A Northwestern Medicine study found that inducing inflammation in lung epithelial cells contributes to the development of chronic obstructive pulmonary disease (COPD), according to findings published in the journal Science Advances.
“This study found that mouse models with just a slight increase in epithelial inflammation induced by the loss of one copy of the gene MIZ1 looked normal when they were young, but developed emphysema as they aged, mirroring what we see in human patients,” said Scott Budinger, MD, the Ernest S. Bazley Professor of Airway Diseases, chief of Pulmonary and Critical Care in the Department of Medicine and co-senior author of the study.
Jing Liu, MD, a former postdoctoral fellow in the Budinger laboratory and currently an associate professor of Surgery at the University of Illinois, Chicago, was co-senior author of the study.
Inflammation is directly involved in the development of COPD, a group of lung diseases including emphysema and chronic bronchitis that block airflow and make breathing difficult. Currently, COPD is the fourth-leading cause of death in the world due to cigarette use, a direct cause of inflammation in the lungs. However, current therapies for COPD are not curative and only treat symptoms of the disease.
“Anti-inflammatory therapies like steroids have been used, but they increase the risk of pneumonia. Our findings suggest better targeted anti-inflammatory treatments might help prevent or slow the progression of COPD,” said Budinger, also a professor of Medicine in the Division of Pulmonary and Critical Care, of Cell and Developmental Biology, and a member of the Robert H. Lurie Comprehensive Center of Northwestern University.
“It has long been known that cigarette smoke induces inflammation in almost every cell in the lung. It’s also known that in some people, this inflammation persists even after they stop smoking. However, it was not known if inflammation was causing COPD or was just a marker of a susceptible person,” Budinger said.
By utilizing mouse models chronically exposed to cigarette smoke, the investigators were able to replicate the features of COPD by deleting one copy of MIZ1, which is necessary to turn off inflammation in lung epithelial cells. Over time, the investigators observed the progressive development of COPD in the mice, similar to what is seen in humans who develop the disease.
The scientists also found that the level of the MIZ1 protein was reduced in the lungs of patients with COPD from Northwestern Medicine’s lung transplant program. Furthermore, they found that loss of MIZ1 upregulated the expression of ACE2, the receptor for the SARS-CoV-2 virus, providing another explanation for the observed link between cigarette smoking and an increased risk of developing severe COVID-19.
As for next steps, Budinger said the team is currently studying how the levels of MIZ1 in lung epithelial cells are regulated, with an end goal of developing targeted treatments.
“One can imagine a personalized approach to COPD prevention in which MIZ1 or other inflammatory proteins could be measured in lung or even nasal epithelial cells after people stop smoking. Targeted anti-inflammatory therapy could be given to those who have continued lung inflammation,” Budinger said.
This study was supported by the National Institutes of Health grants HL114763, HL141459, ES013995, HL071643, AG049665 R01HL131745, HL145478, HL147290, HL147575 and K08HL146943; the Veterans Administration grant BX000201; the Department of Defense grant PR141319; the National Institute of Allergy and Infectious Diseases grant AI135964; the David W. Cugell and Christina Enroth-Cugell Fellowship; Parker B. Francis Fellowship; and the ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF.