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.
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.
| Gu, Bon-Hee; Madison, Matthew C; Corry, David et al. (2018) Matrix remodeling in chronic lung diseases. Matrix Biol 73:52-63 |
| Hong, M J; Gu, B H; Madison, M C et al. (2018) Protective role of ?? T cells in cigarette smoke and influenza infection. Mucosal Immunol 11:894-908 |
| Kheradmand, Farrah; You, R; Hee Gu, Bon et al. (2017) Cigarette Smoke and DNA Cleavage Promote Lung Inflammation and Emphysema. Trans Am Clin Climatol Assoc 128:222-233 |
| Tung, Hui-Ying; Landers, Cameron; Li, Evan et al. (2016) Allergen-encoded signals that control allergic responses. Curr Opin Allergy Clin Immunol 16:51-8 |
| Yuan, X; Shan, M; You, R et al. (2015) Activation of C3a receptor is required in cigarette smoke-mediated emphysema. Mucosal Immunol 8:874-85 |
| Casal, Roberto F; Nogueras-González, Graciela; Kheradmand, Farrah (2015) Reply: Is Endobronchial Ultrasound Influenced by Sedation Strategy? Comparing Apples to Apples. Am J Respir Crit Care Med 191:1470-1 |
| Bhavani, Sivasubramanium; Tsai, Chu-Lin; Perusich, Sarah et al. (2015) Clinical and Immunological Factors in Emphysema Progression. Five-Year Prospective Longitudinal Exacerbation Study of Chronic Obstructive Pulmonary Disease (LES-COPD). Am J Respir Crit Care Med 192:1171-8 |
| Lu, Wen; You, Ran; Yuan, Xiaoyi et al. (2015) The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote T(H)17 cell-dependent emphysema. Nat Immunol 16:1185-94 |
| Chen, Min; Hong, Monica Jeongsoo; Sun, Huanhuan et al. (2014) Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med 20:503-10 |
| Xu, Chuang; Hesselbacher, Sean; Tsai, Chu-Lin et al. (2012) Autoreactive T Cells in Human Smokers is Predictive of Clinical Outcome. Front Immunol 3:267 |
Showing the most recent 10 out of 11 publications
