Quercetin as a therapeutic agent activate the Nrf2/Keap1 pathway to alleviate lung ischemia-reperfusion injury

Abstract

Lung ischemia-reperfusion injury (LIRI) causes oxidative stress, inflammation, and immune system activation. The Nrf2/Keap1/HO-1 pathway is important in cellular defense against these effects. Quercetin, a flavonoid with antioxidant, anti-inflammatory, and anti-cancer properties, has been investigated. Our aim in this study was to investigate the effect of quercetin on preventing lung ischemia-reperfusion injury and the role of the Nrf2/Keap1/HO-1 pathway. Sixty-four male Wistar rats were divided into four distinct groups(n = 16). Sham, lung ischemia-reperfusion (LIR), Saline + LIR, Quercetin + LIR (30 mg/kg i.p for a week before LIR). LIR groups were subjected to 60 min of ischemia (left pulmonary artery, vein, and bronchus) and 120 min of reperfusion. Our assessment encompassed a comprehensive analysis of various factors, including the evaluation of expression Nrf2, Keap1, and Heme Oxygenase-1 (HO-1) levels and NF-κB protein. Furthermore, we examined markers related to inflammation (interleukin-1β and tumor necrosis factor alpha), oxidative stress (malondialdehyde, total oxidant status, superoxide dismutase, glutathione peroxidase, total antioxidant capacity), lung edema (Wet/dry lung weight ratio and total protein concentration), apoptosis (Bax and Bcl2 protein), and histopathological alterations (intra-alveolar edema, alveolar hemorrhage, and neutrophil infiltration). Our results show that ischemia-reperfusion results in heightened inflammation, oxidative stress, apoptosis, lung edema, and histopathological damage. Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.

Keywords: Inflammation; Lung ischemia-reperfusion injury; Nrf2/Keap1 pathway; Oxidative stress; Quercetin.

Fig. 1

The effects of quercetin on wet-to-dry weight ratio(n = 6) and total protein content)n = 4). The data was presented as means ± SEM. BALF bronchoalveolar lavage fluid, Sh sham group, LIR lung ischemia-reperfusion group, Veh vehicle group, Que quercetin group. * P < 0.05, *** P < 0.001.

Fig. 2

The effects of quercetin on oxidative stress and inflammation factors in lung tissue. The data was presented as means ± SEM, (n = 6). Sh sham group, LIR lung ischemia-reperfusion group, Veh vehicle group, Que quercetin group. *** P < 0.001.

Fig. 3

The effect of quercetin on the expression of Bax, Bcl2, NF-κB, Nrf2, HO-1 and Keap1 proteins in lung tissue. The data was presented as means ± SEM, (n = 6). Sh sham group, LIR lung ischemia-reperfusion group, Veh vehicle group, Que quercetin group. * P < 0.05, ** P < 0.01, *** P < 0.001.

Fig. 4

Histopathological images depicting the effects of intraperitoneal administration of quercetin on histopathological indices of lung tissue(n = 6). Magnification 10X. Sh sham group, LIR lung ischemia-reperfusion group, Veh vehicle group, Que quercetin group. *** P < 0.001.