Prior work from our Emphysema/COPD Research Center (ECRC), in collaboration with colleagues at the? University of British Columbia, Vancouver, has provided strong evidence that adaptive immune abnormalities? play a critical role in the pathogenesis of peripheral airway remodeling in Chronic Obstructive Pulmonary? Disease. We will outline our evidence from both lung tissue explants and peripheral blood markers that? supports this hypothesis. We further hypothesize that modulation of these immune responses with specific? biologic agents could ablate, or ameliorate these pathogenic mechanisms, and alter the natural history of? COPD. This proposal outlines a prototype aerosol intervention protocol based upon the long-term experience? at the University of Pittsburgh with the use of aerosol cyclosporine (aCsA) for the prevention of bronchiolar? inflammation in the lung transplantation population.? This project will outline sequential Phase I and Phase I/I I trials to explore the short (28 days) and? intermediate term (6 month) safety of aCsA immunotherapy applied to a population of patients with? moderately severe (Gold III) COPD. A Phase I initial dose escalation-deescalation protocol (DEP) will? examine short-term safety issues with attention to airway reactivity and infection risk. The observations? learned from the DEP, will be incorporated into the design and execution of a randomized, parallel-design,? moderate duration Phase I/I I exploratory trial. Our therapeutic goal in both the DEP and AIC will be to define? the minimum tolerated aCsA dose associated with biologic efficacy, using peripheral blood marker? bioassays.? The data and human specimens from this intervention trial will be used collaboratively with Projects 1-3 of? this proposal to gain insight into the pathogenesis of moderately advanced COPD under the influence of? immunoregulatory control.? We believe aCsA provides an immediately available, innovative, approach to potentially treat the adaptive? immune response documented in COPD patients. The clinical investigation protocol outlined in this proposal? will fulfill the stated application goal to identify, """""""" high-risk/high-gain tests of novel therapeutic approaches,? both in animal models and as Phase l/ll clinical trials.""""""""

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084948-02
Application #
7700623
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
2
Fiscal Year
2008
Total Cost
$305,414
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ajala, Oluremi; Zhang, Yingze; Gupta, Aman et al. (2018) Decreased serum TRAIL is associated with increased mortality in smokers with comorbid emphysema and coronary artery disease. Respir Med 145:21-27
Radder, Josiah E; Zhang, Yingze; Gregory, Alyssa D et al. (2017) Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction. Am J Respir Crit Care Med 196:159-171
de-Torres, Juan P; Wilson, David O; Sanchez-Salcedo, Pablo et al. (2015) Lung cancer in patients with chronic obstructive pulmonary disease. Development and validation of the COPD Lung Cancer Screening Score. Am J Respir Crit Care Med 191:285-91
Wilson, David O (2015) Sedation Options for Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. Am J Respir Crit Care Med 192:397-8
Sanchez-Salcedo, Pablo; Wilson, David O; de-Torres, Juan P et al. (2015) Improving selection criteria for lung cancer screening. The potential role of emphysema. Am J Respir Crit Care Med 191:924-31
Sze, Marc A; Utokaparch, Soraya; Elliott, W Mark et al. (2015) Loss of GD1-positive Lactobacillus correlates with inflammation in human lungs with COPD. BMJ Open 5:e006677
Thalanayar, Prashanth M; Altintas, Nejat; Weissfeld, Joel L et al. (2015) Indolent, Potentially Inconsequential Lung Cancers in the Pittsburgh Lung Screening Study. Ann Am Thorac Soc 12:1193-6
Bon, Jessica; Kahloon, Rehan; Zhang, Yingze et al. (2014) Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers. PLoS One 9:e105066
Gu, Suicheng; Meng, Xin; Sciurba, Frank C et al. (2014) Bidirectional elastic image registration using B-spline affine transformation. Comput Med Imaging Graph 38:306-14
Gingo, Matthew R; He, Jiayan; Wittman, Catherine et al. (2014) Contributors to diffusion impairment in HIV-infected persons. Eur Respir J 43:195-203

Showing the most recent 10 out of 86 publications