| Title: |
Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration. |
| Authors: |
Mikami, Yu; Grubb, Barbara R.; Rogers, Troy D.; Dang, Hong; Asakura, Takanori; Kota, Pradeep; Gilmore, Rodney C.; Okuda, Kenichi; Morton, Lisa C.; Sun, Ling; Chen, Gang; Wykoff, Jason A.; Ehre, Camille; Vilar, Juan; van Heusden, Catharina; Livraghi-Butrico, Alessandra; Gentzsch, Martina; Button, Brian; Stutts, M. Jackson; Randell, Scott H. |
| Source: |
Science Translational Medicine; 6/7/2023, Vol. 15 Issue 699, p1-15, 15p |
| Subject Terms: |
Lungs; Lung diseases; Airway (Anatomy); Chronic obstructive pulmonary disease; Mucus; Hypoxemia |
| Abstract: |
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 O2, 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 EGLN3 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. Editor's summary: Airway hypoxia is common in obstructive pulmonary diseases caused by viral infection, foreign bodies, or mucus plugs, but the specific effects of chronic hypoxia on airway epithelial function are not clear. Here Mikami and colleagues found that in vitro exposure of airway epithelia to chronic hypoxia led to increased hyperconcentrated mucus production that was at least partially HIF1/HIF2 dependent. Using hypoxic lung tissue from patients with a variety of muco-obstructive lung diseases (MOLDs), including cystic fibrosis, they showed that increased sodium and fluid absorption may contribute to this phenotype. These results suggest that chronic hypoxia in airway epithelia may contribute to mucus production and airway damage in patients with MOLDs. —Allison Williams [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |