Fungal Translocation in Chronic Obstructive Pulmonary Disease

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PROJECT SUMMARY Although smoking is a leading risk factor for chronic obstructive pulmonary disease (COPD), other factors likely contribute to disease pathogenesis since only a subset of smokers develop COPD. Tissue hypoxia related to acute exacerbations or physical activity impairs gut epithelial barrier function in COPD and may result in microbial translocation, or movement of microbes or microbial products across the intestinal mucosa. Once in circulation, these microbial products may cause immune cell activation or direct lung injury, augmenting inflammation and lung function decline in patients with COPD. Although studies of microbial translocation have largely focused on the translocation of bacteria, we have preliminary data suggesting that fungal translocation occurs in smokers and may contribute to COPD pathogenesis. We show that 1,3 beta-d-glucan (BDG), a pattern associated molecular pattern that is a major polysaccharide component of the fungal cell wall, is elevated in COPD patients in the absence of invasive fungal infection and correlates with lung function, symptoms, and exacerbations. In vitro, BDG increases lung epithelial cell expression of inflammatory cytokines involved in the pathogenesis of COPD. With this project, we will test the overarching hypothesis that impaired gut epithelial barrier integrity in COPD patients leads to fungal microbial translocation that contributes to lung function decline and worse respiratory morbidity through heightened immune cell activation and direct lung pathogenic effects. Aim 1 will assess the relationship between gut epithelial barrier integrity measured by the lactulose/mannitol differential sugar absorption test, lung function, respiratory morbidity (symptoms, exacerbations), and circulating BDG levels in a cohort of current and former smokers with COPD. Aim 2 will determine the association between circulating BDG levels, immune cell activation, prospective exacerbations, and two-year change in lung function, symptoms, and CT indices of emphysema and airways in COPD. Aim 3 will determine whether BDG increases cytokine expression and secreted protein levels by binding to the lung epithelial cell pattern recognition receptors Dectin- 1 and EphA2 in human bronchial epithelial cells in vitro, and if this effect is potentiated by co-exposure to cigarette smoke. Aim 3 will also investigate if BDG effects on cytokine expression and secreted protein levels are attenuated by treatment with metformin. At the completion of this project, we will have gained critical insight into the role of microbial translocation in COPD pathogenesis and will have built the foundation for future clinical trials targeting the gut-lung axis by either improving gut epithelial barrier function, blocking BDG’s actions, or modulating BDG’s downstream effects as a novel approach to therapy in COPD.