**7. Potential strengths and limitations of proteinase inhibitors and antiinflammatory drugs as new therapeutic strategies to limit proteinasemediated lung pathologies in COPD**

### **7.1 Proteinase inhibition**

Perhaps the most obvious role for intervention in this setting is to replace AAT in patients with COPD who have known severe, inherited AAT deficiency (AATD). Although we do not have conclusive randomized controlled trials, human clinical research has shown that AAT augmentation reduced exacerbation frequency and slows the rate of lung function decline in these patients (138). More recent work has attempted augmentation of AAT through gene therapy. This involves administration of recombinant adeno-associated virus (rAAV) vectors expressing human AAT (rAAV1-CB-hAAT) to patients with AATD (139). These studies are currently in phase 2 clinical trials and have shown increased expression of normal (PiM) AAT in serum occurs safely in patients for up to 90 days. Further optimization of the vector is likely to be required to generate sustained therapeutic AAT plasma levels. The concept of augmentation of AAT in COPD, outside the setting of AATD, is less clear.

Secretory leukocyte peptidase inhibitor (SLPI) and elafin are naturally occurring antiproteinases with anti-NE activity whose roles in COPD are not fully eludicated but may have potential as future treatment options (140). A number of synthetic low molecular

Diverse Activities for Proteinases in the

anti-trypsin (AAT), α2-macroglobulin (α2-M)

respiratory research Institute Consortium.

*Respiration* 68: 117-128.

*Respir. Crit Care Med.* 160: S17-S20.

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cysteine protease. *J. Biol. Chem.* 267: 7258-7262.

activity of human cathepsin L. *Biochem. J.* 233: 925-927.

**10. Acknowledgements** 

2645-2653.

**11. References** 

**9. Abbreviations** 

Pathogenesis of Chronic Obstructive Pulmonary Disease 59

*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-

This work was supported by PHS NHLBI HL96814 and P01 HL105339, the Flight Attendants Medical Research Institute, and the Brigham and Women's Hospital-Lovelace

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

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.
