title: N-acetylcysteine downregulation of lysyl oxidase activity alleviating bleomycin-induced pulmonary fibrosis in rats.
abstract: 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.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Li
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
authors.forename: Wande
authors.initials: W
authors.lastname: Li
authors.forename: Jingjie
authors.initials: J
authors.lastname: Li
authors.forename: Xingwen
authors.initials: X
authors.lastname: Su
authors.forename: Lijun
authors.initials: L
authors.lastname: Chen
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D001761:Bleomycin / Q000009:adverse effects; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D008249:Protein-Lysine 6-Oxidase / Q000187:drug effects / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D000111:Acetylcysteine; D000199:Actins; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D003094:Collagen; D016166:Free Radical Scavengers; D005978:Glutathione; D008249:Protein-Lysine 6-Oxidase; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat