Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, United Kingdom.
NIHR Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, United Kingdom.
Front Immunol. 2021 Mar 24;12:653969. doi: 10.3389/fimmu.2021.653969. eCollection 2021.
Under normal physiological conditions, the lung remains an oxygen rich environment. However, prominent regions of hypoxia are a common feature of infected and inflamed tissues and many chronic inflammatory respiratory diseases are associated with mucosal and systemic hypoxia. The airway epithelium represents a key interface with the external environment and is the first line of defense against potentially harmful agents including respiratory pathogens. The protective arsenal of the airway epithelium is provided in the form of physical barriers, and the production of an array of antimicrobial host defense molecules, proinflammatory cytokines and chemokines, in response to activation by receptors. Dysregulation of the airway epithelial innate immune response is associated with a compromised immunity and chronic inflammation of the lung. An increasing body of evidence indicates a distinct role for hypoxia in the dysfunction of the airway epithelium and in the responses of both innate immunity and of respiratory pathogens. Here we review the current evidence around the role of tissue hypoxia in modulating the host-pathogen interaction at the airway epithelium. Furthermore, we highlight the work needed to delineate the role of tissue hypoxia in the pathophysiology of chronic inflammatory lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease in addition to novel respiratory diseases such as COVID-19. Elucidating the molecular mechanisms underlying the epithelial-pathogen interactions in the setting of hypoxia will enable better understanding of persistent infections and complex disease processes in chronic inflammatory lung diseases and may aid the identification of novel therapeutic targets and strategies.
在正常生理条件下，肺部保持着富含氧气的环境。然而，缺氧的显著区域是感染和炎症组织的常见特征，许多慢性炎症性呼吸系统疾病与黏膜和全身缺氧有关。气道上皮代表了与外部环境的关键接口，是抵御包括呼吸道病原体在内的潜在有害因子的第一道防线。气道上皮的保护机制以物理屏障的形式提供，并且通过受体激活产生一系列抗菌宿主防御分子、促炎细胞因子和趋化因子。气道上皮固有免疫反应的失调与肺的免疫功能受损和慢性炎症有关。越来越多的证据表明，缺氧在气道上皮功能障碍以及固有免疫和呼吸道病原体反应中起着独特的作用。在这里，我们回顾了关于组织缺氧在调节气道上皮的宿主-病原体相互作用中的作用的现有证据。此外，我们强调需要阐明组织缺氧在哮喘、囊性纤维化和慢性阻塞性肺疾病等慢性炎症性肺部疾病以及 COVID-19 等新型呼吸道疾病的病理生理学中的作用。阐明缺氧条件下上皮-病原体相互作用的分子机制将有助于更好地理解慢性炎症性肺部疾病中的持续性感染和复杂疾病过程，并可能有助于确定新的治疗靶点和策略。
