Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in rats.
OBJECTIVE
To investigate the effects of the PPAR-γ agonist rosiglitazone on acute lung injury induced by the herbicide paraquat (PQ) and the underlying mechanisms of action.


METHODS
Male Sprague-Dawley rats were injected with PQ (20 mg/kg, ip). Rosiglitazone (3 or 10 mg/kg, ip) was administered 1 h before PQ exposure. Peripheral blood was collected at 4, 8, 24 and 72 h after PQ exposure for measuring the levels of MDA, TNF-α and IL-1β, and the SOD activity. Lung tissues were collected at 72 h after PQ exposure to determine the wet-to-dry (W/D) ratios and lung injury scores, as well as the protein levels of NF-κBp65, PPAR-γ, Nrf2, IκBα and pIκBα.


RESULTS
At 72 h after PQ exposure, the untreated rats showed a 100% cumulative mortality, whereas no death was observed in rosiglitazone-pretreated rats. Moreover, rosiglitazone pretreatment dose-dependently attenuated PQ-induced lung edema and lung histopathological changes. The pretreatment significantly reduced the levels of TNF-α, IL-1β and MDA, increased SOD activity in the peripheral blood of PQ-treated rats. The pretreatment also efficiently activated PPAR-γ, induced Nrf2 expression and inhibited NF-κB activation in the lung tissues of PQ-treated rats. Furthermore, the pretreatment dose-dependently inhibited IκB-α degradation and phosphorylation, thus inhibiting NF-κB activation.


CONCLUSIONS
Pretreatment with rosiglitazone protects rats against PQ-induced acute lung injury by activating PPAR-γ, inducing Nrf2 expression and inhibiting NF-κB activation.
Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Zhen-Ning
ZN
Liu
Min
M
Zhao
Qiang
Q
Zheng
Hong-Yu
HY
Zhao
Wei-Jian
WJ
Hou
Shu-Ling
SL
Bai
D055371:Acute Lung Injury / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000633:toxicity; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010269:Paraquat / Q000633:toxicity*; D011654:Pulmonary Edema / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013482:Superoxide Dismutase / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D006540:Herbicides; D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D010269:Paraquat