Alleviation of Acute Lung Injury in Rats with Sepsis by Resveratrol via the Phosphatidylinositol 3-Kinase/Nuclear Factor-Erythroid 2 Related Factor 2/Heme Oxygenase-1 (PI3K/Nrf2/HO-1) Pathway

Abstract

BACKGROUND Resveratrol (Res) is a type of polyphenol found in many plants, which can protect important organs from the damage induced by sepsis. However, the exact mechanism of its protective effect has not been established. This study investigated the effect of Res on the PI3K/Nrf2/HO-1 signaling pathway in rats with sepsis-induced acute lung injury (ALI). MATERIAL AND METHODS Male Wistar rats were treated with 30 mg/kg Res by intraperitoneal administration for 1 hour immediately after cecal ligation and puncture. Levels of MIP-2, IL-18, and IL-10 in bronchoalveolar lavage fluid (BALF) were determined. Lung tissues were collected to measure the wet-to-dry (W/D) ratios, oxidative stress index, and lung injury scores. Expression levels of Akt, p-Akt, HO-1, Nrf-2, and active caspase-3 proteins were determined by western blotting; expression of HO-1 mRNA was determined by RT-PCR. RESULTS Treatment with Res significantly decreased the levels of MIP-2 and IL-18 and increased IL-10 in the BALF of rats with sepsis-induced ALI. In addition, Res also effectively reduced the W/D lung weight ratio, lung injury score, and the levels of MDA (malondialdehyde) and 8-OHdG. Conversely, Res increased SOD (superoxide dismutase) activity in the lung tissue. Moreover, Res significantly induced higher HO-1 mRNA expression, upregulated HO-1 and Nrf-2 protein expression, and the phosphorylation of Akt in the lung tissue. In contrast, the levels of activated caspase-3 protein were decreased in Res-treated rats (P<0.05). CONCLUSIONS Res could inhibit inflammation, oxidative stress, and cell apoptosis to alleviate ALI in septic rats through the inhibition of the PI3K/Nrf2/HO-1 signaling pathway.

Figure 1

Resveratrol decreased the MIP-2 and IL-18 levels and increased the IL-10 levels in the BALF of rats with CLP-induced acute lung injury. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01. BALF – bronchoalveolar lavage fluid; CLP – cecal ligation and puncture.

Figure 2

Resveratrol reduced MDA and 8-OHdG levels and increased SOD activity in lung tissues. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01. MDA – malondialdehyde; SOD – superoxide dismutase.

Figure 3

Resveratrol reduced the lung wet-to-dry ratio in rats with CLP-induced acute lung injury. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01. CLP – cecal ligation and puncture.

Figure 4

Resveratrol ameliorated the histopathological changes in the lung tissues of rats with CLP-induced acute lung injury. (A) Photomicrograph of lung tissue from a sham rat. (B) Photomicrograph of lung tissue from a septic rat. (C) Photomicrograph of lung tissue from a septic rat treated with resveratrol. (D) Histopathologic scoring of lung injury in the 3 groups. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01. CLP – cecal ligation and puncture.

Figure 5

Resveratrol upregulates HO-1mRNA expression in rats with sepsis-induced acute lung injury. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01.

Figure 6

Resveratrol significantly upregulated HO-1 and Nrf-2 protein expression and increased Akt phosphorylation in rats with sepsis-induced acute lung injury. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01.

Figure 7

Resveratrol significantly decreased the expression of activated caspase-3 in rats with sepsis-induced acute lung injury. Data are presented as the mean ±SD (n=10 for each group). * P≤0.05, ** P≤0.01.