**9. Abbreviations**

58 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

weight inhibitors have been developed and are potential therapeutic agents for COPD. These include irreversible inhibitors such as the peptide chloromethyl ketones (141) and reversible inhibitors such as peptide boronic acids, peptide aldehydes (142), substituted tripeptide ketones (143), or β-lactams (144). One of the problems with the low-molecularweight reversible inhibitors is that they can release NE, allowing it to destroy tissue. Although the irreversible inhibitors such as chloromethyl ketone have been shown to function effectively *in vivo* in hamsters to reduce many of the effects of intratracheally

Some support for potential use of these inhibitors comes from *in vitro* studies showing that low-molecular-weight, synthetic inhibitors of serine proteinases and MMPs effectively inhibit both soluble and membrane-bound proteinases (122,123,126,127), and studies of animal models of COPD showing that proteinase inhibitors effectively block both airspace enlargement and lung inflammation. In animals acutely exposed to cigarette smoke, delivery of synthetic or natural inhibitors of serine proteinases and synthetic inhibitors of MMPs blocks PMN influx into the lung and ECM destruction (68,145,146). In other animal work, a therapeutic effect demonstrated with daily oral delivery of synthetic MMP inhibitors to mice. This prevented airspace enlargement and macrophage accumulation in the lungs of mice exposed to cigarette smoke for 6 months (74). In additional experiments in which MMP inhibitor therapy was initiated after mice were exposed to cigarette smoke for 3 months to initiate airspace enlargement, therapy prevented progression of airspace enlargement as smoking continued (74). These results suggested a role for proteinase inhibition in potentially preventing disease progression in human COPD patients. However, it remains unclear which proteinases should be targeted. The counter argument to these theories is that proteinases have been shown to have beneficial as well as deleterious roles in the lung (roles in innate host defense, dampening inflammation, and inhibiting tumor

growth and metastasis), which may prove to limit the usefulness of their inhibition.

Strategies to reduce the burden of lung inflammatory cells in COPD would thereby reduce the amount of proteinase that they are responsible for releasing. Inhibitors of phosphodiesterase E4, the major isoenzyme in inflammatory cells, decrease inflammatory cell migration, activation, and release of proteinases. Clinical trials of phosphodiesterase E4 inhibitors in COPD have resulted in one selective PDE4 inhibitor, roflumilast (Daxas ®), being approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD (147). Other antiinflammatory approaches, such as inhibiting NF-B activation to reduce pro-inflammatory gene expression, could also potentially inhibit proteinase- and oxidant-mediated lung injury

Proteinases have diverse activities in the pathogenesis of COPD. With over 40 years having elapsed, since the initial breakthroughs showed a role for these enzymes in this disease, much work has elucidated many further elements of the roles they play. It is clear that the proteinase-antiproteinase balance is not the sole cause of all the pathology seen, but it

continues to be a major contributor and a potential target for future therapies.

**7.2 Anti-inflammatory strategies** 

in COPD patients.

**8. Conclusions** 

administered NE, the toxicity of chloromethyl ketones prevents clinical use.

*ADAM.* Proteinase **a d**isintegrin and **a m**etalloproteinase domain; cathepsin G (CG), chronic obstructive pulmonary disease (COPD), epithelial growth factor receptor (EGFR), extracellular matrix (ECM), g*ranzymes (GRZ), i*nducible protein 10 (IP-10), interferon gamma (IFN-), membrane-type MMPs (MT-MMPs), metalloproteinase (MMP), neutrophil elastase (NE), polymorphonuclear neutrophils (PMN), protease-activated receptor-1 (PAR-1), proteinase 3 (PR3), reactive oxygen species (ROS), secretory leukocyte proteinase inhibitor (SLPI), serine proteinase inhibitors (Serpins), transforming growth factor (TGF)-, tumor necrosis factor (TNF-), urokinase-type plasminogen activator (uPA), wild type (WT), α1 anti-trypsin (AAT), α2-macroglobulin (α2-M)
