Eicosanoids and Lung Macrophage Antimicrobial Mechanisms

描述（由申请人提供）：调节先天肺防御机制以获得治疗优势需要更好地了解介导吞噬细胞抗菌作用的分子。虽然这一领域的大多数研究都集中在肽介质上，但我们的实验室已经确定了花生四烯酸衍生的类二十烷脂质介质的重要作用。我们的研究表明，白三烯（LTs） B4和D4增强，而前列腺素E2 （PGE2）抑制免疫球蛋白G （IgG）活化微生物的肺泡巨噬细胞（AM）吞噬，这一过程通过FcR介导的结合和信号传导进行。此外，内源性LTs:PGE2比例的降低可能导致在HIV感染、营养不良和衰老等情况下对感染的易感性增加。对于初代am对FcR或G蛋白偶联的二十烷类受体的信号转导反应知之甚少。本研究的重点是LTs和PGE2如何调节FcR下游的一系列信号转导事件，包括Syk、磷酸肌肽3激酶、Akt、局灶黏附激酶和细胞外信号相关激酶。假设二十烷类化合物对AM吞噬的调节作用分别反映了LTs和PGE2对这些信号的放大或抑制，这部分是通过细胞内环磷酸腺苷的改变发生的。这一假设将在一系列体外实验中得到验证，这些实验利用igg包被红细胞挑战培养的AMs。外源性和内源性类二十烷酸调节吞噬作用的受体、G蛋白和信号靶点将通过遗传学和药理学工具的结合来确定。通过对am中的FcR信号传导和类二十烷酸调节这一过程的机制提供新的见解，这些研究将增强我们对肺先天免疫研究不足但临床相关的知识。

DESCRIPTION (provided by applicant): Modulating innate pulmonary defense mechanisms for therapeutic advantage requires a better understanding of the molecules that mediate the antimicrobial actions of phagocytic cells. Although most research in this area has focused on peptide mediators, our laboratory has established an important role for eicosanoid lipid mediators derived from arachidonic acid. Our work has demonstrated that leukotrienes (LTs) B4 and D4 enhance, while prostaglandin E2 (PGE2) inhibits, alveolar macrophage (AM) phagocytosis of immunoglobulin G (IgG)-opsonized microbes, a process that proceeds via Fcgamma receptor (FcR)-mediated binding and signaling. Moreover, decreases in the ratio of endogenously generated LTs:PGE2 may contribute to the increased susceptibility to infection observed in such conditions as HIV infection, malnutrition, and aging. Little is known about signal transduction in primary AMs in response to ligation of either FcR or G protein-coupled eicosanoid receptors. This proposal focuses on how LTs and PGE2 modulate the cascade of signal transduction events downstream from FcR which includes Syk, phosphoinositide 3-kinase, Akt, focal adhesion kinase, and extracellular signal-related kinase. The hypothesis is that the modulatory effects of eicosanoids on AM phagocytosis reflect the amplification or suppression of these signals by LTs and PGE2, respectively, which occur in part via alteration in intracellular cyclic adenosine monophosphate. The hypothesis will be tested in a series of in vitro experiments utilizing cultured AMs challenged with IgG-coated erythrocytes. The receptors, G proteins, and signaling targets through which exogenous and endogenous eicosanoids act to modulate phagocytosis will be defined by employing a combination of genetic and pharmacologic tools. By providing new insight into FcR signaling in AMs and the mechanisms by which eicosanoids modulate this process, these studies will enhance our knowledge of an understudied but clinically relevant arm of pulmonary innate immunity.