application): 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 arena has focused on peptide mediators, or laboratory has recently identified an important and heretofore unrecognized role in antimicrobial defense for an alternative group of mediators, namely, leukotrienes (LTs) and other metabolites of the 5-lipoxygenase (5-LO) pathway of arachidonate metabolism. The investigators' work has demonstrated that LTs are produced by phagocytes in the context of bacterial infection, that LTs are required for optimal bacterial clearance from the lung, and that LTs enhance the capacity of alveolar macrophages (AMs) for bacterial phagocytosis and killing. Despite this progress, we have an incomplete understanding of the molecular mechanisms by which microbes trigger endogenous LT synthesis during their encounter with phagocytes, and by which LTs augment microbial phagocytosis and killing. Moreover, preliminary data suggest that other arachidonate metabolites (eicosanoids), including prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (15-HETE), suppress antimicrobial activity of AMs. The central hypothesis of the present proposal is that the effects of eicosanoids on AM phagocytosis and killing reflect the amplification (in the case of LTs) or down-regulation (in the case of PGE2 and 15-HETE) or molecular signals generated upon cellular interaction with immunoglobulin-opsonized phagocytic targets. This hypothesis will be tested in a series of in vitro experiments utilizing cultured AMs challenged with either IgG-coated erythrocytes or bacteria.
The aims are to: 1) determine the enzymatic pathways that mediate arachidonate release and metabolism triggered by ligation of the AM receptor for the Fc portion of IgG (FcR), and the post-receptor signal transduction events that are responsible for eicosanoid generation; 2) identify the signal transduction events amplified by LTs that result in augmented FcR-dependent phagocytosis and killing; and 3) determine the relative importance of inhibition of LT synthesis vs. inhibition of FcR-dependent signaling in the ability of PGE2 and 15-HETE to down-regulate phagocytosis and killing by AMs. These studies will provide critical mechanistic information about an understudied and clinically relevant arm of the innate host defense system.
|Zas?ona, Zbigniew; Scruggs, Anne M; Peters-Golden, Marc et al. (2016) Protein kinase A inhibition of macrophage maturation is accompanied by an increase in DNA methylation of the colony-stimulating factor 1 receptor gene. Immunology 149:225-37|
|Bourdonnay, Emilie; Zas?ona, Zbigniew; Penke, Loka Raghu Kumar et al. (2015) Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling. J Exp Med 212:729-42|
|Zaslona, Zbigniew; Peters-Golden, Marc (2015) Prostanoids in Asthma and COPD: Actions, Dysregulation, and Therapeutic Opportunities. Chest 148:1300-1306|
|Wang, Zhuo; Filgueiras, Luciano Ribeiro; Wang, Soujuan et al. (2014) Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation. J Immunol 192:2349-56|
|Degraaf, Angela Juliette; Zas?ona, Zbigniew; Bourdonnay, Emilie et al. (2014) Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation. Am J Respir Cell Mol Biol 51:242-50|
|Brogliato, Ariane R; Moor, Andrea N; Kesl, Shannon L et al. (2014) Critical role of 5-lipoxygenase and heme oxygenase-1 in wound healing. J Invest Dermatol 134:1436-1445|
|Monteiro, Ana Paula T; Soledade, Erico; Pinheiro, Carla S et al. (2014) Pivotal role of the 5-lipoxygenase pathway in lung injury after experimental sepsis. Am J Respir Cell Mol Biol 50:87-95|
|Zas?ona, Zbigniew; Okunishi, Katsuhide; Bourdonnay, Emilie et al. (2014) Prostaglandin E? suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. J Allergy Clin Immunol 133:379-87|
|Zas?ona, Zbigniew; Przybranowski, Sally; Wilke, Carol et al. (2014) Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma. J Immunol 193:4245-53|
|O'Brien, E; Bergin, I L; Dolinoy, D C et al. (2014) Perinatal bisphenol A exposure beginning before gestation enhances allergen sensitization, but not pulmonary inflammation, in adult mice. J Dev Orig Health Dis 5:121-31|
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