Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sci Transl Med. 2023 Jun 7;15(699):eabo7728. doi: 10.1126/scitranslmed.abo7728.
Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal airway obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to airway disease, including cystic fibrosis (CF). Consistent with requirements for luminal O, airway epithelia surrounding mucus plugs in chronic obstructive pulmonary disease (COPD) lungs are hypoxic. Despite these observations, the effects of chronic hypoxia (CH) on airway epithelial host defense functions relevant to pulmonary disease have not been investigated. Molecular characterization of resected human lungs from individuals with a spectrum of muco-obstructive lung diseases (MOLDs) or COVID-19 identified molecular features of chronic hypoxia, including increased expression, in epithelia lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic airway epithelia revealed conversion to a glycolytic metabolic state with maintenance of cellular architecture. Chronically hypoxic airway epithelia unexpectedly exhibited increased MUC5B mucin production and increased transepithelial Na and fluid absorption mediated by HIF1α/HIF2α-dependent up-regulation of β and γENaC (epithelial Na channel) subunit expression. The combination of increased Na absorption and MUC5B production generated hyperconcentrated mucus predicted to perpetuate obstruction. Single-cell and bulk RNA sequencing analyses of chronically hypoxic cultured airway epithelia revealed transcriptional changes involved in airway wall remodeling, destruction, and angiogenesis. These results were confirmed by RNA-in situ hybridization studies of lungs from individuals with MOLD. Our data suggest that chronic airway epithelial hypoxia may be central to the pathogenesis of persistent mucus accumulation in MOLDs and associated airway wall damage.
与实体器官不同，人类气道上皮细胞从吸入的空气中获取氧气，而不是从脉管系统中获取。许多肺部疾病与腔内气道阻塞有关，这些阻塞是由吸入的异物、病毒感染、肿瘤或气道疾病固有的黏液栓引起的，包括囊性纤维化 (CF)。与管腔 O 的需求一致，慢性阻塞性肺疾病 (COPD) 肺部中黏液栓周围的气道上皮细胞缺氧。尽管有这些观察结果，但慢性缺氧 (CH) 对与肺部疾病相关的气道上皮宿主防御功能的影响尚未得到研究。对患有各种黏液阻塞性肺部疾病 (MOLDs) 或 COVID-19 的个体的切除肺进行的分子特征分析，确定了慢性缺氧的分子特征，包括在衬里黏液阻塞气道的上皮细胞中表达增加。使用培养的慢性低氧气道上皮细胞进行的体外实验显示，细胞代谢状态向糖酵解转化，同时保持细胞结构。出人意料的是，慢性低氧气道上皮细胞表现出增加的 MUC5B 粘蛋白产生和跨上皮 Na 和液体吸收增加，这是由 HIF1α/HIF2α 依赖性上调 β 和 γENaC（上皮 Na 通道）亚基表达介导的。Na 吸收增加和 MUC5B 产生的组合产生了预测会持续阻塞的高浓度黏液。慢性低氧培养气道上皮细胞的单细胞和批量 RNA 测序分析显示，涉及气道壁重塑、破坏和血管生成的转录变化。这些结果通过对患有 MOLD 的个体的肺进行 RNA 原位杂交研究得到了证实。我们的数据表明，慢性气道上皮缺氧可能是 MOLD 中持续黏液积聚和相关气道壁损伤发病机制的核心。
