Chronic obstructive pulmonary disease (COPD), the fifth leading cause of death worldwide, is estimated by the World Health Organization (WHO) to affect 80 million people.1 Cigarette smoking is the major risk factor for COPD, which includes both emphysema and chronic bronchitis, also called small airway disease. In emphysema, peripheral air spaces in the lung are enlarged and walls of bronchioles and alveoli are destroyed. Chronic bronchitis, which may occur concurrently with emphysema, includes airway wall repair-induced fibrosis.1 Inflammation, proteinase imbalance, oxidative stress, and apoptosis all appear to be interwoven in the pathogenesis of COPD, and the matrix metalloproteinase 12 (MMP-12) plays a role in each of these processes (Figure 1).
||Figure 1. MMP-12 is produced by alveolar macrophages, smooth muscle cells, and epithelia in response to cigarette smoke. It is a key molecule in the recruitment of inflammatory cells, release of TNF-alpha, and pathways downstream of TGF-beta activation. These activities lead to the airway damage, fibrogenesis, repair, and remodeling that are the hallmarks of COPD.
Disruption of the balance between proteolytic enzymes, such as elastases and their inhibitors, has long been considered the major cause of COPD.2 This protease-antiprotease imbalance is now thought to be caused by chronic inflammation.2 Macrophage elastase MMP-12 (inhibited by TIMP-1) and neutrophil elastase (inhibited by alpha-1-antitrypsin) are the most abundant elastases in the lung. TNF alpha, which is released from the cell membrane by MMP-12, is the major recruiter of neutrophils to the lung; IFN-gamma also recruits neutrophils and stimulates MMP-12 activity.2, 3, 4 Once present, neutrophil elastases and oxidants secreted in the inflammatory environment mediate much of the destruction of lung tissue.5 Elastin fragments are also chemotactic, recruiting monocytes that differentiate to form alveolar macrophages that comprise the bulk of the inflammatory cells accumulating in the interstitium, septum, and alveolar airspaces in emphysema.6
Some elements of COPD pathogenesis precede macrophage or neutrophil accumulation. Studies on airway cells in vitro bypass the influence of inflammatory cells and show direct effects of smoke or smoke condensates. For example, the oxidative effects of smoke induce MMP-12 expression via a TNF-alpha-dependent pathway in cultured airway-like epithelia.7 Oxidants are also involved in release of TGF-beta from latency in tracheal explants.8 Active TGF-beta is likely to mediate fibrogenic airway remodeling, an effect that is blocked in MMP-12-deficient mice.8 Similarly, apoptotic pathways induced by either TGF-beta or Fas (CD95) may cause lung fibrosis that can be ameliorated by deletion of MMP-12.9, 10 Human airway smooth muscle cells have also been shown to contribute active MMP-12 in response to IL-1 beta and TNF-alpha.11
A pivotal study showed that deletion of mouse MMP-12 abrogates development of cigarette smoke-induced COPD.12 Since then, other studies have shown that deletion or inhibition of neutrophil elastase, TGF-beta, or TNF-alpha substantially reduces lung damage in response to cigarette smoke.3, 4, 7, 8, 13 Conversely, naturally occurring human deficiency of alpha-1-antitrypsin, the major human inhibitor of neutrophil elastase, confers susceptibility to COPD.1, 2 It is clear that the entire story of COPD pathogenesis involves these and other players in a complex, interwoven cascade. The development of COPD in response to cigarette smoke is not universal and, when it does occur, varies in time of onset for both humans and rodent strains.1, 2 This variation likely results from interaction of genetic influences with environment. One example is the increased susceptibility to COPD in smokers that have specific polymorphisms in both human MMP-1 and MMP-12.14
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