6-aminonicotinamide ameliorates pulmonary fibrosis by suppressing the TGF-beta1 activated Smad signalling pathway

Introduction: Pentose phosphate (PP) pathway is one of the major metabolic pathways associated with glucose metabolism. Glucose 6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of PP pathway and its function is inhibited by 6-aminonicotinamide (6-AN). Aim: To assess the role of the PP pathway in idiopathic pulmonary fibrosis (IPF). Methods: The metabolites of PP pathway were analyzed with Agilent 7890/5975 GC/MSD system and HP-5 MS column in the human lung tissues ( IPF = 31, control=20 ). The function of 6-AN was evaluated in vitro and in vivo models of pulmonary fibrosis. Results: The levels of PP pathway metabolites in IPF lung tissues were significantly elevated than those in control lung tissues. 6-AN and G6PD specific siRNA reduced TGF -beta 1 induced protein expression levels of fibrotic markers in fibroblasts. In addition, 6-AN decreased the TGF -beta 1 induced mRNA and protein expression levels of EMT factor in Beas-2b cells. In bleomycin treated mice, 6-AN also decreased levels of hydroxyproline in the lung compared to that of control mice (Figure). Conclusions: Our findings indicate that inhibition of G6PD may have anti-fibrotic effects on pulmonary fibrosis, suggesting that G6PD is implicated as a potential therapeutic target in IPF. Figure: Comparison of hydroxyproline levels in the bleomycin induced lung fibrosis mouse model according to the treatment