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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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Special Emphasis Panel (ZHL1-CSR-A)
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University of Pittsburgh
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