Ghanizada Muzhda, Malm Tillgren Sofia, Praeger-Jahnsen Louis, Said Nihaya Mahmoud, Ditlev Sisse, Frost Andreassen Helle, Dyhre-Petersen Nanna, Cerps Samuel, Sverrild Asger, Porsbjerg Celeste, Uller Lena, Lapperre Therese, Menzel Mandy
Respiratory Research Unit, Department of Respiratory and Infectious Diseases, Bispebjerg Hospital, Copenhagen, Denmark.
Unit of Respiratory Immunopharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Front Allergy. 2025 Jun 17;6:1605109. doi: 10.3389/falgy.2025.1605109. eCollection 2025.
Azithromycin (AZM) effectively reduces asthma exacerbations and enhances bronchial epithelial cell (BEC) antiviral immunity . However, its clinical impact on different asthma phenotypes is not fully elucidated and differences in treatment response to AZM may be attributable to differences in immune activation to rhinovirus (RV) infection in different inflammatory asthma phenotypes.
To explore bronchial epithelial antiviral properties in response to AZM treatment in eosinophilic and non-eosinophilic as well as atopic and non-atopic asthma phenotypes, and to investigate the effects of AZM on the release of RV-induced alarmins and pro-inflammatory cytokines in these asthma phenotypes.
In this cross-sectional study, we have collected BECs from patients with moderate-to-severe asthma ( = 20). The cells were pre-treated with or without 10 µM AZM 24 h before infection with 0.05 MOI RV. Release of IFN-β, IFN-λ, alarmins and pro-inflammatory cytokines were measured 48 h after infection by Mesoscale Discovery (S-plex and U-plex) and then compared across asthma phenotypes, based on blood eosinophils and atopy status.
AZM significantly enhanced IFN-β and IFN-λ protein release in response to RV infection both in eosinophilic and in non-eosinophilic asthma as well as in non-atopic asthma. A less pronounced IFN-β and IFN-λ protein release was also observed in the atopic group. AZM's interferon-inducing effect was, however, largely similar regardless of blood eosinophil count and atopy status. Additionally, AZM prompted the release of TSLP and IL-6 in the non-eosinophilic group only.
Our data suggest that , AZM works primarily by improving bronchial epithelial antiviral resistance by increasing interferons independent of eosinophilia and atopy status, highlighting the broad applicability of AZM in modulating antiviral immunity in asthma as well as the need for identifying predictors of AZM response beyond inflammatory phenotypes.
阿奇霉素（AZM）可有效减少哮喘发作并增强支气管上皮细胞（BEC）的抗病毒免疫力。然而，其对不同哮喘表型的临床影响尚未完全阐明，对AZM治疗反应的差异可能归因于不同炎症性哮喘表型对鼻病毒（RV）感染的免疫激活差异。
探讨嗜酸性粒细胞性和非嗜酸性粒细胞性以及特应性和非特应性哮喘表型对AZM治疗的支气管上皮抗病毒特性，并研究AZM对这些哮喘表型中RV诱导的警报素和促炎细胞因子释放的影响。
在这项横断面研究中，我们收集了中重度哮喘患者（n = 20）的BEC。在感染0.05 MOI RV前24小时，细胞用或不用10 μM AZM进行预处理。感染后48小时，通过中尺度发现（S-plex和U-plex）测量IFN-β、IFN-λ、警报素和促炎细胞因子的释放，然后根据血液嗜酸性粒细胞和特应性状态在不同哮喘表型之间进行比较。
在嗜酸性粒细胞性和非嗜酸性粒细胞性哮喘以及非特应性哮喘中，AZM均显著增强了对RV感染的IFN-β和IFN-λ蛋白释放。在特应性组中也观察到较不明显的IFN-β和IFN-λ蛋白释放。然而，无论血液嗜酸性粒细胞计数和特应性状态如何，AZM的干扰素诱导作用在很大程度上相似。此外，AZM仅在非嗜酸性粒细胞性组中促使TSLP和IL-6释放。
我们的数据表明，AZM主要通过增加干扰素来提高支气管上皮抗病毒抵抗力，而与嗜酸性粒细胞增多和特应性状态无关，这突出了AZM在调节哮喘抗病毒免疫力方面的广泛适用性，以及识别炎症表型以外的AZM反应预测指标的必要性。
