Mann Tracy S, Larcombe Alexander N, Wang Kimberley C W, Shamsuddin Danial, Landwehr Katherine R, Noble Peter B, Henry Peter J
School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
Wal-yan Respiratory Research Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia.
Am J Physiol Lung Cell Mol Physiol. 2022 May 1;322(5):L683-L698. doi: 10.1152/ajplung.00487.2021. Epub 2022 Mar 29.
Excessive production, secretion, and retention of abnormal mucus is a pathological feature of many obstructive airways diseases including asthma. Azithromycin is an antibiotic that also possesses immunomodulatory and mucoregulatory activities, which may contribute to the clinical effectiveness of azithromycin in asthma. The current study investigated these nonantibiotic activities of azithromycin in mice exposed daily to intranasal house dust mite (HDM) extract for 10 days. HDM-exposed mice exhibited airways hyperresponsiveness to aerosolized methacholine, a pronounced mixed eosinophilic and neutrophilic inflammatory response, increased airway smooth muscle (ASM) thickness, and elevated levels of epithelial mucin staining. Azithromycin (50 mg/kg sc, 2 h before each HDM exposure) attenuated HDM-induced airways hyperresponsiveness to methacholine, airways inflammation (bronchoalveolar lavage eosinophil and neutrophils numbers, and IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, and RANTES levels), and epithelial mucin staining (mucous metaplasia) by at least 50% (compared with HDM-exposed mice, < 0.05). Isolated tracheal segments of HDM-exposed mice secreted Muc5ac and Muc5b (above baseline levels) in response to exogenous ATP. Moreover, ATP-induced secretion of mucins was attenuated in segments obtained from azithromycin-treated, HDM-exposed mice ( < 0.05). In additional ex vivo studies, ATP-induced secretion of Muc5ac (but not muc5b) from HDM-exposed tracheal segments was inhibited by in vitro exposure to azithromycin. In vitro azithromycin also inhibited ATP-induced secretion of Muc5ac and Muc5b in tracheal segments from IL-13-exposed mice. In summary, azithromycin inhibited ATP-induced mucin secretion and airways inflammation in HDM-exposed mice, both of which are likely to contribute to suppression of airways hyperresponsiveness.
异常黏液的过度产生、分泌和潴留是包括哮喘在内的许多阻塞性气道疾病的病理特征。阿奇霉素是一种抗生素，还具有免疫调节和黏液调节活性，这可能有助于阿奇霉素在哮喘治疗中的临床疗效。本研究调查了阿奇霉素在每天经鼻给予屋尘螨（HDM）提取物处理10天的小鼠中的这些非抗生素活性。暴露于HDM的小鼠表现出对雾化乙酰甲胆碱的气道高反应性、明显的嗜酸性粒细胞和中性粒细胞混合性炎症反应、气道平滑肌（ASM）厚度增加以及上皮黏蛋白染色水平升高。阿奇霉素（50 mg/kg皮下注射，在每次HDM暴露前2小时）使HDM诱导的对乙酰甲胆碱的气道高反应性、气道炎症（支气管肺泡灌洗嗜酸性粒细胞和中性粒细胞数量以及IL-4、IL-5、IL-6、IL-10、IL-12、IL-13和RANTES水平）和上皮黏蛋白染色（黏液化生）至少减轻50%（与暴露于HDM的小鼠相比，P<0.05）。暴露于HDM的小鼠的离体气管段对外源性ATP有反应，分泌Muc5ac和Muc5b（高于基线水平）。此外，在从接受阿奇霉素治疗、暴露于HDM的小鼠获得的气管段中，ATP诱导的黏蛋白分泌减弱（P<0.05）。在另外的体外研究中，体外暴露于阿奇霉素可抑制暴露于HDM的气管段中ATP诱导的Muc5ac（但不是Muc5b）分泌。体外阿奇霉素还抑制IL-13暴露的小鼠气管段中ATP诱导的Muc5ac和Muc5b分泌。总之，阿奇霉素抑制暴露于HDM的小鼠中ATP诱导的黏蛋白分泌和气道炎症，这两者可能都有助于抑制气道高反应性。
