title: N-acetylcysteine inhibits RhoA and promotes apoptotic cell clearance during intense lung inflammation.
abstract: BACKGROUND
  The resolution of pulmonary inflammation seen in various inflammatory lung conditions depends on the clearance of apoptotic cells to prevent permanent tissue damage or progressive disease. Uptake of apoptotic cells by alveolar macrophages is suppressed by oxidants through the activation of Rho signaling.
  
  
  OBJECTIVE
  We hypothesized that antioxidant exposure would increase the ability of alveolar macrophages to clear pulmonary apoptotic cells through the inhibition of RhoA.
  
  
  METHODS
  The effects of the antioxidant N-acetylcysteine (NAC) on the pulmonary immune response were seen in mice treated intratracheally with LPS, LPS + NAC, or saline. Apoptotic cell clearance, RhoA activity, and changes in the lung inflammatory responses were analyzed in vivo or ex vivo.
  
  
  RESULTS
  Neutrophil accumulation, apoptosis, necrosis, and oxidant production peaked at 3 days post LPS treatment. NAC enhanced the clearance of apoptotic cells and inhibited RhoA activity in alveolar macrophages at 3 days post LPS treatment. NAC suppressed LPS-induced proinflammatory mediators, enhanced the production of transforming growth factor-beta1, reduced the accumulation of inflammatory cells, and reduced levels of protein and lactate dehydrogenase in bronchoalveolar lavage fluid. In the presence of ex vivo apoptotic cells, alveolar macrophages exposed to LPS or LPS + NAC had reduced tumor necrosis factor-alpha levels and increased transforming growth factor-beta1 levels. A Rho kinase inhibitor mimicked the effects of NAC on the clearance of apoptotic cells and the inflammatory responses.
  
  
  CONCLUSIONS
  These results indicate that NAC can expedite the resolution of LPS-induced pulmonary inflammation through the inhibition of RhoA activity and the enhancement of apoptotic cell clearance.
authors: Department of Physiology, School of Medicine, Ewha Womans University 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-056, Korea. jihee@ewha.ac.kr
authors: Changsuk
authors: C
authors: Moon
authors: Ye-Ji
authors: YJ
authors: Lee
authors: Hyun-Jeong
authors: HJ
authors: Park
authors: Young H
authors: YH
authors: Chong
authors: Jihee Lee
authors: JL
authors: Kang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology; D011014:Pneumonia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000975:Antioxidants; D016328:NF-kappa B; D011725:Pyridines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C066737:RHOA protein, human; C108830:Y 27632; D007770:L-Lactate Dehydrogenase; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000111:Acetylcysteine