While the causal relationship between cigarette smoke exposure and development of chronic obstructive pulmonary disease (COPD) has been firmly established, the mechanisms underlying differing susceptibilities and manifestations of lung disease in humans remains unclear. Experimental models suggest that cigarette smoke exposure induces pro-inflammatory cytokines and increased apoptosis within the lung, leading to airways remodeling and emphysema-predominant subphenotypes of COPD. Chronic viral infection has been demonstrated to augment the development of emphysema in animal models. In this application, we plan to investigate these potential mechanisms for COPD subphenotype development in a group of individuals from the Study of HIV Epidemiology in Lung Disease (SHIELD). SHIELD is an ongoing cohort study of individuals at-risk or with HIV that seeks to understand how HIV infection affects various lung diseases. In this proposal, we will conduct an ancillary study that explores proposed mechanisms of COPD development in this population with chronic viral infection. Specifically, we will correlate the presence of obstruction on spirometric testing with high resolution computed tomography (HRCT) quantification of airways remodeling and emphysema in 500 SHIELD participants. We will assess the effect of HIV infection on HRCT scores in individuals with and without obstruction. We will also collect bronchoalveolar lavage and airway epithelial brushings in a subset of participants. These biological samples will be used to assay inflammatory and apoptotic markers, correlating the levels with presence of obstruction, HRCT quantification of airways remodeling/emphysema and serum levels of viremia. We will identify 20 individuals initiating anti-retroviral therapy (ART) in the setting of clinical care and obtain HRCT quantification and bronchoscopic samples before and after initiating ART to determine the effects of ART and viremic reduction on these measures. Ultimately, the information gained from this application will contribute to the understanding of mechanisms underlying the development of COPD subphenotypes. Additionally, these data will allow for a better understanding of the impact of chronic viral infections, specifically HIV, on COPD susceptibility. The applicant, a current K12 awardee, has demonstrated a dedication to a career in clinical research. Early in his career, he has demonstrated motivation and productivity in his ongoing research endeavors. This application is structured to allow the candidate to achieve his long term career goal of becoming an independent clinical investigator exploring potential therapies that improve the treatment and outcomes of those affected by COPD. In the immediate timeframe, this proposal would allow the applicant dedicated time to conduct the outlined research project as well as pursue didactic training in advanced biostatistics and immunology relevant to this project and future research plans. Additionally, the data generated from this research proposal will form the basis for an R01 application. The research career development plan for this applicant includes a structured approach to mentoring, didactic coursework focused on specific research goal, participation in local and national meetings, and identification and regular assessment of career milestones. The research environment provided by Johns Hopkins University as well as the mentorship team outlined in this application will assist in a successful completion of the candidate's career and research goals. The Division of Pulmonary and Critical Care Medicine and Johns Hopkins University have a long history of training successful clinical researchers in a supportive and collaborative environment. The pre-existing structure of SHIELD, the umbrella project for this application, will ensure that study procedures will be completed within the timeframe of this award. We have assembled a mentoring team of established faculty with many years of productive research experience and substantial prior mentoring experience. Each has distinct, complementary strengths in areas of research relevant to this proposal. In addition, each member of the mentoring committee serves as an excellent role model for the applicant's career development into an independent investigator. Project Narrative: This project seeks to understand the different ways that cigarette smoke leads to the development of chronic obstructive pulmonary disease (COPD). As well, we set out to determine how human immunodeficiency virus (HIV) infection increases the risk of COPD. Ultimately, these studies should help reduce illness and death among those with COPD and HIV.

Public Health Relevance

This project seeks to understand the different ways that cigarette smoke leads to the development of chronic obstructive pulmonary disease (COPD). As well, we set out to determine how human immunodeficiency virus (HIV) infection increases the risk of COPD. Ultimately, these studies should help reduce illness and death among those with COPD and HIV.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL103192-03
Application #
8277870
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Tigno, Xenia
Project Start
2010-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$162,704
Indirect Cost
$11,454
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Drummond, M Bradley (2014) Obstructive airway disease in urban populations. Curr Opin Pulm Med 20:180-5
Lambert, Allison A; Kirk, Gregory D; Astemborski, Jacquie et al. (2014) A cross sectional analysis of the role of the antimicrobial peptide cathelicidin in lung function impairment within the ALIVE cohort. PLoS One 9:e95099
Drummond, M Bradley; Kirk, Gregory D (2014) HIV-associated obstructive lung diseases: insights and implications for the clinician. Lancet Respir Med 2:583-92
Drummond, M Bradley; Kirk, Gregory D; Astemborski, Jacquie et al. (2012) Association between obstructive lung disease and markers of HIV infection in a high-risk cohort. Thorax 67:309-14
Drummond, M Bradley; Kirk, Gregory D; Astemborski, Jacquie et al. (2011) Prevalence and risk factors for unrecognized obstructive lung disease among urban drug users. Int J Chron Obstruct Pulmon Dis 6:89-95