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.
Showing the most recent 10 out of 61 publications
