Effects of quercetin pretreatment on lung tissue damage,inflammatory/oxidative stress responses,ferroptosis,and Nrf2/HO-1 signaling pathway activation in ALI rats
Objective To observe the effects of quercetin pretreatment through intragastric administration on lung tissue injury,inflammatory response,oxidative stress response,ferroptosis,and the activation of the Nrf2/HO-1 signaling pathway in rats with lipopolysaccharide(LPS)-induced acute lung injury(ALI)in order to investigate quercetin's preven-tive effect and mechanism on ALI.Methods Twenty-four Sprague-Dawley rats were divided into the low-dose,medium-dose,and high-dose quercetin groups,positive control group(dexamethasone),model group,and normal control group,respectively.Rats in the low-dose,medium-dose,and high-dose quercetin groups received quercetin via gavage at doses of 25,50,and 100 mg/kg,respectively,once a day for 7 consecutive days.On the fourth day of quercetin treatment,5 mg/kg LPS was instilled into the trachea of the rats.Rats in the positive control group received dexamethasone at a dose of 1.04 mg/kg via gavage,following the same treatment regimen as the quercetin groups.Rats in the model group received normal saline via gavage once a day for 7 consecutive days,with the same additional treatments as the quercetin groups.Rats in the normal control group received normal saline via gavage for 7 consecutive days.After the final administration,lung tissue injury(lung function,pathological changes,positive expression rate of fibrous tissues,and apoptosis rate of al-veolar epithelial cells),inflammatory response[levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and in-terleukin-1β(IL-1β)]in bronchoalveolar lavage fluid,oxidative stress response[levels of superoxide dismutase(SOD),glutathione(GSH),malondialdehyde(MDA)in bronchoalveolar lavage fluid,and ROS in lung tissue],ferroptosis(Fe2+levels),and activation of the Nrf2/HO-1 signaling pathway[levels of nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),superoxide dismutase 2(SOD2),and catalase(CAT)proteins in lung tissues]were observed in each group.Results Compared with the normal control group,PaCO2 level increased,PaO2 and SaO2 levels de-creased,alveolar epithelial cells were degenerated and necrotic in lung tissues,the positive expression rate increased in fi-ber tissues,the apoptosis rate increased,the levels of TNF-α,IL-6,and IL-1β in alveolar lavage fluid increased,SOD and GSH levels decreased,MDA and Fe2+levels increased,and ROS levels in lung tissues increased in the model group(all P<0.01).Compared with the model group,PaCO2 in the medium-dose and high-dose quercetin groups and positive control group decreased(all P<0.05),and PaO2 and SaO2 levels increased in the high-dose quercetin group(all P<0.05);the inflammatory infiltration and fibrous hyperplasia of lung tissue were significantly reduced in the high-dose quer-cetin group and positive control group,and the physiological structure of the alveolar was restored to normal;the positive fi-ber expression rates of the low-,medium-,and high-dose quercetin groups and the positive control group decreased(all P<0.05)with the lowest positive fiber expression rate in the high-dose quercetin group;the apoptosis rates decreased(all P<0.01),the levels of TNF-α,IL-6,and IL-1β in alveolar lavage fluid decreased,the levels of SOD and GSH increased,the levels of MDA and Fe2+decreased,and the levels of ROS decreased in the low-,medium-,and high-dose quercetin groups and positive control group(all P<0.01).Compared with the normal control group,the protein expression levels of CAT,HO-1,Nrf2,and SOD2 in the lung tissues of the model group were lower(all P<0.01);compared with the model group,the protein expression levels of CAT,HO-1,Nrf2,and SOD2 in the lung tissues of the medium-dose and high-dose quercetin groups and the positive control group were higher(all P<0.05).Conclusions Quercetin pretreatment via ga-vage reduces lung tissue injury,inflammatory response,oxidative stress response,and ferroptosis,and activates the Nrf2/HO-1 signaling pathway in rats with LPS-induced ALI.Quercetin pretreatment can prevent LPS-induced ALI in rats,possi-bly by inhibiting inflammatory response,oxidative stress response,and ferroptosis,and the protective effects of quercetin may be mediated through up-regulation of the Nrf2/HO-1 signaling pathway.Both 50 mg/kg and 100 mg/kg doses of quer-cetin can effectively prevent LPS-induced ALI in rats,with the better effect in the 100 mg/kg dose.
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