Chronic mucus hypersecretion (CMH) and chronic bronchitis (CB) are variable but significant symptoms in COPD. They have been associated with a more rapid decline in lung function and an increased risk of hospitalization and infection. This is characterized pathologically by mucous metaplasia of the airway epithelial layer. As opposed to asthma, where the inflammatory mechanisms of mucous metaplasia are established, the inflammatory mechanisms leading to the development of mucous metaplasia in COPD are not known. The clinical and radiographic characteristics of COPD patients with CB have not been well characterized, and the inflammatory biomarkers of disease activity that can predict outcomes in COPD patients with or without CB are also not known. Based on the literature and our prior studies, I believe that we can establish the role of Th17 inflammation in mucous metaplasia development and as biomarkers of disease. We will establish the causal relationship of individual Th17 cytokines, as well as combinations of cytokines, on mucin gene expression in vitro in human airway epithelial cell studies. We will enroll COPD patients and assess their symptoms of sputum production using a comprehensive symptom diary. To validate our in vitro data, we will obtain bronchoscopic mucosal biopsies and epithelial brushings to quantitate mucous metaplasia and bronchoalveolar lavage fluid to measure Th17 cytokines. Finally, we will be able to relate Th17 inflammation with respiratory symptomatology in our enrolled subjects. All together, we will establish that Th17 inflammation is responsible for mucous metaplasia in COPD and pave the way towards developing a clinico-pathologic mucous metaplasia phenotype. I will pursue my goal of becoming an independent investigator in translational medicine by obtaining a Masters Degree of Clinical Research and Translational Medicine, obtaining further education in the responsible conduct of clinical research, and learning more bench research skills. I will rely on the mentorship of Gerard Criner, MD for his expertise in clinical research, Thomas J. Rogers, PhD for his expertise in lung immunology, and K. Chul Kim, PhD, for his expertise in mucin biochemistry.

Public Health Relevance

Chronic mucus hypersecretion, chronic bronchitis, and mucous metaplasia have been associated with a more rapid decline in lung function and an increased risk of hospitalization and infection. The mechanisms behind the development of mucous metaplasia are not known, and the clinical and radiographic characteristics of patients with these phenomena are not well characterized. Identification of the mechanisms behind mucous metaplasia as well as the clinical, radiographic, and inflammatory characteristics can help predict disease course more accurately than our current means of disease classification.

Agency
National Institute of Health (NIH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL094696-04
Application #
8703162
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Tigno, Xenia
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Kim, Victor; Davey, Adam; Comellas, Alejandro P et al. (2014) Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. Respir Res 15:52
Washko, G R; Diaz, A A; Kim, V et al. (2014) Computed tomographic measures of airway morphology in smokers and never-smoking normals. J Appl Physiol (1985) 116:668-73
Ramos, Frederick L; Krahnke, Jason S; Kim, Victor (2014) Clinical issues of mucus accumulation in COPD. Int J Chron Obstruct Pulmon Dis 9:139-50
Kim, Victor; Criner, Gerard J (2013) Chronic bronchitis and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 187:228-37
Diaz, Alejandro A; Han, Meilan K; Come, Carolyn E et al. (2013) Effect of emphysema on CT scan measures of airway dimensions in smokers. Chest 143:687-93
Kim, Victor; Sternberg, Alice L; Washko, George et al. (2013) Severe chronic bronchitis in advanced emphysema increases mortality and hospitalizations. COPD 10:667-78