因子表达及抗菌作用的研究 体外活性，b)测定体外IL-10和MCP-1的作用 中和，或干扰素-γ给药对逆转能力的影响 脓毒症引起的巨噬细胞失活。这些研究将提供洞察力 开发新的治疗策略以应用于 ALI患者合并医院内肺炎。

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.