Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-β1 activity

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. 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 increased and decreased ECM component production by lung fibroblasts, respectively. 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 lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-β1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

Targeting OAT: a potential therapeutic pathway for fibrotic lung disease

Idiopathic pulmonary fibrosis (IPF, a chronic lung disease marked by excessive buildup of extracellular matrix or ECM, substances that provide structural support to cells, in the lungs) is still not fully understood, especially the role of ornithine aminotransferase (OAT, an enzyme that helps convert ornithine into proline). This study found that OAT was more present in the lungs of IPF patients, especially in areas with severe fibrotic (excessive tissue) remodeling. Increased OAT led to more fibroblast (cells that produce collagen and other fibers) growth, while less OAT reduced it. The study concluded that high OAT levels in IPF lungs contribute to fibrosis progression by enhancing TGF-β1 (a protein that controls cell growth and division) activity and increasing mitochondrial ROS generation. The findings suggest that stopping OAT may reduce fibrosis, offering a potential new treatment for IPF. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.