The Clinical Significance And Mechanism Of ST2 And ILC2 In Fibrotic Interstitial Lung Disease

Section 1:The role of soluble suppression of tumorigenicity 2 in the differential diagnosis of usual interstitial pneumoniaObjective:To explore the differential diagnostic role of soluble suppression of tumorigenicity 2(sST2)and B cell-activating factor of the TNF family(BAFF)between idiopathic pulmonary fibrosis(IPF)and usual interstitial pneumonia(UIP)associated with autoimmune diseases(AIDs).Methods:Plasma levels of sST2 and BAFF were measured by ELISA method in 23 patients with AIDs-UIP,34 patients with IPF,and 21 healthy subjects as control.The correlation between plasma sST2 and BAFF levels and other clinical results from patients was analyzed.Receiver operating characteristics(ROC)analysis for distinguishing AIDs-UIP from IPF patients was examined and the maximum of area under curve(AUC)was found.Results:Plasma levels of sST2 and BAFF were significantly elevated in AIDs-UIP patients and IPF patients compared to healthy subjects(P<0.005).AIDs-UIP patients had higher level of sST2 and BAFF than IPF patients(P<0.005).Plasma sST2 levels in AID-UIP patients were negatively correlated with DLCO%in pulmonary function results(r ＝-0.524,P = 0.007)and positively correlated with serum LDH levels(r = 0.794,P = 0.000).Plasma BAFF levels in AIDs-UIP patients were inversely correlated with pulmonary function results,including FVC%(r =-0.435,P = 0.040)and TLC%(r =-0.449,P = 0.041),as well as DLCO%(r =-0.491,P = 0.024).The ROC curve of the plasma sST2 level to distinguish CTD-UIP from IPF patients(Area under the curve[AUC]= 0.934,P = 0.000,cut-off = 23.5 ng/mL,sensitivity 80.0%,specificity 91.3%,95%CI 0.881～0.994).When the cut off value of BAFF was set as 1.5 ng/mL to distinguish the AIDs-UIP patients from IPF patients,the sensitivity and the specificity was 64.5%and 90.0%,respectively,and the area under ROC curve reached the maximum of 0.784(P=0.000,95%CI 66.3%～90.5%).Conclusion:Plasma sST2 and BAFF levels were significantly higher and inversely correlated with pulmonary function,reflecting the severity of AIDs-UIP patients.Plasma sST2 and BAFF levels may be a useful marker for distinguishing AIDs-UIP from IPF patients.Section 2:The role of Bone Marrow Derived ILC2 in Bleomycin induced Pulmonary FibrosisBackground:Recent evidence suggests that bone marrow(BM)-derived hematopoietic progenitor cells play an important role in lung injury and fibrosis.While these cells give rise to multiple cell types,the ST2-expressing group 2 innate lymphoid cells(ILC2)derived from BM progenitors have been implicated in tissue repair and remodeling,including in lung fibrosis.Objective:To further investigate the precise role of BM-derived ILC2 in the pathogenesis of fibrotic lung disease.Methods:Bleomycin-induced lung fibrosis model was evaluated by analyzing the effects of selective ST2 deficiency in the BM compartment.Results:The results showed that while ST2 sufficient control mice exhibited activation of lung IL-33/ST2 signaling,ILC2 recruitment,IL-13 induction and fibrosis,these responses were significantly diminished in ST2 deficient-BM chimera mice with selective loss of ST2 expression only in the BM.This diminished response to bleomycin was similar to that seen in ST2 global knockout mice,suggesting the predominant importance of ST2 from the BM compartment.In wild type mice ILC2 recruitment to the lung was accompanied by concomitant decrease in ST2+ BM cells.ST2 deficient BM cells were unresponsive to IL-33 induced ILC2 maturation.Finally,lineage negative wild type,but not ST2 deficient BM cells from bleomycin-treated mice stimulated lung fibroblast type Ⅰ collagen expression,which was associated with elevated TGFβ expression in the BM cells.Conclusion:Taken together,these findings suggested that the BM-derived ILC2 were recruited to fibrotic lung through IL-33/ST2 pathway and contributed to fibroblast activation to promote lung fibrosis.