Epithelial cell-specific loss of function of Miz1 causes a spontaneous COPD-like phenotype and up-regulates Ace2 expression in mice

被引：15

作者：

Do-Umehara, Hanh Chi ^{[1
,2
]}

Chen, Cong ^{[3
]}

Zhang, Qiao ^{[3
]}

Misharin, Alexander, V ^{[3
]}

Abdala-Valencia, Hiam ^{[3
]}

Casalino-Matsuda, S. Marina ^{[3
]}

Reyfman, Paul A. ^{[3
]}

Anekalla, Kishore R. ^{[3
]}

Gonzalez-Gonzalez, Francisco J. ^{[3
]}

Sala, Marc A. ^{[3
]}

Peng, Chao ^{[4
]}

Wu, Ping ^{[4
]}

Wong, Catherine C. L. ^{[5
]}

Kalhan, Ravi ^{[3
]}

Bharat, Ankit ^{[3
,6
]}

Perlman, Harris ^{[7
]}

Ridge, Karen M. ^{[3
]}

Sznajder, Jacob, I ^{[3
]}

Sporn, Peter H. S. ^{[3
,13
]}

Chandel, Navdeep S. ^{[3
]}

Yu, Jindan ^{[8
]}

Fu, Xiangdong ^{[9
,10
]}

Petrache, Irina ^{[11
,12
]}

Tuder, Rubin ^{[12
]}

Budinger, G. R. Scott ^{[3
,13
]}

Liu, Jing ^{[1
,2
]}

机构：

[1] Univ Illinois, Coll Med, Dept Surg, Chicago, IL 60612 USA

[2] Univ Illinois, Univ Illinois, Canc Ctr, Chicago, IL 60612 USA

[3] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60611 USA

[4] Chinese Acad Sci, Natl Facil Prot Sci Shanghai, Zhangjiang Lab, SARI, Shanghai 201210, Peoples R China

[5] Peking Univ, Sch Pharmaceut Sci, Beijing 100191, Peoples R China

[6] Northwestern Univ, Dept Surg, Div Thorac Surg, Feinberg Sch Med, Chicago, IL 60611 USA

[7] Northwestern Univ, Div Rheumatol, Feinberg Sch Med, Chicago, IL 60611 USA

[8] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA

[9] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[10] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA

[11] Natl Jewish Hlth, 1400 Jackson St,Molly Blank Bldg,J203, Denver, CO 80206 USA

[12] Univ Colorado, Hlth Sci Ctr, Dept Med, Div Pulm Sci & Crit Care Med, Denver, CO 80206 USA

[13] Jesse Brown Vet Affairs Med Ctr, Chicago, IL 60612 USA

来源：

SCIENCE ADVANCES | 2020年 / 6卷 / 33期

关键词：

GENOME-WIDE ASSOCIATION; NF-KAPPA-B; OBSTRUCTIVE PULMONARY-DISEASE; SMOKE-INDUCED EMPHYSEMA; SURFACTANT PROTEIN-D; RNA-SEQ STRATEGY; LUNG-FUNCTION; INFLAMMATION; MACROPHAGES; INJURY;

D O I：

10.1126/sciadv.abb7238

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13