The Role of TRAF6 in Primary Alveolar Epithelial Cell Injury
Abstract
We will address the Respiratory Health in FY20 PRMRP Topic Areas. Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States with 15.4 million physician visits and 1.5 million emergency department visits each year costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema belongs to COPD and causes shortness of breath. In people with emphysema, the air sacs in the lungs (alveoli) are damaged. Over time, the inner walls of the air sacs weaken and rupture — creating larger air spaces instead of many small ones. Cigarette smoke is the most common risk factor of this emphysema development, and the significance of this proposal is that there is very limited effective treatment available. Lung transplant is the common option, however, has a high mortality risk. Smoking during deployments and in soldiers with combat exposure is a growing health problem, particularly among junior-enlisted personnel, who have the highest smoking rates in the military personnel. The potential adverse effects of cigarette smoke on the lung function of U.S. military personnel are substantial. Besides the long-term health risks of smoking, new-onset smoking has been associated with lung injury, especially in deployed military personnel. Moreover, the synergistic effect of smoking and harmful exposure to environmental factors during deployment increases the risk of emphysema development. The alveolar cells are localized in the distal part of the lung and provide the barrier between inhaled air and the underlying tissue. To maintain this barrier, continuous cell replacement and repair is necessary after lung injury induced by harmful factors such as cigarette smoke and environmental exposure. Alveolar cells have a stem cell potential with the ability to self-renew, proliferate, and differentiate to restore the epithelium after damage and regenerate the lung. Cigarette smoke accelerates alveolar cell senescence, which decreases their function and proliferation. Our published studies indicate human lung damage after exposure to cigarette smoke. We also found that emphysematous changes in the lungs are associated with alveolar cell dysfunction and death. If alveolar cell loss is not compensated by cell proliferation, it leads to alveoli damage, impaired breathing, and emphysema progression. We first showed impaired repair of DNA damage in human alveolar cells isolated from patients with this disease. Human alveolar cell proliferation and differentiation in emphysema are unstudied. Poor understanding of the mechanisms that drive alveolar cell proliferation contributes to the lack of strategies to enhance lung regeneration and prevent this disease progression. There are no therapies available to restore alveolar cells, which urgently needs to be addressed. The molecular mechanisms leading to loss of alveolar cells and emphysema progression are not well understood. Recently, it has been reported that TRAF6 is a crucial protein that is essential for alveoli formation. TRAF6-mediated signaling is also critical for the homeostasis of stem cells and muscle tissue regeneration. However, its role in human alveolar cells, lung regeneration, and emphysema is unknown. In this project, we will use human alveolar cells to study the function of TRAF6 protein as a novel therapeutic target in emphysema. Cells will be isolated from de-identified organ donors whose lungs are not suitable for transplantation and were donated for medical research through the Gift of Life Foundation. We will use the lungs obtained from control non-smoker and smoker organ donors. We will use both females and males with matched race, age, and smoking status. We obtain approximately 3-4 lungs per month from organ donors without a history of chronic lung diseases. Alveolar cells will be also isolated from lung transplants of patients with emphysema performed at Temple University. There are only a few laboratories that can
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110414
Entities
People
- Beata Kosmider
Organizations
- Temple University
- United States Army