Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, reduces acute lung injury in endotoxemic rats.
OBJECTIVE
Rosiglitazone, a potent agonist of peroxisome proliferator-activated receptor (PPAR)-gamma, exerts anti-inflammatory effects in vitro and in vivo. This study was designated to determine the effects of rosiglitazone on endotoxin-induced acute lung injury in rats.


METHODS
Prospective, experimental study.


METHODS
University research laboratory.


METHODS
Thirty-six male Wistar rats.


METHODS
All the animals were randomly assigned to one of six groups (n = 6 per group) and were given either lipopolysaccharide (6 mg/kg intravenously) or saline, pretreated with rosiglitazone (0.3 mg/kg intravenously) or vehicle (10% dimethyl sulphoxide) 30 mins before lipopolysaccharide. The selective PPAR-gamma antagonist GW9662 (0.3 mg/kg intravenously) or its vehicle (10% dimethyl sulphoxide) was given 20 mins before rosiglitazone.


RESULTS
Endotoxemia for 4 hrs induced evident lung histologic injury and edema, both of which were significantly attenuated by rosiglitazone pretreatment. The protective effects of rosiglitazone were correlated with the reduction by 71% of the increase of myeloperoxidase activity and the reduction by 84% of the increase of malondialdehyde in the lung tissue. The pulmonary hyperproduction of nitric oxide was reduced by 82% of the increase related to lipopolysaccharide challenge. Pretreatment with rosiglitazone also markedly suppressed lipopolysaccharide-induced expression of inducible nitric oxide synthase messenger RNA and protein in the lung, as demonstrated by reverse transcription-polymerase chain reaction or Western blot analysis. Immunohistochemical analysis revealed that rosiglitazone inhibited the formation of nitrotyrosine, a marker for peroxynitrite reactivity, in the lung tissue. In addition, the specific PPAR-gamma antagonist GW9662 antagonized the effects of rosiglitazone.


CONCLUSIONS
This study provides evidence, for the first time, that the PPAR-gamma agonist rosiglitazone significantly reduces endotoxin-induced acute lung injury in rats.
Liu
Dong
D
Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Zeng
Bang-Xiong
BX
Zhang
Shi-Hai
SH
Wang
Yue-Lan
YL
Zeng
Lian
L
Geng
Zhi-Long
ZL
Zhang
Shi-Fan
SF
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D008070:Lipopolysaccharides; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; C482199:lipopolysaccharide, E coli O55-B5; D000077154:Rosiglitazone; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II