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The Role of Cigarette Smoke Exposure-Induced Activation of the Innate and Adaptive Pulmonary Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Motz, Gregory T.

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Toxicology (Environmental Health).
Chronic obstructive pulmonary disease (COPD) is expected to be the fourth leading cause of worldwide deaths within 20 years. The economic burden of COPD is measured by the billions of dollars in the United States, and increasing worldwide disease prevalence will place additional strains on the global economy. The chief cause of COPD is long term cigarette smoking, and most smokers will develop COPD if smoking-related, extrapulmonary diseases don’t claim their lives beforehand. In conjunction with smoking, the development of COPD is modified by genetics, environmental exposures (e.g., air pollution, occupational exposures), and infections. COPD is ultimately a failure of proper breathing, and most patients initially seek doctor consultation for dyspnea. Airflow restriction is brought about by a combination of chronic bronchitis, emphysema, and small airway disease, though the extent of each varies within individual patients. These pulmonary maladies result from inflammation, fibrosis, mucus hypersecretion, and alveolar destruction. The inflammation is the best correlate of disease severity in patients, and is critically involved in disease development experimentally. Attention has traditionally been centered on the roles of macrophages and neutrophils in disease development, but the roles of lymphocytes (T cells, B cells, NK cells) have recently received increased attention. However, the cellular mechanisms involved in COPD pathogenesis are not well-characterized. The stimulus driving the inflammatory response in COPD patients is obfuscated by frequent infections, smoking history, frequent coincidence of tumors, environmental exposures, and aging. The hypothesis tested in this dissertation is that chronic cigarette smoke exposure, as the sole stimulus, activates the pulmonary immune system. Further, I hypothesize that activation of both the innate and adaptive pulmonary immune system drives the development and progression of COPD. Using this hypothesis as a guide, I have completed a number of projects aimed at characterizing the effects of chronic cigarette smoke exposure on the pulmonary immune system in a mouse model of COPD. Utilization of a mouse model of COPD avoids complicating, immunologically relevant factors such as infections, tumors, and aging found in COPD patients. Therefore, a mouse model of COPD can provide key insights into the immunological mechanisms that trigger disease development. Chapter 2 of this dissertation provides evidence that chronic cigarette smoke exposure drives an adaptive immune response in the lungs. I demonstrate that cigarette smoke exposure causes antigen-driven oligoclonal expansions of T cells in the lungs of mice, and that these oligoclonal expansions persist 6 months following smoking cessation. Chapter 3 examines the pathological consequences of T cell activation in a mouse model of COPD, and demonstrates that transfer of pathogenic T cells from smoke-exposed mice into unexposed recipient mice results in severe pulmonary changes pathognomonic of COPD. Chapter 4 dissects the mechanisms of leukocyte recruitment in smoke-exposed mice and COPD patients by examining the regulation of chemokine expression in the lungs. Chapter 5 of this dissertation examines a novel form of NK cell priming following smoke exposure that has implications for the development of an adaptive immune response as well as provides a mechanism for COPD exacerbations. The results provided throughout this dissertation provide new insights into the effects of cigarette smoke exposure on the immune system, and will hopefully aid in the development of new therapies for COPD patients.
Michael Borchers, PhD (Committee Chair)
Divaker Choubey, PhD (Committee Member)
George Deepe, MD (Committee Member)
Ranjan Deka, PhD (Committee Member)
Dennis McGraw, PhD (Committee Member)
256 p.

Recommended Citations

Citations

  • Motz, G. T. (2010). The Role of Cigarette Smoke Exposure-Induced Activation of the Innate and Adaptive Pulmonary Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1265989482

    APA Style (7th edition)

  • Motz, Gregory. The Role of Cigarette Smoke Exposure-Induced Activation of the Innate and Adaptive Pulmonary Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1265989482.

    MLA Style (8th edition)

  • Motz, Gregory. "The Role of Cigarette Smoke Exposure-Induced Activation of the Innate and Adaptive Pulmonary Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1265989482

    Chicago Manual of Style (17th edition)