Dissecting Mechanisms of Emphysema and Lung Fibrosis in COPD
Abstract
Topic Area: Respiratory Health The burden of medical and social resources slated for tobacco-smoke-related diseases is predicted to be US$47 trillion by 2030 and is especially relevant for the Military and Veteran population with high incidence of smokers. Chronic Obstructive Pulmonary Disease (COPD) is a composite entity that includes chronic bronchitis and emphysema. Many of these patients also develop fibrosis or lung scarring. It is the fourth leading cause of death in the U.S. with tobacco smoking to be one of the major causes. Fifteen million people in the U.S. have COPD, with another 10 million undiagnosed. Unfortunately, the prevalence of tobacco use among Veterans (39%) is staggeringly higher than the general population (19.8%). Even though it is clear that cigarette smoke (CS) is the major cause of COPD, only 10%-15% of the patients who smoke develop COPD, suggesting that CS alone is not enough. Additional events are needed to induce the disease process. Respiratory infections also have more severe consequences in individuals who have been exposed to CS than in those who are not. The mechanisms that underlie the exaggerated virus-induced pathological lung responses in CS-exposed individuals have not been adequately addressed. Respiratory viruses cause increased levels of inflammation, tissue destruction, and fibrosis in CS-exposed mice. Influenza (Flu) infections are more severe, with more cough, phlegm production, and breathlessness in smokers. CS exposure was an important risk factor in the 1978 H1N1 influenza epidemic in healthy young military recruits. Pulmonary fibrotic changes (where the lung tissues are scarred due to many factors) often occur with emphysema (where the alveolar sacs important for gas exchanged are destroyed and become enlarged). This has been described in COPD patients with emphysema and with parenchymal fibrosis as combined pulmonary fibrosis and emphysema (CPFE). These interstitial lung abnormalities (ILA) such as fibrosis in COPD patients are associated with a greater risk of mortality. There is a group of COPD patients who have frequent flares or exacerbation of their COPD that results in increased rate of disease progression and loss of lung function. Acute exacerbations due to viruses are more severe, last longer, and are associated with heightened responses than exacerbations due to other non-viral causes. One of the biggest questions in COPD is how, in one patient, destructive emphysematous changes and proliferative fibrotic processes can take place in the same lung. The origin and nature of the underlying signals that dictate the destruction of the tissue or the proliferation of the tissue are not known. We propose to study how the lung epithelium, which lines the inside of the lungs, in COPD dictates these signals in close proximity to cause varying lung pathologies. It is possible that either the composition of COPD matrix or the properties of COPD lung epithelium dictate these divergent signals in response to CS with or without viral infections. The overall goal of this project is to determine what drives the COPD lung epithelium to signal to either fibrotic or emphysema response in the same lung given the same exposure of CS and/or viral infections. We will leverage spatial core sectioning of COPD lungs with both emphysema or fibrosis, single cell RNA sequencing, matrix protein analyses, in vivo cell-matrix and cell-cell co-culture models to address our questions. For Aim 1, we will identify the different signaling in the lung epithelium at the fibrotic foci and emphysematous foci and in between normal lung using single cell RNA sequencing and matrix protein analyses on precisely core-cut blocks of human COPD lungs. For Aim 2, we will determine the impact of the lung epithelium on matrix modified by composition and physical stiffness. For this aim, we will use a static model of air liquid interface using lung epithelial cells overlaying a tunable extracellula
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310034
Entities
People
- Charles S Dela Cruz
Organizations
- United States Army
- Yale University