Review
The role of neutrophil elastase in acute lung injury

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Abstract

Beside its physiological function as a powerful host defense, neutrophil elastase is also known as one of the most destructive enzymes in the body. Current notion holds that neutrophil elastase is able to escape from regulation by multiple protease inhibitors at inflammatory sites. Once unregulated, this enzyme disturbs the function of the lung permeability barrier and induces the release of pro-inflammatory cytokines. These actions then cause symptoms that are typical in the pathophysiology of acute lung injury. In this article, we review recent progress in the understanding of the physiological activity of neutrophil elastase and its role in acute lung injury. Evidence in this review that supports the involvement of neutrophil elastase in the pathophysiology of acute lung injury includes: (1) neutrophil elastase levels are increased in both clinical and animal models of acute lung injury; (2) topical or systemic administration of neutrophil elastase produces typical symptoms of acute lung injury both in vitro and in vivo; and (3) inhibition of increased neutrophil elastase activity reduces symptoms of acute lung injury in animal models. A greater understanding of the role of this enzyme in the pathophysiology of acute lung injury will lead to better treatments for this complicated disease.

Introduction

Reactive oxygen species and proteases are neutrophil-derived toxic molecules that have long been considered important in the pathophysiology of acute lung injury (Janoff, 1985). Neutrophil elastase (E.C.3.4.21.37) is one such molecule in particular that has received attention as an enzyme capable of degrading almost all extracellular matrix proteins as well as a variety of key plasma proteins (Havemann and Gramse, 1984). In addition to its proteolytic activity, neutrophil elastase induces the release of pro-inflammatory cytokines such as interleukin-6 (Bedard et al., 1993) and interleukin-8 (Nakamura et al., 1992). Under physiological conditions, neutrophil elastase is a powerful host defense and its activity is tightly regulated by endogenous protease inhibitors (Travis and Salvesen, 1983). At inflammatory sites, however, this enzyme appears to remain active due to an imbalance between its own elevated level and that of the endogenous protease inhibitors Weiss, 1989, Morrison et al., 1990, Kawabata et al., 1996. In lung and its surrounding environment, the unregulated proteolytic activity of neutrophil elastase leads to a variety of changes that are directly and indirectly related to the pathophysiology of acute lung injury.

In this article, we review the findings of recent studies on neutrophil elastase and its role in acute lung injury. First, we survey neutrophil elastase, its natural substrates, target cells, and endogenous protease inhibitors. We then examine the mechanism by which this enzyme is able to escape endogenous protease inhibition at inflammation sites. In the latter part of this article, we focus on: (1) whether neutrophil elastase levels are increased in clinical or animal models of acute lung injury; (2) whether topical or systemic application of neutrophil elastase produces typical symptoms of acute lung injury both in vitro and in vivo; and (3) whether inhibition of increased neutrophil elastase activity reduces symptoms of acute lung injury in animal models. Finally, we propose a general pathophysiological role for neutrophil elastase and sum up with a brief conclusion.

Section snippets

Neutrophil elastase

Neutrophil elastase, a member of the chymotrypsin superfamily of serine proteases, is a 33-kDa enzyme with several isoforms that differ in their extent of glycosylation Bieth, 1986, Ohlsson and Olsson, 1974. Commercially, the most readily available enzyme is sputum elastase, which is isolated from human sputum and has at least five distinct isozymes (Twumasi and Liener, 1977). This elastase is both immunologically and catalytically indistinguishable from human neutrophil elastase, indicating

Neutrophil elastase and acute lung injury

Acute lung injury is a syndrome that results from a variety of unrelated insults, including infection by Gram-negative bacteria. The most severe form, adult respiratory distress syndrome, is a high mortality disease that resists most therapies. The pathophysiological characteristics of this disease include interstitial and alveolar edema associated with a large amount of neutrophil infiltration into these spaces (Wiener-Kronish et al., 1990). Recent studies suggest that neutrophil elastase

Mechanism by which neutrophil elastase might induce acute lung injury

As mentioned earlier in this article, a substantial amount of evidence supports the current hypothesis that neutrophil elastase plays an important role in the pathophysiology of acute lung injury, although the precise mechanism by which neutrophil elastase contributes to acute lung injury remains speculative. This is because the multisubstrate specificity of neutrophil elastase hampers the identification of its primary target protein in vivo. Recent studies have suggested that cell junction

Conclusion

Results from the studies discussed in this review indicate that: (1) neutrophil elastase levels are increased in clinical and animal models of acute lung injury, (2) topical or systemic application of neutrophil elastase produces typical symptoms of acute lung injury both in vitro and in vivo, and (3) inhibition of increased neutrophil elastase activity reduces symptoms of acute lung injury. This evidence strongly supports the current hypothesis that neutrophil elastase plays an important role

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