Although tobacco smoke is the primary risk factor for development of chronic obstructive pulmonary disease (COPD), additional pathologic processes appear to be critical for disease progression. Our previously published findings show the lesions of small airways that define COPD are highly associated with histologic evidence of adaptive immune responses. Recent preliminary observations by our group also show that the severity of COPD is closely correlated with expressions of selected immune and injury response mediators in airways and sera of afflicted patients. Furthermore, peripheral T-cells among these patients exhibit strikingly abnormal activation phenotypes and effector functions that correlate with disease severity. We have also demonstrated a soluble mediator(s), uniquely elaborated by the T-cells from COPD patients, induces marked abnormalities of differentiated human airway epithelial cells. In addition, we have documented the presence of circulating anti-epithelial IgG antibodies in COPD patients, and the pathogenic relevance of this observation is corroborated by findings of IgG deposition within COPD lungs. We hypothesize abnormalities of adaptive immunity play an important role in the pathogenesis of COPD progression. The investigations proposed in this Project will further define the nature and role of these injurious processes. The antigen specificity of the T-cells that incite and sustain these responses will be confirmed by findings of clonal proliferations proximate to diseased small airways. Additional correlative immune and injury gene expressions in situ from among lesions of varying severity will identify and confirm important pathogenic mechanisms of COPD progression. The mediators elaborated by COPD T-cells that directly injure airway epithelium will be identified with a unique in vitro model, using cellular materials derived from COPD lungs. Detailed characteristics of the autoantibody productions in COPD patients will be further defined, and correlates with clinical and T-cell functions will be established. These interrelated investigations will further our basic understandings of COPD pathogenesis, and will likely illustrate cellular subpopulations and mechanisms that may be amenable to novel therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084948-03
Application #
7750500
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2009
Total Cost
$513,505
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

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