BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine (NAC) added to prednisone and azathioprine has been found to improve lung function in IPF patients, though the mechanism of action remains poorly understood. OBJECTIVE: Based on our previous findings showing elevation of glutathione (GSH) content associated with downregulation of lysyl oxidase (LOX) activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates IPF by regulating LOX function. METHODS: We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-β(1) (TGF-β(1)) and α-smooth muscle actin (α-SMA) expression in bleomycin (BLM)-induced pulmonary fibrosis in a rat model. Then, we focused our studies on NAC modulation of LOX activity. RESULTS: LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-β(1) protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated pulmonary fibrosis and inhibited TGF-β(1) and α-SMA expression in this model. CONCLUSIONS: Our study supports a novel mechanism of NAC alleviating IPF by inhibition of LOX activity via elevation of lung GSH in BLM-induced pulmonary fibrosis. The TGF-β(1)/α-SMA pathway may also play an important role in modulation of LOX activity.
BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine (NAC) added to prednisone and azathioprine has been found to improve lung function in IPF patients, though the mechanism of action remains poorly understood. OBJECTIVE: Based on our previous findings showing elevation of glutathione (GSH) content associated with downregulation of lysyl oxidase (LOX) activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates IPF by regulating LOX function. METHODS: We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-β(1) (TGF-β(1)) and α-smooth muscle actin (α-SMA) expression in bleomycin (BLM)-induced pulmonary fibrosis in a rat model. Then, we focused our studies on NAC modulation of LOX activity. RESULTS:LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-β(1) protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated pulmonary fibrosis and inhibited TGF-β(1) and α-SMA expression in this model. CONCLUSIONS: Our study supports a novel mechanism of NAC alleviating IPF by inhibition of LOX activity via elevation of lung GSH in BLM-induced pulmonary fibrosis. The TGF-β(1)/α-SMA pathway may also play an important role in modulation of LOX activity.
Authors: Victor J Thannickal; Craig A Henke; Jeffrey C Horowitz; Paul W Noble; Jesse Roman; Patricia J Sime; Yong Zhou; Rebecca G Wells; Eric S White; Daniel J Tschumperlin Journal: Am J Pathol Date: 2014-04-13 Impact factor: 4.307
Authors: Long Shuang Huang; Biji Mathew; Haiquan Li; Yutong Zhao; Shwu-Fan Ma; Imre Noth; Sekhar P Reddy; Anantha Harijith; Peter V Usatyuk; Evgeny V Berdyshev; Naftali Kaminski; Tong Zhou; Wei Zhang; Yanmin Zhang; Jalees Rehman; Sainath R Kotha; Travis O Gurney; Narasimham L Parinandi; Yves A Lussier; Joe G N Garcia; Viswanathan Natarajan Journal: Am J Respir Crit Care Med Date: 2014-06-01 Impact factor: 21.405