Pathogenesis of emphysema: from the bench to the bedside

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.

Figure 1.

Macrophages are activated by cigarette smoke and recruit neutrophils and CD8⁺ lymphocytes to cause elastolysis and emphysema. Similarly, cigarette smoke activates airway epithelium to trigger airway remodeling. Both of these processes result in airflow obstruction. CXCR3 = chemokine CXC receptor 3; EGF = epidermal growth factor; GROα = chemokine growth-regulated protein alpha; IP-10 = IFN-gamma-inducible 10 kD protein; LTB₄ = leukotriene B₄; Mig = monokine induced by IFN-gamma; MMPs = matrix metalloproteinases; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β.