The Role Of Long Form Of Thymic Stromal Lymphopoietin In Airway Epithelial Barrier Disruption On Virus-Induced Asthma

Background AND Objective:Asthma exacerbations are characterized by a progressive increase in symptoms of shortness of breath,cough,wheezing or chest tightness and progressive decrease in lung function caused by respiratory viruses and other factors,and usually require modification of treatment.Asthma exacerbations can do a lot of harm to the patients and cause of disability and death.As the first barrier of respiratory system,the imbalance of cell damage and repair of airway epithelium plays an important role in the pathogenesis of asthma,especially in the asthma exacerbation,accelerating the injury of airway epithelial cells directly affects the outcome of the disease.Focus on the role of respiratory viruses in the airway epithelial barrier is of great significance for elucidating the pathogenesis of acute asthma and looking for more accurate biotherapy.Thymic stromal lymphopoietin plays an important role in the prevention and treatment of asthma.It has been found that the primary bronchial epithelial cells of asthmatic patients infected by respiratory virus can induce the high expression of TSLP.Due to the existence of two different subtypes of TSLP in human airway epithelial cells,lfTSLP and sfTSLP play different biological roles.Our previous study found that lfTSLP is highly expressed in house dust mite-induced asthma cell model and can participate in HDM-induced airway epithelial barrier dysfunction,while sfTSLP can ameliorate HDM and lfTSLP-mediated airway epithelial barrier dysfunction.However,the role of lfTSLP in the airway epithelial barrier function of virus-induced asthma is not clear.Aiming at this problem,in vitro experiments we explore:1.Whether Viral induced overproduction of lfTSLP on asthmatic airway epithlium?2.To explore the effect of lfTSLP on asthmatic airway epithelial barrier dysfunction induced by virus and its mechanism.Methods:1.Western blot and RT-PCR were used to detect the expression of lfTSLP and sfTSLP in normal human bronchial epithelial cells and HDM-sensitized human bronchial epithelial cells induced by poly(I:C).2.Using poly(I:C)to establish virus-induced asthma model.Western blot,RT-PCR,ELISA,LDH and cellular immunofluorescence were used to detect the activation of RIG-1/NLRP3/caspasel pathway,the expression and activation level of GSDMD and the release of inflammatory factor IL-1β in human bronchial epithelial cells induced by poly(I:C).3.The effect of lfTSLP on the barrier function of human bronchial epithelial cells induced by polyI:C was detected by TER and FITC.Results:1.The expression of lfTSLP in asthmatic airway epithelial cells induced by poly(I:C)was significantly increased.2.Deficiency of antiviral immune response in airway epithelial cells sensitized by HDM.3.IfTSLP aggravates the pyroptosis of asthmatic airway epithelial cells induced by poly(I:C).4.Poly(I:C)induces the pyroptosis of asthmatic airway epithelial cells through activating RIG-1-NLRP3-caspase1-GSDMD pathway,which can be aggravated by lfTSLP.5.lfTSLP aggravates the damage of airway epithelial barrier induced by poly(I:C)in asthma.6.lfTSLP aggravates the pyroptosis of asthmatic airway epithelial cells induced by poly(I:C)through TSLPR activating STAT5 signal pathway,which leads to the destruction of airway epithelial barrier.Conclusion:lfTSLP aggravates the pyroptosis of asthmatic airway epithelium induced by poly(I:C)and functionally deteriorates the damage of airway epithelial barrier,suggesting that targeted lfTSLP may interfere with the process of asthma exacerbation and provide a new perspective for the prevention and treatment of asthma exacerbation...