The Inhibitory Effect Of CXCR7 In Pulmonary Epithelial Cell Injury And Epithelial-mesenchymal Transition

BackgroundAcute respiratory distress syndrome(ARDS)is an acute diffuse pulmonary inflammation,which lead to pulmonary vascular permeability increase.ARDS is still a major life-threatening disease currently.High mortality among moderate and severe ARDS patients remains above 40% and it is still a main concern in critical care and lung fibrosis might be an important cause to it.There are a lot of factors that can lead to ARDS associated lung fibrosis.Mechanical stress and its wide use can be one of the factors,and acid inspiration which can develop lung inflammation can also induce lung fibrosis.Numbers of studies have proven that acid aspiration lead to epithelium injury and induces epithelial mesenchymal transition(EMT).EMT is fully differentiated epithelium which transform into the phenotype of mesenchymal cell,including lengthening morphology,enhancing migratory and invasive ability,accelerating the production of extracellular matrix(ECM)components,being the transition phase of the liver,kidney,lung and other organs undergone fibrosis.CXCR7 is a chemokine receptor that can change the ECM acceleration,improve cells regeneration and controls immune cells transfection.Present evidence has shown that CXCR7 can inhibit lung fibrosis and improve lung epithelium injury in hydrochloric acid induced mice model,but the mechanism under it has yet to be found.Here,we find that hydrochloric acid induces inflammation and EMT in the lung epithelial cell and decreases CXCR7 expression.Through CXCR7 agonist TC14012,we found the elevation of CXCR7 expression and trend of inhibitory effect in EMT and inflammation.The result shows that CXCR7 might be a therapeutic target in lung fibrosis and TC14012 might be a possible treatment.ObjectivesTo investigate the hydrochloric acid induced EMT and the association between CXCR7 and EMT,providing molecular theory and a new therapeutic target for the diagnosis and treatment of pulmonary fibrosis.MethodsHuman lung epithelial cells BEAS-2B were pretreated with hydrochloric acid and cell culture medium for 30 min.Observe the morphology of cells under the inverted microscope.Examine the expression of IL-6,IL-8 by q-PCR and epithelial markers(cytokeratin-8,E-cadherin,SPB)and mesenchymal markers(?-smooth muscle actin,vimentin and N-cadherin)at protein level by western blotting.Apply TC14012 right after the hydrochloric acid and culture medium pretreatment,detect IL-6,IL-8,CXCR7 expression and EMT biomarkers expression to examine the inhibitory effect of TC14012 in hydrochloric acid induced lung epithelial cell EMT model.Results1,The HCl pretreated BEAS-2B cells displayed EMT morphology for changing to spindle-shaped structure with loss of polarity,and the expression of cytokeratin-8,Ecadherin and SPB decreased,while ?-smooth muscle actin,vimentin and N-cadherin increased.2,The HCl leads the increased in inflammatory cytokines and the decreased in CXCR7 expression.3,TC14012 improved the expression of CXCR7 in the HCl pretreated BEAS-2B cells and had trends in decreasing inflammatory cytokines and EMT.ConclusionsHydrochloric acid induces the decreased expression of CXCR7 which is contributing to EMT in human lung epithelial cells.CXCR7 may serve as a novel mechanism and a potential therapeutic target in the context of ARDS associated lung fibrosis.