Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future.

中文翻译：

---

大环内酯类的非抗菌作用：概述和未来发展前景

大环内酯类是处方最广泛的广谱抗菌药之一，特别是用于呼吸道感染。现在已经认识到，这些药物，特别是阿奇霉素，也发挥时间依赖性免疫调节作用，这有助于它们在感染性疾病和其他慢性炎症性疾病中的治疗效果。然而，它们在气道炎症中的长期使用增加，以及最近在 COVID-19 中使用阿奇霉素，导致细菌耐药性增加。慢性气道炎症（例如慢性阻塞性肺病以及其他炎症性疾病）的另一个重要方面是上皮屏障对病原体和污染物的保护丧失。近年来，随着时间的推移，阿奇霉素已被证明可以增强气道上皮细胞的屏障特性，对其治疗效果有重要贡献的作用。在本文中，我们回顾了大环内酯类对炎症过程和上皮的各种免疫调节和时间依赖性作用的背景和证据，并重点介绍了正在研究的新型非抗菌大环内酯类，其免疫调节和屏障强化特性，以规避细菌耐药性的风险发生在大环内酯类抗菌药中。我们还简要回顾了大环内酯类药物在与上皮损伤相关的呼吸道疾病和其他炎症性疾病中的临床作用，并提出非抗菌阿奇霉素衍生物在慢性炎症中的有益上皮作用，即使是预防性给药，在未来也可能受到越来越多的关注。