Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in rats

Abstract

Aim: 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.

Conclusion: Pretreatment with rosiglitazone protects rats against PQ-induced acute lung injury by activating PPAR-γ, inducing Nrf2 expression and inhibiting NF-κB activation.

Figure 1

Cumulative poisoning rate of rats exposed to paraquat (PQ) at different doses and different time points. Rats were intraperitoneally administered of PQ at the doses of 10, 20, 30, 40, and 50 mg/kg. Cumulative poisoning rate was observed at different time points (4, 8, 24, 72, and 168 h) after the administration of PQ.

Figure 2

Cumulative mortality of rats exposed to paraquat (PQ) at different doses and different time points. Rats were intraperitoneally administered PQ at the doses of 10, 20, 30, 40, and 50 mg/kg. Cumulative mortality was observed at different time points (4, 8, 24, 72, and 168 h) after the administration of PQ.

Figure 3

Effects of rosiglitazone on lung W/D ratio and histopathological changes in lung tissues of paraquat (PQ)-induced acute lung injury rats. Rosiglitazone was intraperitoneally administered 1 h before intraperitoneal administration of PQ. The lung W/D ratio (A, B) and lung histological evaluation (C, D, HE staining, 100×) was determined after PQ administration for 72 h. RSGL: rosiglitazone at the low dose of 3 mg/kg, RSGH: rosiglitazone at the high dose of 10 mg/kg. The values presented are the mean±SD (n=6). ^bP<0.05 vs PQ group.

Figure 4

Effects of rosiglitazone on the cytokine production, SOD activity and MDA level, in peripheral blood of PQ-induced acute lung injury rats. Rosiglitazone was intraperitoneally administered 1 h before intraperitoneal administration of PQ. Peripheral blood was collected after PQ administration for 4, 8, 24, and 72 h to analyze MDA level and SOD activity (A, B), levels of IL-1β and TNF-α (C, D). RSGL: rosiglitazone at the dose of 3 mg/kg, RSGH: rosiglitazone at the dose of 10 mg/kg. The values presented are the mean±SD (n=6). ^bP<0.05 vs PQ group.

Figure 5

Effects of rosiglitazone on Nrf2, PPAR-γ, and NF-κB signal transduction in lung tissues of paraquat (PQ)-induced acute lung injury rats. Rosiglitazone was intraperitoneally administered 1 h before intraperitoneal administration of PQ. Lung tissue was collected after PQ administration for 72 h, to determine the expression of Nrf2, PPAR-γ, and NF-κBp65 by immunohistochemistry (C, ×400) and Western blotting (A), IκB-α and pIκB-α by Western blotting (B). RSGL: rosiglitazone at the dose of 3 mg/kg, RSGH: rosiglitazone at the dose of 10 mg/kg. The values presented are the mean±SD (n=5). ^bP<0.05 vs PQ group.