TSLP Promotes Asthmatic Airway Remodeling Via P38-STAT3 Signaling Pathway In Human Fibroblast

Background:Bronchial asthma is featured by airway inflammation and airway remodeling.The characteristics of airway remodeling include thicking of reticular basement membrane,epithelial shedding,sub-epithelial fibrosis,goblet cell hyperplasia,increased smooth muscle mass and angiogenesis.It is reported that airway dysfunction and exacerbated clinical symptoms are attributed to airway remodeling.Thymic stromal ltmphopoietin(TSLP)has been recognized as a critical cytokine involved in asthma.Mitogen-activated protein kinase(MAPK)and signal transducer and activator of transcription 3(STAT3)are vital signaling molecules and participate in the development of airway remodeling in asthma.Substantial evidences have demonstrated that airway epithelial cells and fibroblasts both participate in airway remodeling.However,the crosstalk between them is still not clear.Objective:Our study aimed to investigate the role of TSLP in asthmatic airway remodeling and characterize the crosstalk between airway epithelial cells and fibroblasts regulated by TSLP through the signaling pathways of MAPK and STAT3.Methods:Human biopsy specimens and lung tissues from mice were stained with hematoxylin and eosin(H&E)and immunohistochemistry(IHC).Human lung fibroblasts were stimulated with human recombinant TSLP.The protein expression of phosphorylation of STAT3(p-STAT3)and phosphorylation of MAPK(p-extracellular signal-regulated kinase 1 and 2(p-ERK1/2),p-protein-38(p-p38)and p-c-Jun N-terminal kinases(p-JNK))as well as the expression of collagen I and alpha-smooth muscle actin(a-SMA)were detected by Western blotting and immunofluorescence.Co-culture was performed to detect the influence of TSLP secreted by airway epithelial cells on fibroblasts.An ovalbumin(OVA)-induced asthmatic murine model was established with or without intraperitoneal injection of SB203580(inhibitor of p-38).Protein expression in lung tissue was detected by immunohistochemistry and western blotting.Results:TSLP could activate MAPK(ERK1/2,JNK,p38)in HLF-1.SB203580 could inhibit the activation of p38,attenuate phosphorylation of STAT3,and decrease the expression of collagen I and a-SMA consequently in human fibroblasts.Co-culture demonstrated that TSLP secreted by epithelial cells could promote the expression of collagen I and a-SMA and aggravate airway remodeling in fibroblasts.In vivo,expression of TSLP,collagen 1,a-SMA,p-p38 and p-STAT3 was upregulated in airway tissue of OVA-challenged mice and downregulated in mice which were treated by SB203580.The tissue staining showed that airway structure change was attenuated by SB203580 compared with OVA challenged mice as well.Conclusions:TSLP might promote asthmatic airway remodeling via p38-STAT3 axis activation and the crosstalk between airway epithelial cells and fibroblasts could aggravate remodeling.Blockade of p38 could alleviate airway remodeling which might provide a new therapeutic target for asthma.