PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the United States and its global prevalence continues to rise due to lack of an effective cure. Although cigarette smoke (CS) is by far the most important risk factor of COPD, repeated and sustained infections are clearly linked to disease pathogenesis (e.g., exacerbations). Interestingly, COPD exacerbations are a risk factor for having more exacerbations, suggesting that a vicious cycle of ineffective resolution of inflammation predisposes individuals for future episodes. Thus, identifying patients likely to have recurrent exacerbations may allow early implementation of appropriate preventive strategies and would be an important new approach in the treatment of the disease. We have discovered that Fatty Acid Binding Protein 5 (FABP5) is important for the resolution of inflammation. However we do not fully comprehend the mechanisms behind FABP5 protective role in COPD exacerbations. In this proposal we will focus on FABP5 in mononuclear phagocytes because these cells are at the center of the processes required for the resolution of inflammation, including engulfment of apoptotic cells and activation of anti-inflammatory nuclear receptors such as Peroxisome Proliferator-Activated Receptor γ (PPARγ). Our preliminary studies indicate impaired apoptotic cell engulfment by alveolar macrophages and reduced monocyte recruitment following bacterial infection in FABP5-/- mice. In addition, FABP5-/- mice have increased bacterial and viral-induced lung inflammation, compared to wild type (WT) mice. The clinical significance of these findings is supported by decreased FABP5 mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) of COPD patients, especially among those with a history of episodes of bronchitis, pneumonia or COPD exacerbations and by the discovery of new SNPs in the FABP5 gene that are associated with severe exacerbations. We hypothesize that decreased FABP5 following CS exposure worsens infection- induced lung inflammation by preventing mononuclear lung phagocyte reprogramming, which is necessary for resolution of lung inflammation in COPD exacerbations. To test this hypothesis, we propose 3 specific aims. Under specific aim 1, we will test the hypothesis that CS impairs FABP5-mediated mononuclear lung phagocytes recruitment and efferocytosis. Using WT, FABP5-/- or FABP5-/- mice complemented with FABP5 in mononuclear phagocytes we will determine how FABP5 expression affects mononuclear phagocyte recruitment in response to infection in the presence or absence of CS. We will also determine how FABP5 expression affects mononuclear phagocyte engulfment capabilities following CS and/or infection in vivo and in vitro. Under aim 2, we will test the hypothesis that FABP5/PPARγ interaction is necessary to promote resolution of inflammation and return to homeostasis and determine whether CS impairs this interaction. We will manipulate FAB...