Treatment of pulmonary fibrosis through normalization of alveolar macrophages

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronically advanced interstitial lung disease with unclear etiology and poor prognosis. Despite numerous studies, the pathogenesis of IPF has not been completely understood. In this study, we searched for a drug that can decrease chronic lung inflammation without deteriorating lung fibrosis. We found that fenofibrate, a PPARα agonist that is clinically used to control dyslipidemia, had therapeutic effects on pulmonary fibrosis through normalization of alveolar macrophages. We first showed that 6 days of oral administration of fenofibrate blocked the progression of bleomycin-induced pulmonary fibrosis and resolved inflammation. In addition, fenofibrate suppressed the LPS-induced pro-inflammatory mediators in bone marrow-derived macrophages in a PPARα-independent manner; however, it promoted the expression of tissue repair and anti-inflammatory genes. Finally, we examined the expression of the pro-inflammatory, tissue-repair, and anti-inflammatory genes in alveolar macrophages at days 2 or 6 after oral administration of fenofibrate in mice with advancing pulmonary fibrosis. Administration of fenofibrate resulted in decreased expression of proinflammatory cytokines and increased expression of tissue repair and anti-inflammatory genes at day 2. However, the gene expression pattern of alveolar macrophages of fenofibrate-treated mice at day 6 became similar to that of naïve alveolar macrophages. Taken together, this study suggests that fenofibrate can rapidly reprogram inflammatory macrophage polarization toward normal state through a transient resolving and anti-inflammatory macrophage polarization stage, which is linked to amelioration of pulmonary fibrosis.