Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease

Abstract

Since the early 1960s, a compelling body of evidence has accumulated to show that proteinases play critical roles in airspace enlargement in chronic obstructive pulmonary disease (COPD). However, until recently the causative enzymes and their exact roles in pathologic processes in COPD have not been clear. Recent studies of gene-targeted mice in murine models of COPD have confirmed roles for proteinases not only in airspace enlargement, but also in airway pathologies in COPD. These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung. They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury. This review will discuss the biology of proteinases and the mechanisms by which they contribute to the pathogenesis of COPD. In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients.

Figure 1

Mechanisms by which different classes of proteinases contribute to pathologies in COPD. Cigarette smoke stimulates inflammatory cell recruitment, proteinase production, and proteinase release from inflammatory, immune, and structural cells in the lung. Proteinases contribute to airspace enlargement by degrading ECM and promoting death of structural cells of the alveolar walls. Proteinases also amplify lung inflammation and promote mucus hypersecretion and small airway fibrosis. Abbreviations: COPD, chronic obstructive pulmonary disease; ECM, extracellular matrix; MAC, macrophages; PMN, polymorphonuclear neutrophils; IP-10, interferon-γ-inducible protein-10; SP, serine proteinases; MMP, matrix metalloproteinases; ADAMs, proteinases with a disintegrin and a metalloproteinase domain; CP, cysteine proteinases; GRZ, granzymes.

Figure 2

Interactions between proteinases regulate inflammation and matrix destruction in mice acutely exposed to cigarette smoke. Cigarette smoke drives macrophage MMP-12 production, at least in part by inducing thrombin- and plasmin-mediated activation of protease-activated receptor-1 (PAR-1) on macrophages. MMP-12 stimulates PMN accumulation in the lung by shedding pro-TNF-α from the macrophage surface, generating soluble, active TNF-α. Active TNF-α stimulates PMN trans-endothelial migration by up-regulating endothelial E selectin expression. PMN proteinases, such as neutrophil elastase (NE), amplify macrophage MMP-12 mediated destruction of the lung ECM.

Figure 3

Interactions between proteinases regulate inflammation and ECM destruction in mice chronically exposed to cigarette smoke. Neutrophil elastase (NE) promotes inflammation and ECM destruction in mice chronically exposed to cigarette smoke by increasing the influx of PMN and monocytes into the lung (by unknown mechanisms), and by cleaving and inactivating TIMPs to promote MMP-12 mediated ECM degradation. MMP-12 amplifies NE-mediated lung inflammation and destruction by cleaving and inactivating α₁-PI, the major inhibitor of NE in the lower respiratory tract. Fragments of elastin generated by MMP-12 (and possibly by NE) amplify MMP-12-mediated lung injury by stimulating the recruitment of blood monocytes into the lung.

Figure 4

Mechanisms by which proteinases circumvent proteinase inhibitors in the extracellular space to cause lung injury in COPD. PMN store preformed proteinases within intracellular granules, and proteinases are released into the extracellular space when pro-inflammatory mediators induce PMN degranulation. Proteinases freely released by PMN are inhibited when they form complexes with extracellular inhibitors. However, proteinases can circumvent inhibitors by: 1) cleaving or degrading inhibitors; 2) being released at very high concentrations into the extracellular space, thereby overwhelming inhibitors; 3) binding to cell membranes in inhibitor-resistant forms; 4) binding to matrix substrates in inhibitor-resistant forms; or 5) being released into sequestered microenvironments formed by tight adhesion of PMN to ECM into which diffusion of large inhibitors is impaired.