Abstract
Secretory leukocyte proteinase inhibitor and elafin are two low-molecular-mass elastase inhibitors that are mainly synthesized locally at mucosal sites. It is thought that their physicochemical properties allow them to efficiently inhibit target enzymes, such as neutrophil elastase, released into the interstitium. Historically, in the lung, these inhibitors were first purified from secretions of patients with chronic obstructive pulmonary disease and cystic fibrosis. This suggested that they might be important in controlling excessive neutrophil elastase release in these pathologies. They are upregulated by 'alarm signals' such as bacterial lipopolysaccharides, and cytokines such as interleukin-1 and tumor necrosis factor and have been shown to be active against Gram-positive and Gram-negative bacteria, so that they have joined the growing list of antimicrobial 'defensin-like' peptides produced by the lung. Their site of synthesis and presumed functions make them very attractive candidates as potential therapeutic agents under conditions in which the excessive release of elastase by neutrophils might be detrimental. Because of its natural tropism for the lung, the use of adenovirus-mediated gene transfer is extremely promising in such applications.
Highlights
Cytokines form one of the major classes of chemical mediator responsible for initiating, regulating and terminating the inflammatory response
To migrate from the vascular space and gain access to the inflammatory site through the interstitium, it has been hypothesized that these inflammatory cells use a variety of proteases
Regulation of SLPI and elafin It has been shown that ‘alarm signals’ such as bacterial LPS, IL-1, tumor necrosis factor (TNF), neutrophil elastase and defensins are able to switch on the production of these inhibitors [3,14,15]; anti-inflammatory and ‘remodelling’ cytokines such as transforming growth factor-β can switch them off
Summary
Cytokines form one of the major classes of chemical mediator responsible for initiating, regulating and terminating the inflammatory response. SLPI is produced in vitro by tracheal, bronchial, bronchiolar and type II alveolar cells, and by monocytes, alveolar macrophages and neutrophils [1,6].
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