Role of p53 and PAI-1 in Tobacco Smoke-Induced Lung Injury
Abstract
Topic Area: Respiratory Health (excludes lung cancer and mesothelioma). Chronic exposure to tobacco smoke (TSE) due to active cigarette smoking or passive TSE or exposure to toxic particulates causes irritation of and damage to the lung epithelium. This can lead to chronic obstructive pulmonary disease (COPD). U.S. military personnel deployed in support of combat operations in different parts of the world may be at increased risk for developing lung disease including COPD. Acute exacerbations of COPD are the second leading cause of hospital stays and incur costs of >18 billion dollars annually in the US. It affects up to 24 million people. COPD is the third leading cause of death by disease in the United States. More than 11 million people have been diagnosed with COPD, but millions more may have the disease without even knowing it. COPD causes serious long-term disability and early death. Currently there is no cure, and the number of people dying from COPD is growing. Pathogenesis of COPD has been directly linked to a loss of alveolar structure due to alveolar type II epithelial cell (A2C) senescence and apoptosis. TSE and COPD lung injury are also characterized by lung inflammation, telomere dysfunction, and senescence and apoptosis in A2Cs. These changes are intricately linked to induction of tumor suppressor protein, p53 and plasminogen activator inhibitor-1 (PAI-1), telomere dysfunction in A2Cs, and all are clinically relevant and occur in COPD patients. There is currently no treatment available to reverse the progression of COPD-related lung injury. We will define how p53 and PAI-1 affect TSE-induced telomere dysfunction in A2Cs. We will use a novel treatment approach with a peptide (CSP7) in liquid or dry powder formulation for airway delivery to mitigate deleterious effects of TSE. TSE induces recruitment of specialized immune cells and these cells secrete protein (IL-17A), which contributes to chronic lung inflammation and destruction of the lung epithelium, leading to narrowing of small airways and distal lung wall destruction. This can lead to COPD characterized with symptoms of chronic cough and shortness of breath. We found that increased IL-17A is linked to p53 and PAI-1 induction in TSE-induced lung injury. We will use a range of molecular and novel treatment approaches, including CSP7 delivered via inhalation, to inhibit lung injury or COPD caused by chronic TSE. This project offers an opportunity to develop effective targeting strategies to improve lung injury associated with chronic TSE including COPD/emphysema.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010142
Entities
People
- Sreerama Shetty
Organizations
- United States Army
- University of Texas Health Science Center at Tyler