鼻病毒感染的支气管上皮可诱导重症哮喘患者支气管平滑肌细胞特异性迁移
2022/04/14
摘要
背景：重症哮喘患者的急性发作频率与支气管平滑肌 (BSM) 质量均有所增加。支气管上皮 (BE) 的鼻病毒 (RV) 感染是哮喘急性发作的主要诱因。活检组织结果表明，BE和肥厚性BSM之间的密切联系是哮喘严重程度的标准之一。
目的：假设RV 感染的BE会增加哮喘患者的BSM细胞特异性迁移。
方法：纳入86例重症哮喘患者和31例非哮喘受试者，采集血清样本、活检标本或者BSM细胞。在气液界面中培养非哮喘受试者的BE细胞并暴露于RV-16。使用趋化实验评估BSM对于BE上清的迁移反应。通过转录组学和ELISA检测趋化因子浓度。免疫组化、蛋白质印迹和流式细胞术用于量化CXCR3异构体分布。通过钙成像和蛋白质印迹评估CXCR3下游信号通路。
结果：重症哮喘患者的BSM细胞可向RV感染的BE特异性迁移，但是非哮喘受试者的BSM细胞则无特异性迁移。这种特异性迁移是由BE细胞分泌的CXCL-10驱动，CXCL-10水平在体外RV感染的BE上清及重症哮喘急性发作患者的血清中增加。重症哮喘BSM的迁移机制与其BSM细胞中CXCR3-B表型的表达和活化降低有关。
结论：本研究证实了 RV感染后重症哮喘患者BSM重塑的新机制。CXCL-10/CXCR3-A 轴可能是重症哮喘的潜在治疗靶点。
Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients
Celle A, Esteves P, Cardouat G, Beaufils F, Eyraud E et al.
J Allergy Clin Immunol. 2022 Feb 7;S0091-6749(22)00148-8.
ABSTRACT：
Background: Patients with severe asthma show an increase in both exacerbation frequency and bronchial smooth muscle (BSM) mass. Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of asthma exacerbations. Histological analysis of biopsies shows that a close connection between BE and hypertrophic BSM is a criterion for severity of asthma.
Objective: We hypothesized that RV infection of BE specifically increases BSM-cell migration from patients with asthma.
Methods: Serum samples, biopsies, or BSM cells were obtained from 86 patients with severe asthma and 31 subjects without asthma. BE cells from subjects without asthma were cultured in an air-liquid interface and exposed to RV-16. Migration of BSM cells was assessed in response to BE supernatant using chemotaxis assays. Chemokine concentrations were analyzed by transcriptomics and ELISAs. immunocytochemistry, western blotting, and flow cytometry were used to quantify CXCR3 isoform distribution. CXCR3 downstream signaling pathways were assessed by calcium imaging and western blots.
Results: BSM cells from patients with severe asthma specifically migrated toward RV-infected BE, whereas those from subjects without asthma did not. This specific migration is driven by BE C-X-C motif chemokine ligand 10, which was increased in vitro in response to RV infection as well as in vivo in serum from exacerbating patients with severe asthma. The mechanism is related to both decreased expression and activation of the CXCR3-B–specific isoform in BSM cells from those with severe asthma.
Conclusions: We have demonstrated a novel mechanism of BSM remodeling in patients with severe asthma following RV exacerbation. This study highlights the C-X-C motif chemokine ligand 10/CXCR3-A axis as a potential therapeutic target in severe asthma.
背景：重症哮喘患者的急性发作频率与支气管平滑肌 (BSM) 质量均有所增加。支气管上皮 (BE) 的鼻病毒 (RV) 感染是哮喘急性发作的主要诱因。活检组织结果表明，BE和肥厚性BSM之间的密切联系是哮喘严重程度的标准之一。
目的：假设RV 感染的BE会增加哮喘患者的BSM细胞特异性迁移。
方法：纳入86例重症哮喘患者和31例非哮喘受试者，采集血清样本、活检标本或者BSM细胞。在气液界面中培养非哮喘受试者的BE细胞并暴露于RV-16。使用趋化实验评估BSM对于BE上清的迁移反应。通过转录组学和ELISA检测趋化因子浓度。免疫组化、蛋白质印迹和流式细胞术用于量化CXCR3异构体分布。通过钙成像和蛋白质印迹评估CXCR3下游信号通路。
结果：重症哮喘患者的BSM细胞可向RV感染的BE特异性迁移，但是非哮喘受试者的BSM细胞则无特异性迁移。这种特异性迁移是由BE细胞分泌的CXCL-10驱动，CXCL-10水平在体外RV感染的BE上清及重症哮喘急性发作患者的血清中增加。重症哮喘BSM的迁移机制与其BSM细胞中CXCR3-B表型的表达和活化降低有关。
结论：本研究证实了 RV感染后重症哮喘患者BSM重塑的新机制。CXCL-10/CXCR3-A 轴可能是重症哮喘的潜在治疗靶点。
(何丽秀1 张红萍2 王刚1 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（J Allergy Clin Immunol. 2022 Feb 7;S0091-6749(22)00148-8.）
（J Allergy Clin Immunol. 2022 Feb 7;S0091-6749(22)00148-8.）
Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients
Celle A, Esteves P, Cardouat G, Beaufils F, Eyraud E et al.
J Allergy Clin Immunol. 2022 Feb 7;S0091-6749(22)00148-8.
ABSTRACT：
Background: Patients with severe asthma show an increase in both exacerbation frequency and bronchial smooth muscle (BSM) mass. Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of asthma exacerbations. Histological analysis of biopsies shows that a close connection between BE and hypertrophic BSM is a criterion for severity of asthma.
Objective: We hypothesized that RV infection of BE specifically increases BSM-cell migration from patients with asthma.
Methods: Serum samples, biopsies, or BSM cells were obtained from 86 patients with severe asthma and 31 subjects without asthma. BE cells from subjects without asthma were cultured in an air-liquid interface and exposed to RV-16. Migration of BSM cells was assessed in response to BE supernatant using chemotaxis assays. Chemokine concentrations were analyzed by transcriptomics and ELISAs. immunocytochemistry, western blotting, and flow cytometry were used to quantify CXCR3 isoform distribution. CXCR3 downstream signaling pathways were assessed by calcium imaging and western blots.
Results: BSM cells from patients with severe asthma specifically migrated toward RV-infected BE, whereas those from subjects without asthma did not. This specific migration is driven by BE C-X-C motif chemokine ligand 10, which was increased in vitro in response to RV infection as well as in vivo in serum from exacerbating patients with severe asthma. The mechanism is related to both decreased expression and activation of the CXCR3-B–specific isoform in BSM cells from those with severe asthma.
Conclusions: We have demonstrated a novel mechanism of BSM remodeling in patients with severe asthma following RV exacerbation. This study highlights the C-X-C motif chemokine ligand 10/CXCR3-A axis as a potential therapeutic target in severe asthma.
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通过上皮细胞对鼻病毒的反应识别成人早期哮喘的表型
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哮喘中针对未折叠蛋白反应的机制
