Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces pulmonary inflammatory response in a rat model of endotoxemia.
OBJECTIVE
The effect of rosiglitazone, a potent peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, on pulmonary inflammation in endotoxemia was investigated.


METHODS
Male Wistar rats were given either lipopolysaccharide (LPS, 6 mg/kg i.v.) or saline, pretreated with rosiglitazone (0.3 mg/kg i.v.) or its vehicle (dimethyl sulphoxide) 30 min before LPS. The selective PPAR-gamma antagonist GW9662 (0.3 mg/kg i.v.) was given 20 min before rosiglitazone. Wet/dry weight (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) as well as TNF-alpha and CINC-1 concentrations were measured in lung tissues 4 h after LPS injection. Expression of ICAM-1, NF-kappaB p65 and PPAR-gamma were also determined by immunohistochemistry or Western blot analysis.


RESULTS
Rosiglitazone pretreatment significantly attenuated the increases in W/D ratio, MPO activity and MDA levels, and reduced pulmonary overproduction of TNF-alpha and CINC-1 as well as expression of ICAM-1 following endotoxemia. Rosiglitazone also inhibited the nuclear localization of NF-kappaB and up-regulated the expression of PPAR-gamma protein. The specific PPAR-gamma antagonist GW9662 abolished the effect of rosiglitazone.


CONCLUSIONS
These findings suggest that PPAR-gamma agonists might be used as therapeutic agents in the therapy of inflammatory lung injury related to endotoxemia.
Liu
D
D
Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. dongliu67@yahoo.com.cn
Zeng
B X
BX
Zhang
S H
SH
Yao
S L
SL
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents; D015153:Blotting, Western; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D019446:Endotoxemia / Q000473:pathology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000473:pathology*; D011654:Pulmonary Edema / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000893:Anti-Inflammatory Agents; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; D009195:Peroxidase