Emphysema may result from an imbalance between excessive protease activity and deficient endogenous antiproteases (Fig. 11.5, Table 11.2). A logical
Table 11.2 Protease inhibitors
• Neutrophil elastase inhibitors (ICI 200355, ONO-5046)
• Cathepsin inhibitors (suramin)
• Matrix metalloproteinase inhibitors (batimastat, marimastat, selective MMP inhibitors)
• aj-Antitrypsin (purified, human recombinant, gene transfer)
• Secretory leukoprotease inhibitor (human recombinant) MMP, matrix metalloproteinase.
approach to treatment is to inhibit endogenous proteases or to supplement endogenous antiproteases.
As neutrophil elastase is a major constituent of lung elastolytic activity and also potently stimulates mucus secretion, it is a potential target for inhibition. Several potent neutrophil elastase inhibitors have been developed, including peptide inhibitors, such as ICI 200355, and non-peptide inhibitors, such as ONO-5046. There are few clinical studies in COPD; the neutrophil elastase inhibitor MR889 administered for 4 weeks showed no overall effect on plasma elastin-derived peptides or urinary desmosine (markers of elastolytic activity) . It may be difficult to inhibit enzyme activity, as neutrophils adhere to connective tissue, so that access of the enzyme inhibitor may be a problem. Intracellular inhibitors may be more effective.
Although neutrophil elastase is likely to be the major mechanism mediating elastolysis in patients with aj-antitrypsin (aj-AT) deficiency, it may well not be the major elastolytic enzyme in smoking-related COPD, and it is important to consider other enzymes, such as cathepsins and proteinase-3, as targets for inhibition.
Matrix metalloproteinases (MMPs) derived from macrophages, neu-trophils and epithelial cells may also play a role in connective tissue destruction, suggesting that MMP inhibitors may be beneficial. Several MMPs are increased in COPD and have the capacity to destroy lung elastin fibres. Several MMP inhibitors are now in development, but non-selective inhibitors have been associated with musculoskeletal side effects, so that more selective drugs may be needed in the future.
The association of ax-AT deficiency with early onset emphysema suggested that this endogenous inhibitor of neutrophil elastase may be of therapeutic benefit in COPD. Cigarette smoking may inactivate ax-AT, resulting in unopposed activity of neutrophil elastase and cathepsins. Extraction of ax-AT from human plasma is very expensive and extracted a1-antitrypsin is only available in a few countries. This treatment has to be given intravenously and has a half-life of only 5 days. Human ax-AT has now been available for over 10 years, but even in patients with severe ax-AT deficiency and emphysema, there is only a marginal effect on the rate of decline in forced expiratory volume in 1s (FEVj) . Inhaled a^AT formulations, although these are inefficient and expensive . Recombinant a1-AT with amino acid substitutions to increase stability may result in a more stable product. Gene therapy is another possibility using an adenovirus vector or liposomes, but there have been major problems in developing efficient delivery systems. There is a particular problem with gene transfer in a1-AT deficiency, in that large amounts of protein (1-2 g) need to be synthesized each day. There is no evidence that a1-AT treatment would halt the progression of COPD and emphysema in patients who have normal plasma concentrations.
Other serum protease inhibitors (serpins), such as elafin, may also be important in counteracting elastolytic activity in the lung. Elafin, an elastase-specific inhibitor is found in bronchoalveolar lavage and is synthesized by epithelial cells in response to inflammatory stimuli. Serpins may not be able to inhibit neutrophil elastase at the sites of elastin destruction, due to tight adherence of the inflammatory cell to connective tissue. Furthermore, these proteins may become inactivated by the inflammatory process and the action of oxidants, so that they may not be able to adequately counteract elastolytic activity in the lung unless used in conjunction with other therapies. Secretory leukoprotease inhibitor (SLPI) is a 12-kDa serpin that appears to be a major inhibitor of elastase activity in the airways and is secreted by epithelial cells. In vitro, recombinant human SLPI is more effective at inhibiting neutrophil mediated proteolysis than a1-AT . Recombinant human SLPI given by aerosolization increases antineutrophil elastase activity in epithelial lining fluid for over 12 h, indicating potential therapeutic use .
Was this article helpful?