TSLP/STAT3通路调控气道平滑肌细胞自噬及促进哮喘气道重塑的作用及机制

Airway epithelial cells and airway smooth muscle cells (ASMCs) play crucial roles on development of asthmatic airway remodeling. Of that, the enhancement of proliferation and migration capacities of ASMCs can promote this process. However, the regulatory mechanisms of ASMCs proliferation and migration remain unclear. Epithelium-derived cytokines play important roles in it. According to our former studies, we found that epithelium-derived thymic stromal lymphopoietin (TSLP) could induce asthmatic airway remodeling. Treatment of primary ASMCs with recombinant TSLP (rTSLP) could activate the STAT3 signal pathway, and increase the expression levels of autophagy-related proteins. Based on these previous studies, we hypothesized that TSLP might regulate autophagy of ASMCs by activating STAT3 signal pathway, and then promoted proliferation and migration of ASMCs, which consequently resulted in airway remodeling. To verify our hypothesis, we will detect the expression levels of epithelium-derived TSLP, autophagy-related proteins in human tissues. Then, we establish primary ASMCs based on asthmatic mouse models, and disclose the regulatory roles of autophagy on primary ASMCs. Additionally, in vivo and in vitro, we will explore the important roles and mechanisms of TSLP in regulating phenotype, autophagy of ASMCs and airway remodeling. This research is expected to disclose the roles and mechanisms of TSLP/STAT3 signal pathway in regulating autophagy of ASMCs, and the effects of TSLP/STAT3/autophagy on ASMCs, which may provide new ideas for understanding the mechanisms of asthmatic airway remodeling.

气道上皮细胞及平滑肌细胞（airway smooth muscle cells，ASMCs）在支气管哮喘气道重塑的进展中发挥重要的作用，其中ASMCs主要表现为增殖、肥大及跨膜迁移。但是，ASMCs获得这类表型的机制并不清楚。我们前期研究发现，气道上皮来源的胸腺基质淋巴生成素（TSLP）通过STAT3通路参与气道重塑及ASMCs自噬活化。基于此，我们推测：TSLP可能通过调控STAT3信号通路，进而激活ASMCs自噬，从而诱导ASMCs增殖、跨膜迁移，导致哮喘气道重塑。本课题拟结合临床标本，分析气道上皮来源的TSLP与ASMCs自噬的相关性；并基于小鼠哮喘模型，建立原代ASMCs细胞系，体内外实验探索TSLP对ASMCs表型、自噬的调控作用及其调控信号通路。通过研究，有望明确TSLP/STAT3信号通路对ASMCs自噬及细胞表型的调控作用及机制，有望深入了解哮喘气道重塑的机制。

气道上皮细胞及平滑肌细胞（airway smooth muscle cells，ASMCs）在支气管哮喘气道重塑的进展中发挥重要的作用，其中ASMCs主要表现为增殖、肥大及跨膜迁移。但是，ASMCs获得这类表型的机制并不清楚。我们前期研究发现，气道上皮来源的胸腺基质淋巴生成素（TSLP）通过STAT3通路参与气道重塑及ASMCs自噬活化。有研究发现短链TSLP可以缓解HDM引起的细胞屏障损伤，但是不同长度的TSLP(Long TSLP or short TSLP)在哮喘发病过程中的作用尚不确定。本课题结合临床标本，分析气道上皮来源的TSLP与ASMCs自噬的相关性；并基于小鼠哮喘模型，建立原代ASMCs细胞系，体内外实验探索长链和短链TSLP对ASMCs表型、自噬的调控作用及其调控的信号通路。我们发现短链TSLP对ASMCs自噬及气道重塑起到保护作用，我们的研究深入了哮喘气道重塑的机制研究。主要研究成果以论著的形式发表在（Jiping Zhao, Jinxiang Wu,* et al. Immunobiology. 226(2021)152124)。同时也对细胞焦亡在急性肺损伤中的作用进行研究，并以论著的形式进行发表（JinxiangWu, et al. Frontiers in Cell and Developmental Biology. 11 November 2021 ）。