Tobacco related lung diseases, including chronic obstructive pulmonary disease (COPD) with and without emphysema, are among the major causes of lung-related disability and death worldwide. The immediate cause of emphysema is destruction of lung matrix, especially elastin, resulting in loss of elastic recoil, dynamic airway collapse during exhalation, air trapping and lung hyperinflation. We and others have shown that 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?). We found that autoreactive lymphocytes isolated from emphysematous lung express IFN? inducible protein of 10 kD (IP-10, CXCL10), and monokine induced by IFN? (MIG, or CXCL9) and strongly up-regulate macrophage elastolytic proteinases, in particular MMP12 and MMP9. T cells isolated in the blood and lungs of current and former smokers recognize neutrophil elastase derived elastin fragments as foreign antigen and that individuals with stronger response to elastin peptides, have more advanced emphysema. In this application we will test the central hypothesis that elastin-specific autoimmunity characterized by the presence of activated T helper subsets, is linked to the pathological and physiological abnormalities in the lungs of smokers.
In aim one of this proposal we will determine the mechanisms for T cell responses that may contribute to the persistence of auto-reactive T cells in subjects that have long ceased smoking but continue to have a decline in lung function.
This aim will further pinpoint the underlying immunological derangement that occurs in emphysema by determining the relative contribution of Th1, Th17 and regulatory T cells in emphysema.
In aim two of this proposal we will identify the regions within the elastin molecule that trigger immune cell activation as determined by T cell proliferation and cytokine production. Using multiple approaches we will determine the memory response to regions within the elastin molecule that will serve as markers of downstream events that leads into development of emphysema and elastolysis. Collectively, these complementary aims will provide new insights into the pathogenesis of smoke induce emphysema with the long term goals to find new and effective therapies for these conditions.

Public Health Relevance

Cigarette smoke-related lung diseases are one of the most common causes of disability and death worldwide. Chronic Obstructive Pulmonary Disease (COPD) is characterized by shortness of breath, cough, and loss of lung tissue (emphysema), which is irreversible and could be progressive. Little is known as to why the inflammation persists in the lung of some former smokers with COPD. In this application, we will study the role of a subset of cells in the immune system called T helper cells to determine if they could be responsible for the destruction of lung in subjects with COPD and emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072419-06
Application #
7851368
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Croxton, Thomas
Project Start
2002-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$435,346
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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