Chronic Lung Injury Of Methamphetamine:Resveratrol Protects Alveolar Epithelium Barrier Integrity

Objective: Methamphetamine(MA),commonly known as "methamphetamine",has become one of the most serious new amphetamine-type synthetic drugs in the world.Long-term abuse can cause damage to tissues and organs such as the heart,brain,and lungs.MA inhalation methods are mainly divided into nasal inhalation and injection.The inhaled MA is distributed in all organs in the body,the highest concentration in the lung is distributed,and the higher uptake rate of MA in alveolar indicates that the lung is one of the important target organs for MA action and resulted in some pulmonary complications,including pulmonary hypertension and lung injury.SIRT1 is an antioxidative factor,but its effects and mechanism in MA-induced lung injury remains unclear.The purpose of this study is to determine if MA can disrupt the integrity of alveolar epithelial barrier,if SIRT1 is involved in MA-induced chronic lung injury,and if Resveratrol(Res)can protect the integrity of alveolar epithelial cells by regulating ROS to activate SIRT1/PTEN/p-Akt pathway.Methods: The Wister rats were randomly divided into control group and MA group.The alveolar epithelial cells(A549)were treated with MA or/and Res.HE staining and immunohistochemistry were used histopathological evaluation;Western blot was used to detect the expression of tissue and cell-related proteins;LDH method was used to determine cell membrane permeability;DCFH-DA probe method was used to determine ROS content in epithelial cells;V-FITC/PI dual staining was used to determine epithelial cell apoptosis;MOE was used to predict bioinformatics.Results: Compared with the CON group,chronic exposure to MA can cause slower growth ratio of weight,increased RVI and induced lung injury including more compact lung parenchyma,the reduced number of alveolar sacs,the thickened alveolar walls,narrowed lumen and significantly inflammatory infiltration.MA-induced apoptosis of epithelial cells is related to SIRT1-mediated oxidative stress.Res suppressed ROS levels,activated SIRT1,negatively regulated PTEN,phosphorylated Akt,reduced LDH leakage,significantly inhibited MA-induced downregulation of epithelial barrier integrity markerprotein,alleviated increasing expression of apoptotic total Caspase 3,activated Caspase 3,Bax and decreasing expression of anti-apoptotic Bcl-2,which significantly improved the increase of alveolar epithelial permeability and apoptosis.Conclusion: MA disrupted the integrity of alveolar epithelial barrier and SIRT1 was involved in MA-induced chronic lung injury.Res activated the SIRT1/PTEN/p-Akt pathway by inhibiting ROS production,thereby reversed the increasing in MA-induced alveolar epithelial permeability and apoptosis.