Cigarette smoke-related lung diseases is one of the most common causes of disability and death among veterans. Despite an overall decline in the smoking prevalence in the United States, smoking incidence remains higher in veterans when compared to the same age group in the general population. According to nationwide estimates, over 75% of the veterans in the United States are either current or former smokers which puts this group at a very high risk for developing chronic obstructive pulmonary disease (COPD) and emphysema. COPD is characterized by destruction of lung matrix, especially elastin, resulting in loss of elastic recoil, air trapping and lung hyperinflation. In addition to macrophages and neutrophils, lung tissue examined in subjects with emphysema is enriched with T helper type 1 (Th1) cells, CD4+ and CD8+ T lymphocytes that secrete cytokines such as interleukin 2 (IL-2), and interferon gamma (IFN-g). We found that autoreactive lymphocytes isolated from emphysematous lung express IFN-3 inducible protein of 10 kD (IP-10, CXCL10), and strongly up-regulate macrophage elastolytic proteinases, in particular MMP12 and MMP9. Although these data suggest an adaptive immune basis to human COPD/emphysema, we yet know little about how the immune response is initiated and organized against a toxic inhalant such as tobacco smoke. Further, progressive lung destruction as is observed in many subjects with COPD, even years after smoking cessation, suggests the presence of a uniquely persistent antigen or immune response modifier, the nature of which remains entirely undefined, but which promotes maladaptive inflammatory responses. Our two specific objectives are: Objective 1. To determine the role of CD4 T helper subsets in the regulation of MMPs in the pathogenesis of COPD and emphysema. In support of this aim, we have found that Th1 cells persist in the lung of former-smokers with emphysema despite years of smoking cessation. Objective 2. To determine the role of complement proteins in the activation of innate and adaptive immunity in human emphysema/COPD. In support of this aim, we have found in emphysematous lung deposition of large amounts of activated fragments of complement protein 3 (C3; C3b, C3d). Potential Impact on Veteran's Health Care: The success of our proposed studies will provide new understanding behind the mechanism of COPD and emphysema that will move the field towards therapies using novel immune-based medicines. Because smoking related lung diseases are quite prevalent among Veterans, our immune-based studies with an eye towards finding new immune modulators that could be used for treatment of emphysema will uniquely benefit this population. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to investigate the type of white blood cells that are associated with human emphysema in order to develop a treatment plan to stop the progression of the disease. We believe that by isolating the factors that control the secretion of destructive proteins by special white blood cells, we could find drugs that would prevent the progression of emphysema. This is an exciting area of research that could benefit the veterans that make a large portion of the general smoking population.