Inflammation and Treatment in Asthma and COPD

By James F. Donohue, MD, FCCP; and Jill A. Ohar, MD, FCCP

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COPD

Inflammation

The inflammatory process in COPD appears to be fueled by the interaction of several chemokines and proteolytic enzymes. Interleukin (IL-8), tumor necrosis factor (TNF-a), and leukotriene B₄ (LTB₄) are all found in increased concentration in the sputum of patients with COPD.¹¹ Macrophages produce LTB₄, IL-8, and the proteolytic enzymes matrix metalloprotease (MMP) 12, MMP-1 (collagenase), and MMP-9 (gelatinase B). Macrophage-derived TNF-a amplifies neutrophil recruitment and accumulation in lung tissue by activation of neutrophil surface adhesion molecules. TNF-a upregulates cytokine production and is associated with COPD cachexia. Expression of TNF-a, IL-8, and the MMPs is regulated by the transcription factor, nuclear factor kappa B, which is activated by oxidants. Oxidants such as superoxide anion, nitric oxide, hydroxyl radical, peroxide (H₂O₂), and peroxynitrite are abundant in cigarette smoke. The concentration of oxidants may be as high as 10¹⁷/puffs activated. Macrophages and neutrophils also serve as an endogenous source for oxidants such as H₂O₂ and O₂. Oxidants may cause direct tissue damage or augment the inflammatory process indirectly through oxidative inactivation of the inhibitors of neutrophil elastase such as a-antitrypsin. LTB₄ and IL-8 are chemotactic for neutrophils and interact synergistically. IL-8 promotes neutrophil chemotaxis and activation through binding to chemokine CXC receptors, CXCR1 and CXCR2, on their cell surface. Neutrophils produce LTB₄ and the proteolytic enzymes elastase, proteinase 3, cathepsin G, MMP-1, and MMP-9. Both TNF-a and neutrophil elastase promote IL-8 secretion from airway epithelial cells. The role of T lymphocytes in COPD is thought to be through the induction of apoptosis of airway epithelial cells, mediated by CD8 cell release of TNF-a and perforins. The number of both CD8 cells and neutrophils present in lung tissue is proportional to the degree of airways limitation present in COPD.

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