Molecular pathogenesis of emphysema

Abstract

Emphysema is one manifestation of a group of chronic, obstructive, and frequently progressive destructive lung diseases. Cigarette smoking and air pollution are the main causes of emphysema in humans, and cigarette smoking causes emphysema in rodents. This review examines the concept of a homeostatically active lung structure maintenance program that, when attacked by proteases and oxidants, leads to the loss of alveolar septal cells and airspace enlargement. Inflammatory and noninflammatory mechanisms of disease pathogenesis, as well as the role of the innate and adaptive immune systems, are being explored in genetically altered animals and in exposure models of this disease. These recent scientific advances support a model whereby alveolar destruction resulting from a coalescence of mechanical forces, such as hyperinflation, and more recently recognized cellular and molecular events, including apoptosis, cellular senescence, and failed lung tissue repair, produces the clinically recognized syndrome of emphysema.

Figure 1. Normal versus emphysematous alveoli.

Figure 2. Human emphysema.

(A) Chest CT scan of a 56-year-old man with COPD demonstrating a profound loss of the lung parenchyma and paucity of lung vessels. (B) Whole-lung section demonstrating ubiquitous “holes,” i.e., emphysema. (C) Histology of end-stage emphysematous lung. H&E staining; magnification, ×40. The loss of alveolar septal cells is not accompanied (in this specimen) by significant inflammatory cell accumulation.

Figure 3. Proteolytic destruction of the elastin fiber network by cigarette smoke–activated inflammatory cells.

This schematic illustrates the dense elastin fiber network in the lung; the elastin fibers form a particularly dense network around lung capillaries. Neutrophils, macrophages, and dendritic cells have been recognized as producers of proteases. In addition to neutrophil elastase and MMP-12, there have been a myriad of proteases identified in human and animal emphysema that can degrade elastin, collagen, and fibronectin. Loss of the alveolar septal scaffold after enzymatic degradation of various matrix proteins causes airspace enlargement. Elastin peptides are chemotactic and can attract additional inflammatory cells into the lung, thus generating a vicious cycle.

Figure 4. One pathway likely involved in lung cell structure maintenance.

VEGF gene expression is controlled by hypoxia-inducible factor 1α (HIF-1α). In endothelial cells, synthesis of prostacyclin (PGI₂) and NO is one outcome of VEGFR activation. Reactive oxygen species can damage the promoter region of the VEGF gene and thus impair VEGF transcription. Activation of VEGFR2 induces NO production. NO and PGI₂ promote endothelial cell survival. While it is known that VEGFR2 activation promotes NO production, the link between VEGFR2 activation and PGI₂ synthesis still needs to be established.