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Abstract
Idiopathic pulmonary fibrosis (IPF) is localized to the lung, is characterized by a pattern of heterogeneous, subpleural patches of fibrotic, remodeled lung, and is associated with a median survival of 3-5 years after diagnosis. A common gain-of-function MUC5B promoter variant, rs35705950, is the strongest risk factor (genetic and otherwise), accounting for at least 30% of the total risk of developing IPF. The MUC5B promoter variant can be used to identify individuals in the preclinical phase of this progressive disease, and, in the IPF lung, we have found that MUC5B is specifically overexpressed in bronchoalveolar epithelium. Thus, MUC5B represents a key molecule to understand the mechanisms that appear to initiate the fibroproliferative process in the bronchoalveolar epithelium. Moreover, focusing on MUC5B may provide a unique opportunity to define the early molecular events that lead to, and potentially prevent, the development of IPF.
Keywords: IPF; MUC5B; idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is localized to the lung, is characterized by a pattern of heterogeneous, subpleural patches of fibrotic, remodeled lung, and has a median survival of 3-5 years after diagnosis (1). IPF affects 5 million people worldwide, disproportionately affects men, is associated with cigarette smoking (2, 3), increases with age, is inexplicably increasing in prevalence (4, 5), and is likely underdiagnosed (4, 6). Although IPF takes years to develop, most patients with IPF are diagnosed in the advanced stage, and current therapies slow disease progression with little impact on overall survival (7, 8). Earlier diagnosis of IPF will detect subjects with a lower burden of fibrotic lung disease (9, 10), and may create the opportunity to predict and prevent the progression of pulmonary fibrosis before the lung has been irreversibly compromised by extensive scarring and fibrosis. The scientific premise of this presentation is based on recent data from our laboratories and others that inform an emerging understanding of IPF pathogenesis based on the early clinical phenotype of IPF that is linked to enhanced production of the mucin MUC5B in the bronchoalveolar epithelia. Based on these findings, we now propose to focus on the interaction of MUC5B, the airway epithelia, and repair/regeneration to define the biological signatures and biomarkers that will allow us to identify pulmonary fibrosis in its preclinical phase and enable us to...