Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-ß1 activity.

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-ß1 (TGF)-ß1 activity and TGF-ß1 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-ß1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

Corticosteroid-induced drug reaction with eosinophilia and systematic symptoms successfully treated with a tumor necrosis factor alpha inhibitor.

BACKGROUND: Despite recent advances in the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS), the mainstay of treatment involves discontinuing the culprit drugs and administering topical or systemic corticosteroid. OBJECTIVE: The clinical use of a tumor necrosis factor (TNF)-alpha inhibitor was rarely explored in treatment of DRESS. METHODS: We present a case of corticosteroid-induced DRESS that was successfully treated with a TNF-alpha inhibitor without sequalae. RESULTS: This is the first case report that showed the clinical use of a TNF alpha inhibitor in treating corticosteroids- induced DRESS and immediate hypersensitivity reactions. The HLA-B*5801 was identified as a possible genetic factor associated with a corticosteroid-induced DRESS. CONCLUSIONS: A TNF-alpha inhibitor could be a primary option in treating DRESS, especially in patients with hypersensitivity reaction to corticosteroids.