Liuzhao Cao1,2, Fen Liu1,3, Yahui Liu1, Tian Liu1, Jinxiang Wu1, Jiping Zhao1, Junfei Wang1, Shuo Li1, Jiawei Xu1, Liang Dong1. 1. a Department of Pulmonary Diseases , Qilu Hospital, Shandong University , Jinan , Shandong , People's Republic of China. 2. b Department of Respiratory Medicine , Northern Jiangsu People's Hospital , Yangzhou , Jiangsu , People's Republic of China. 3. c Department of Respiratory Medicine , Shandong Provincial Qianfoshan Hospital, Shandong University , Jinan , Shandong , People's Republic of China.
Abstract
PURPOSE: Thymic stromal lymphopoietin (TSLP) acts as a critical cytokine involved in asthmatic airway remodeling. Our study aimed to characterize the crosstalk between airway epithelial cells and fibroblasts regulated by TSLP through the signaling pathways of Mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MATERIALS AND METHODS: Human biopsy specimens and lung tissues from mice were stained with hematoxylin and eosin (H&E) and immunohistochemistry. Human lung fibroblasts were stimulated with human recombinant TSLP. The protein expression of phosphorylation of STAT3 (p-STAT3) and phosphorylation of MAPK as well as the expression of collagen I and alpha-smooth muscle actin (α-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. RESULT: TSLP could activate MAPK in HLF-1. SB203580 could inhibit the activation of p38, attenuate phosphorylation of STAT3, and decrease the expression of collagen I and α-SMA consequently in human fibroblasts. Co-culture demonstrated that TSLP secreted by epithelial cells could promote the expression of collagen I and α-SMA and aggravates airway remodeling in fibroblasts. In vivo, expression of TSLP, collagen I, α-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 MAPK-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.
PURPOSE:Thymic stromal lymphopoietin (TSLP) acts as a critical cytokine involved in asthmatic airway remodeling. Our study aimed to characterize the crosstalk between airway epithelial cells and fibroblasts regulated by TSLP through the signaling pathways of Mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MATERIALS AND METHODS:Human biopsy specimens and lung tissues from mice were stained with hematoxylin and eosin (H&E) and immunohistochemistry. Human lung fibroblasts were stimulated with human recombinant TSLP. The protein expression of phosphorylation of STAT3 (p-STAT3) and phosphorylation of MAPK as well as the expression of collagen I and alpha-smooth muscle actin (α-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. RESULT: TSLP could activate MAPK in HLF-1. SB203580 could inhibit the activation of p38, attenuate phosphorylation of STAT3, and decrease the expression of collagen I and α-SMA consequently in human fibroblasts. Co-culture demonstrated that TSLP secreted by epithelial cells could promote the expression of collagen I and α-SMA and aggravates airway remodeling in fibroblasts. In vivo, expression of TSLP, collagen I, α-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 MAPK-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.
Authors: Ludger Klimek; Jan Hagemann; Hans-Jürgen Welkoborsky; Mandy Cuevas; Ingrid Casper; Ulrike Förster-Ruhrmann; Felix Klimek; Constantin A Hintschich; Tilman Huppertz; Christoph Bergmann; Peter-Valentin Tomazic; Sven Becker Journal: Allergol Select Date: 2022-04-29