LEUKOTRIENES AND PULMONARY ANTIBACTERIAL DEFENSE

描述(根据申请者的抽象和具体目标改编)： 白三烯(LT)是一种强有力的介导物，与卵巢癌的发病机制有关。 炎症性肺病和抑制LT的新药理药物 合成或作用不久将可用于哮喘的治疗。它 通常认为炎症性级联反应是为了达到这个目的而演变的 宿主防御微生物入侵的能力，但对其了解甚少 内源性LTS在调节寄主反应中的可能重要性 感染。这个施用者假设1)内源性LT发挥着一种 在宿主对肺部感染的反应中的整体作用，以及2)外源 它发挥了增强这种反应的药理作用。这些 假说将通过一系列体内和体外实验进行验证。 旨在解决以下具体目标。目标1将确定 特异性内源性5-LO产物在寄主对K。 肺炎，使用抑制LT合成或作用的药物。 目标2将确定LTS的动力学、分布和细胞来源 在克雷伯氏菌肺炎的过程中在小鼠的肺部产生。目标 3将确定特定的5-LO产物的分子机制 增强肺泡巨噬细胞和中性粒细胞对肺炎克雷伯菌的吞噬和杀伤作用。目标4 将测试肺内给药的潜力，以增加 宿主对克雷伯氏菌挑战的反应。

DESCRIPTION (Adapted from applicant's abstract and specific aims): Leukotrienes (LTs) are potent mediators implicated in the pathogenesis of inflammatory lung diseases, and new pharmacologic agents that inhibit LT synthesis or actions will soon be available for the treatment of asthma. It is generally assumed that inflammatory cascades have evolved for the purpose of host defense against microbial invasion, yet little is known about the possible importance of endogenous LTs in mediating the host response to infection. This applicator hypothesize that 1) endogenous LTs play an integral role in the host response to pulmonary infection, and 2) exogenous LTs exert pharmacologic actions which augment this response. These hypotheses will be tested by a series of in vivo and in vitro experiments designed to address the following Specific Aims. Aim 1 will ascertain the roles of specific endogenous 5-LO products in the host response to K. pneumonia, using pharmacologic agents which inhibit LT synthesis or actions. Aim 2 will determine the kinetics, profile, and cellular sources of LTs produced in the murine lung during the course of Klebsiella pneumonia. Aim 3 will determine the molecular mechanisms by which specific 5-LO products augment phagocytosis and killing of K. pneumonia in AMs and PMNs. Aim 4 will test the potential of intrapulmonary LT administration to augment the host response to Klebsiella challenge.