Role of lung ornithine aminotransferase in Idiopathic Pulmonary Fibrosis: regulation of mitochondrial ROS generation and TGF-β1 activity

AbstractIdiopathic pulmonary fibrosis (IPF) exhibits aberrant lung remodeling that is characterized by excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that levels of ornithine aminotransferase (OAT), a principal enzyme of the proline metabolic pathway, were elevated in the lungs of patients with IPF. However, the precise role played by OAT in IPF pathogenesis is not yet clear. The mechanism by which OAT affected fibrogenesis was assessedin vitrousing lung fibroblasts overexpressing and knockdown of OAT. The therapeutic effects of OAT inhibition were assessed in the lungs of mice treated with bleomycin. OAT expression was increased in fibrotic areas, principally interstitial fibroblasts, of the IPF lung. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level > 75.659 ng/mL than in the group with an OAT level ≤ 75.659 ng/mL (HR, 29.53;p = 0.0008). OAT overexpression and knockdown respectively increased and decreased ECM component production by lung fibroblasts. OAT knockdown also inhibited transforming growth factor-β1 (TGF)-β1 activity and TGF-β1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, Increased OAT levels in the lung in IPF contributes to fibrotic progression via excessive mitochondrial ROS production that upregulates TGF-β1 signaling. OAT may be a useful therapeutic target in patients with fibrotic lung disease including IPF.