School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, SW7 2AZ, UK.
Respir Res. 2022 Jul 13;23(1):183. doi: 10.1186/s12931-022-02108-4.
Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction. This study aimed to elucidate the mechanism by which pulmonary pericytes accumulate in the airway wall in a model of chronic allergic airway inflammation.
Mice were subjected to a protocol of chronic airway inflammation driven by the common environmental aeroallergen house dust mite. Phenotypic changes to lung pericytes were assessed by flow cytometry and immunostaining, and the functional capacity of these cells was evaluated using in vitro migration assays. The molecular mechanisms driving these processes were targeted pharmacologically in vivo and in vitro.
Pericytes demonstrated increased CXCR4 expression in response to chronic allergic inflammation and migrated more readily to its cognate chemokine, CXCL12. This increase in migratory capacity was accompanied by pericyte accumulation in the airway wall, increased smooth muscle thickness, and symptoms of respiratory distress. Pericyte uncoupling from pulmonary vessels and subsequent migration to the airway wall were abrogated following topical treatment with the CXCL12 neutraligand LIT-927.
These results provide new insight into the role of the CXCL12/CXCR4 signaling axis in promoting pulmonary pericyte accumulation and airway remodeling and validate a novel target to address tissue remodeling associated with chronic inflammation.
气道重塑是慢性变应性气道疾病导致肺功能受损的重要原因。目前，尚无针对这些结构变化和由此导致的功能丧失的治疗方法。在慢性变应性炎症的背景下，已发现周细胞与肺微血管分离，迁移到炎症部位，并显著促进气道壁重塑和肺功能障碍。本研究旨在阐明在慢性变应性气道炎症模型中，肺周细胞在气道壁中积累的机制。
通过常见的环境变应原屋尘螨，使小鼠发生慢性气道炎症。通过流式细胞术和免疫染色评估肺周细胞的表型变化，并通过体外迁移实验评估这些细胞的功能能力。体内和体外靶向这些过程的分子机制进行药理学干预。
周细胞在慢性变应性炎症中表现出 CXCR4 表达增加，并且更容易向其同源趋化因子 CXCL12 迁移。这种迁移能力的增加伴随着周细胞在气道壁中的积累、平滑肌厚度增加和呼吸窘迫症状。用 CXCL12 中和配体 LIT-927 进行局部治疗后，周细胞从肺血管分离并随后迁移到气道壁的现象被阻断。
这些结果为 CXCL12/CXCR4 信号轴在促进肺周细胞积累和气道重塑中的作用提供了新的见解，并验证了一个针对与慢性炎症相关的组织重塑的新靶点。
