Tang Haixiong, Li Zhongli, Yang Changyun, Fu Lin, Ji Xiaolong, Chen Zemin, Gan Sudan, Zhang Hailing, Zhang PingAn, Li Shiyue, Zhang Wenjun, Chen Xin, Yao Lihong, Li Jing
Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Respir Res. 2024 Dec 24;25(1):441. doi: 10.1186/s12931-024-03077-6.
Mixed granulocytic asthma (MGA) is usually associated with poor response to corticosteroid therapy and a high risk of severe asthma. Cathepsin S (CTSS) has been found to play an important role in various inflammatory diseases. This study was aimed to investigate the role of CTSS in MGA.
Induced sputum was obtained from healthy subjects and asthma patients. Two murine models of MGA were established using either TDI (toluene diisocyanate) alone or OVA emulsified in CFA. LY3000328, a specific antagonist of CTSS, was therapeutically given to BALB/c mice after airway challenge with TDI or OVA. The effects of recombinant CTSS was tested in vivo, and Akt inhibition was used to explore a possible mechanism for CTSS-induced airway inflammation.
MGA patients have a significant higher sputum CTSS level than the health and subjects with other inflammatory phenotypes, which was positively correlated with sputum level of soluble E-cadherin (sE-cadherin), sputum neutrophils, FeNO, FEF25-75% and glucocorticoid dosage. Allergen exposure markedly increased CTSS level and pharmacological antagonism of CTSS with LY3000328 decreased airway hyperresponsiveness, airway neutrophil accumulation, as well as the release of IL-17 and sE-cadherin in murine models of MGA, yet had no effects on eosinophilic inflammation nor type 2 inflammatory cytokines (IL-4 and IL-5). In addition, intratracheal instillation of recombinant CTSS leads to neutrophil recruitment and overproduction of sE-cadherin in the lung tissues, which could be attenuated by inhibition of Akt signaling.
Our data suggested that CTSS contributes to airway neutrophilic inflammation in MGA through an Akt-dependent pathway.
混合性粒细胞性哮喘（MGA）通常与皮质类固醇治疗反应不佳及严重哮喘的高风险相关。组织蛋白酶S（CTSS）已被发现在各种炎症性疾病中起重要作用。本研究旨在探讨CTSS在MGA中的作用。
从健康受试者和哮喘患者中获取诱导痰。使用单独的甲苯二异氰酸酯（TDI）或在弗氏完全佐剂（CFA）中乳化的卵清蛋白（OVA）建立两种MGA小鼠模型。在TDI或OVA气道激发后，将CTSS的特异性拮抗剂LY3000328给予BALB/c小鼠进行治疗。在体内测试重组CTSS的作用，并使用Akt抑制来探索CTSS诱导气道炎症的可能机制。
MGA患者的痰液CTSS水平显著高于健康受试者和其他炎症表型的受试者，且与可溶性E-钙黏蛋白（sE-钙黏蛋白）的痰液水平、痰液中性粒细胞、呼出一氧化氮（FeNO）、用力呼气流量25%-75%以及糖皮质激素剂量呈正相关。变应原暴露显著增加CTSS水平，LY3000328对CTSS的药理拮抗作用降低了MGA小鼠模型中的气道高反应性、气道中性粒细胞积聚以及白细胞介素-17（IL-17）和sE-钙黏蛋白的释放，但对嗜酸性粒细胞炎症和2型炎症细胞因子（IL-4和IL-5）无影响。此外，气管内滴注重组CTSS导致肺组织中性粒细胞募集和sE-钙黏蛋白过度产生，这可通过抑制Akt信号传导来减弱。
我们的数据表明，CTSS通过Akt依赖途径促进MGA中的气道中性粒细胞炎症。
