Cigarette smoke impairs Fatty Acid Binding Protein 5-mediated resolution of inflammation in COPD exacerbations

Abstract

COPD global prevalence continues to rise, indicating an urgent need for more effective therapies. Although cigarette smoking (CS) is the cardinal risk factor for COPD, repeated and sustained infections are clearly linked to disease pathogenesis and are responsible for acute inflammatory flares (i.e. COPD 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. One of the hallmarks of normal inflammatory resolution is an influx of mononuclear phagocytes to the site of inflammation to clear up debris and engulf apoptotic cells. How their recruitment and function are altered in COPD is still a matter of debate. Using integrated genetic and genomic approaches, we have identified Fatty Acid Binding Protein 5(FABP5) as a key player for the resolution of inflammation. Our studies indicate impaired apoptotic cell engulfment by alveolar macrophagesand reduced mononuclear phagocyte recruitment following bacterial infection in FABP5-/-mice. Although the importance of PPAR? in macrophage reprogramming is well described, we have evidence that FABP5 is upstream of PPAR? activity and that in turn, as a positive feedback loop, PPAR? increases FABP5 expression. The clinical significance of these findings is supported by decreased FABP5 mRNA and protein levels as well as PPAR? activity in peripheral blood mononuclear cells of COPD patients, especially among those who reported exacerbations, and by the discovery of new SNPs in the FABP5 gene that are associated with severe exacerbations.