Attenuation of pulmonary inflammation after exposure to blast overpressure by N-acetylcysteine amide.
Lung contusion is a common problem from blunt chest trauma caused by mechanical forces and by exposure to blast overpressure, often with fatal consequences. Lung contusion is also a risk factor for the development of pneumonia, severe clinical acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Infiltrating neutrophils are considered to be central mediators of lung injuries after blunt trauma. Recent studies have demonstrated that antioxidants reduced pulmonary inflammation in different models of lung damage. This study examined the effect of antioxidant N-acetylcysteine amide (NACA) on the progression of lung inflammation after exposure to a moderate level of blast overpressure (140 kPa). Rats were administered with NACA (i.p. 100 mg/kg) or placebo (PBS) 30, 60 min and 24 h after exposure. Nonblasted sham-injected animals served as controls. Neutrophil infiltration measured by myeloperoxidase (MPO) activity in the lung was significantly increased at 2 days after blast and returned to controls at 8 days. This increase corresponded with activation of integrin CD11b mRNA and lung inflammatory chemokine mRNA expression; macrophage inflammatory protein-1 (MIP-1), monocyte chemotactic peptide-1 (MCP-1), and cytokine-induced neutrophil chemoattractant-1 (CINC-1). At 8 days, all inflammatory mediators returned to control levels. In addition, expression of heme oxygenase-1 (HO-1) mRNA increased at 2 days after exposure. No changes were detected in the lung manganase superoxide dismutase (MnSOD) or glutathione reductase (GR) mRNA expression after blast. N-Acetylcysteine amide significantly reduced infiltration of neutrophils and CD11b mRNA activation in lungs, and completely blocked activation of MIP-1, MCP-1 and CINC-1 mRNA. The relatively higher inhibition of chemokine mRNAs compared with reduction in MPO activity and CD11b is in accordance with an antioxidant effect of NACA on reactive oxygen species (ROS) accumulation, rather than by an effect on neutrophil sequestration. The inhibition of HO-1 mRNA activation after blast was likely also related to the drug antioxidant effect.
Chavko
Mikulas
M
Trauma and Resuscitative Medicine Department, Naval Medical Research Center, Silver Spring, MD 20910-7500, USA. Mikulas.Chavko@med.navy.mil
Adeeb
Saleena
S
Ahlers
Stephen T
ST
McCarron
Richard M
RM
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D039481:CD11b Antigen / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics; D005980:Glutathione Reductase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000378:metabolism; D055370:Lung Injury / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008297:Male; D020556:Neutrophil Infiltration / Q000276:immunology / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics
D000975:Antioxidants; D039481:CD11b Antigen; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D019402:Macrophage Inflammatory Proteins; C487056:N-Acetylcysteinamide; D009195:Peroxidase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D000111:Acetylcysteine