Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Acta Pharmacol Sin. 2013 Oct;34(10):1317-24. doi: 10.1038/aps.2013.65. Epub 2013 Aug 12.
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.
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.
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.
Pretreatment with rosiglitazone protects rats against PQ-induced acute lung injury by activating PPAR-γ, inducing Nrf2 expression and inhibiting NF-κB activation.
研究过氧物酶体增殖物激活受体-γ（PPAR-γ）激动剂罗格列酮对百草枯（PQ）诱导的急性肺损伤的影响及其作用机制。
雄性 Sprague-Dawley 大鼠腹腔注射 PQ（20mg/kg）。在暴露于 PQ 前 1 小时给予罗格列酮（3 或 10mg/kg，腹腔注射）。在 PQ 暴露后 4、8、24 和 72 小时采集外周血，以测量 MDA、TNF-α和 IL-1β的水平以及 SOD 活性。在 PQ 暴露后 72 小时采集肺组织，以确定干湿比（W/D）和肺损伤评分，以及 NF-κBp65、PPAR-γ、Nrf2、IκBα 和 pIκBα 的蛋白水平。
在 PQ 暴露后 72 小时，未治疗的大鼠出现 100%的累积死亡率，而罗格列酮预处理的大鼠未观察到死亡。此外，罗格列酮预处理呈剂量依赖性减轻 PQ 诱导的肺水肿和肺组织病理学改变。预处理显著降低了 PQ 处理大鼠外周血中 TNF-α、IL-1β 和 MDA 的水平，增加了 SOD 活性。预处理还能有效激活 PPAR-γ，诱导 Nrf2 的表达，抑制 PQ 处理大鼠肺组织中 NF-κB 的激活。此外，预处理呈剂量依赖性抑制 IκB-α 的降解和磷酸化，从而抑制 NF-κB 的激活。
罗格列酮预处理通过激活 PPAR-γ、诱导 Nrf2 的表达和抑制 NF-κB 的激活，对 PQ 诱导的急性肺损伤大鼠具有保护作用。
