In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation.
We hypothesized that endotoxin injection in rats would stimulate in vivo nuclear factor-kappa B (NF-kappa B) activation in lung tissue and that antioxidant treatment before endotoxin injection would attenuate endotoxin-induced NF-kappa B activation, chemokine gene expression, and neutrophilic lung inflammation. We studied NF-kappa B activation in rat lung tissue following a single i.p. injection of endotoxin (6 mg/kg). After in vivo endotoxin treatment, lung NF-kappa B activation peaked at 2 h and temporally correlated with the expression of cytokine-induced neutrophil chemoattractant mRNA in lung tissue. Treatment with the antioxidant N-acetylcysteine (NAC) 1 h before endotoxin resulted in decreased lung NF-kappa B activation in a dose-dependent manner (from 200-1000 mg/kg) and diminished cytokine-induced neutrophil chemoattractant mRNA expression in lung tissue. Treatment with NAC significantly suppressed endotoxin-induced neutrophilic alveolitis. The average total lung lavage neutrophil count was 5.5 x 10(6) with endotoxin treatment vs 0.9 x 10(6) with NAC treatment before endotoxin. The NF-kappa B pathway represents an attractive therapeutic target for strategies to control neutrophilic inflammation and lung injury.
Blackwell
T S
TS
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 27232, USA.
Blackwell
T R
TR
Holden
E P
EP
Christman
B W
BW
Christman
J W
JW
D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015237:Dinoprost / Q000031:analogs & derivatives / Q000096:biosynthesis; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004731:Endotoxins / Q000633:toxicity*; D028441:F2-Isoprostanes; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis / Q000235:genetics; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy; D018805:Sepsis / Q000139:chemically induced / Q000150:complications
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004731:Endotoxins; D028441:F2-Isoprostanes; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D005978:Glutathione; D000111:Acetylcysteine