期刊
SCIENCE ADVANCES
卷 6, 期 33, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abb7238
关键词
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资金
- NCI CCSG [P30 CA060553]
- U.S. NIH [HL114763, HL141459]
- NIH [K08HL146943, ES013995, HL071643, AG049665, R01HL131745, HL145478, HL147290, HL147575]
- Veterans Administration [BX000201]
- Department of Defense grant [PR141319]
- NIH/NIAID [AI135964]
- David W. Cugell and Christina Enroth-Cugell Fellowship
- Parker B. Francis Fellowship
- ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc.
Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Mizi, which we identified as a negative regulator of nuclear factor kappa B (NF-kappa B) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARS-CoV-2. Concomitant partial loss of NF-kappa B/RelA prevented the development of COPD-like phenotype in Miz1-deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-kappa B-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.
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