| BackgroundLung ischemia-reperfusion(IR)injury is the main cause of primary graft dysfunction.Severe lung IR injury may cause acute lung injury and seriously affect the life and health of patients.At present,there is no therapeutic drug that can be used to prevent pulmonary ischemia-reperfusion injury in clinic,which is limited to supportive treatment.Understanding the cellular and molecular mechanisms of lung IR injury is very important to solve this clinical problem.Autophagy promotes cell survival by allowing periodic degradation and recovery of cellular components;However,the imbalance of endosomes and autophagy pathways after injury will eventually lead to cell death.In the process of lung IR injury,excessive autophagy will damage the lung.Inhibiting autophagy may be an important means to reduce lung IR injury.However,the regulatory mechanism of autophagy in lung IR injury is unclear.Studies have shown that Notch signaling pathway is involved in IR injury of brain,heart,kidney and other organs.Hes1,a downstream effector gene of Notch signaling pathway,is a transcription factor that can bind to the promoter region of PTEN gene and down regulate PTEN expression.PTEN can negatively regulate Akt/mTOR signaling pathway in non-small cell lung cancer.It is worth noting that Akt/mTOR signaling pathway is an important signaling pathway regulating autophagy,metabolism,proliferation and survival.However,in the study of IR injury,there is no report that Notch1-Hesl signal axis affects autophagy through PTEN/Akt/mTOR signal pathway.EGFR is a receptor tyrosine kinase in ErbB family.Many studies in the field of cancer have shown that EGFR is involved in regulating autophagy that affects the survival and death of cancer cells,and plays a key role in whether autophagy leads to cell death or survival.β-Catenin is a protein that interacts widely with EGFR and involves many cellular processes,such as cell proliferation,epithelial mesenchymal transformation and autophagy.In addition,the study found that β-Catenin signaling pathway may play an important role in resisting myocardial IR injury.But it is not clear whether EGFR and β-Catenin are involved in lung IR injury.MicroRNAs are the small endogenous noncoding RNAs that contain about 20-24 nucleotides.It can regulate gene expression at the translation and transcription levels and play an important role in a variety of cellular processes,including IR injury.Our analysis on targetscan website found that miR-141 may target to inhibit the expression of EGFR.In addition,it has been found that inhibiting miR-141 reduces hypoxia induced H9C2 cardiomyocyte apoptosis in vitro.Based on the above observations,we speculate that miR-141,EGFR and β-Catenin may have an interaction pathway and participate in autophagy regulation in pulmonary ischemia-reperfusion.Through a series of studies,this study proved that Notch1 signal was activated during lung IR injury,which would promote the expression of its downstream effector gene Hes1;Hesl can bind to PTEN promoter region to inhibit PTEN expression,and then activate Akt/mTOR signaling pathway to inhibit autophagy,which may play a protective role in the progression of lung IR injury.On the other hand,lung IR injury can also activate miR-141/EGFR/β-Catenin signal axis promotes the increase of miR-141 expression;miR-141 can specifically inhibit the expression of EGFR,and then inhibit the expression of β-Catenin signal,finally promotes autophagy and aggravates lung injury.In conclusion,this study suggests that the autophagy mechanism in the process of lung IR injury involves at least Notch1/Hesl/PTEN/Akt/mTOR signaling pathway and miR-141/EGFR/β-Catenin signal axis.The former mainly plays a protective role by inhibiting autophagy;The latter promotes autophagy and aggravates lung injury,which may provide a new idea for the clinical treatment of lung IR injury. |
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