Figure 1

Proposed proteolytic cascade in emphysema. (a) The exposure to cigarette smoke leads to recruitment of macrophages into the lung. Macrophages secrete cytokines which further augment the inflammatory response leading to the induction and release of proteolytic enzymes by macrophages and neutrophils, including matrix metalloproteinases (MMPs) (MMP-1, -2, -8, -9, -12 and membrane type matrix metalloproteinase-1 [MT1-MMP]), inhibitors (tissue inhibitor of matrix metalloproteinase [TIMP-1]) and neutrophil elastase, that lead to the remodeling of the lung architecture. This proteolytic cascade leads to both collagen and elastin degradation. The cigarette smoke exposure and inflammatory cells also stimulate the lung parenchymal epithelial cells to secrete proteolytic enzymes which contribute to the destructive process in emphysema. The macrophages and cigarette smoke then stimulate the parenchymal lung cells in patients susceptible to emphysema to produce proteolytic enzymes which results in a significant imbalance of collagenase leading to altered fibril arrangement. The initial damage is followed subsequently by a repair process in which fibroblasts participate inremodeling the collagen matrix of the lung. These structural changes alter the balance of opposing forces in the lung and lead to the pathology of emphysema. (b) Disruption of the extracellular matrix (ECM) content by proteolysis upsets the balanced forces within the lung and leads to alterations in alveolar structure.