Incretin Mimetics and Thiazolidinediones as Therapy Against Excessive Airway Mucus to Improve Lung Function in COPD Patients
Abstract
COPD epidemic: This Fiscal Year 2022 (FY22) Peer Review Medical Research Program (PRMRP) application focuses on the Topic Area of Respiratory Health. Especially, we address the Chronic Obstructive Pulmonary Disease (COPD), which affects large numbers of Veterans and their beneficiaries. The prospects for individuals diagnosed with COPD are grim. It is a major cause of disability and the third leading cause of death in the U.S. According to the National Institute of Heart, Lung and Blood, approximately 15 million people in the U.S. have COPD, and another 10 million are undiagnosed. In 2011, there were approximately 730,000 hospitalizations for COPD, costing $5.7 billion. Tobacco smoking is the most common cause of COPD. Other important factors include air pollutants, such as toxic desert dusts inhaled by soldiers in the Middle East theaters, biomass smoke, and genetics. The odds of COPD in cigarette smokers are 318% greater than in nonsmokers. Unfortunately, the prevalence of tobacco use among the Veterans (39% in 2007) is staggeringly higher than the general U.S. population (19.8%). Long-term exposure to these irritants exacerbates inflammatory response, resulting in narrowing of the small airways and emphysema. The most common symptoms of COPD are excessive mucus and sputum production, microbial infection, shortness of breath, productive cough, chest tightness, and wheezing. Advanced COPD may lead to high pressure on the lung arteries, which cause leg swelling and bulging neck veins. A feeling of always being tired is common. COPD often occurs along with diabetes mellitus, ischemic heart disease, high blood pressure, muscle wasting, osteoporosis, lung cancer, anxiety disorder, and depression. An acute exacerbation of COPD is defined as increased cough, shortness of breath, increased sputum production, and a change in the sputum color from clear to green and yellow due to infection. No specific therapies for COPD: Current therapeutic efforts target symptoms and quality of life and include smoking cessation, oxygen infusion, vaccination against pathogens, PDE4 inhibitors, bronchodilators, inhaled corticosteroids, and antibiotics to manage bacterial-mediated acute exacerbations. There is no cure for COPD other than a lung transplant, and none of the U.S. Food and Drug Administration (FDA)-approved therapies have been approved for attenuating disease progression or reducing mortality rates. Thus, new lines of therapeutics for COPD are sorely needed, which is the premise of our proposal. FOXA2 as a therapeutic COPD target: Through multi-year, laborious, time-consuming, and expensive preclinical investigations in human lung cell culture models and in mice, we have shown that important COPD bacterial pathogens such as Pseudomonas aeruginosa cause mucus hypersecretion and emphysema by inactivating FOXA2, a critical lung protein that is needed to maintain healthy levels of mucus and for regulating emphysema development. And this focused effort has paid off: We have identified two classes of FDA-approved drugs for diabetes mellitus 2 - incretin mimetics and thiazolidinediones - that can effectively augment and preserve the function of FOXA2 in various human airway cell culture and mouse models of COPD even when infected by P. aeruginosa or exposed to its toxin pyocyanin. There is considerable data suggesting tremendous potential of FOXA2 as a drug target for COPD. The loss of FOXA2 function in mouse lung causes spontaneous proliferation of goblet cells that produce excessive mucus clogging the airways, as well as emphysema. These observations are supported with studies by us and others showing that FOXA2 expression level is inversely correlated to goblet cell hyperplasia in lung tissues of COPD, bronchiectasis, and asthmatic patients. Regrettably, current COPD treatments do not target FOXA2. Based on our data, there is an opportunity to dramatically improve lives of Veterans stricken with COPD by augment
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310372
Entities
People
- Gee Lau
Organizations
- United States Army
- University of Illinois Urbana–Champaign