Cigarette smoke-related lung diseases remain one of the most significant contributors to the shortening of life span and illness among our veterans. Over the past decade, our research has identified some of the critical mediators of inflammation that promotes the pathophysiology of human emphysema. Our initial discovery of activated T and B cells in the lungs of former smokers with emphysema, provided the rationale for pursing the role of acquired immunity that can perpetuate inflammation in the lungs of susceptible smokers. Despite smoking cessation, we and others have identified autoreactive CD4 T helper 1 (Th1), and Th17 cells that secrete IFN-? and IL-17A directed against lung matrix proteins in smokers with emphysema. In a pre-clinical model of smoke-induced emphysema, we have shown that smoke activates lung myeloid dendritic cells (mDC) and decreases peripheral immune tolerance, in part by activating complement protein 3 (C3). Among the earliest pathological immune events activated by smoking, accumulation of smoke-derived, particulate matter activates the IL-1?-mediated inflammasome pathways, inhibits anti-inflammatory mediators (e.g., PPAR-?), and expands lung Th1 and Th17 cells. IL-17A and chemokines induced by IFN-? (e.g., CXCL10) strongly upregulate matrix metalloproteinase 12 (MMP12) and MMP9 in mDC, which destroy elastin fibrils in the lungs. Mice exposed to cigarette smoke have activated lung mDCs, which stimulate Th1/Th17 cell differentiation and are critical in emphysema development. However, the molecular mechanisms responsible for smoke-mediated activation of mDCs, and the downstream pathways that promote emphysema development remain unknown. Our microarray analysis of human lung mDCs showed significantly reduced expression of complement protein 1 (C1q) mRNA in emphysema, and acquired loss of C1q is associated with autoimmune inflammatory diseases. In this application will test the central hypothesis that cigarette smoke induced suppression of C1q coordinates the dysregulated innate and acquired immune responses that drive emphysema. The premise of our studies is based on our preliminary data that C1q promotes anti-inflammatory T regulatory cells (Tregs) development and C1q-/- mice show exaggerated lung inflammation in response to chronic smoke. Collectively, our findings point to an immune modulatory role for C1q in emphysema; the significance of our proposal includes understanding mechanism that drive smoke-induced lung inflammation that could provide novel complement-based therapeutics to treat emphysema. Our three Aims are: 1) Determine the anti- inflammatory role of C1q in smoke induced lung inflammation and emphysema. Hypothesis: Cigarette smoke suppresses C1q in lung mDCs and/or alveolar macrophages thereby inhibiting Treg differentiation and/or function, and inducing autoreactive T cells. 2) Determine the molecular mechanisms responsible for cigarette smoke-mediated loss of C1q, and reduction of immune tolerance. Hypothesis: Cigarette smoke- induced activation of IL-1?? IL-6, and/or C3a, suppress C1q in lung mDCs and/or alveolar macrophages and reduce lung Tregs. 3) Determine the signaling pathways in T cells responsible for C1q-mediated enhancement of Treg differentiation. Hypotheses: C1q-mediated signaling pathways in T cells are critical for maintenance of immune tolerance.
Cigarette smoke-related lung diseases are the most common causes of disability and death among our veterans. Despite increase in understanding of how cigarette smoke causes lung damage and an overall decline in the smoking prevalence in the United States, smoking prevalence remains high among veterans when compared to the same age group in the general United States population. The proposed research is focused on studying the pathophysiology of COPD and thus has incontrovertible significance and relevance to the healthcare of veterans. Successful completion of this application could provide novel pathways that can be targeted to reverse smoke-induced lung damage. Therefore, success of our proposed studies will move the field towards developing therapies with novel immune-based treatments and gather new insight into disease pathogenesis using pre-clinical models of emphysema.
| 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 |
| 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 |
| 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 |
| 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
