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The Proceedings of the American Thoracic Society 3:424-427 (2006)
© 2006 The American Thoracic Society

Neutrophil Elastase

Mediator of Extracellular Matrix Destruction and Accumulation

Felix Chua and Geoffrey J. Laurent

Centre of Respiratory Research, Royal Free and University College London Medical School, London, United Kingdom

Correspondence and requests for reprints should be addressed to Geoffrey J. Laurent, Ph.D., Centre for Respiratory Research, Royal Free and University College London Medical School, Rayne Building, 5 University Street, London WC1E 6JJ, UK. E-mail: g.laurent{at}ucl.ac.uk

ABSTRACT

Of the myriad proteolytic enzymes implicated in the development of lung disease, neutrophil elastase has undoubtedly some of the most versatile effects. Although its key physiologic role is in innate host defense, it can also participate in tissue remodeling and possesses secretagogue actions that are now recognized as important to local inflammatory responses. Although unopposed neutrophil elastase activity has been implicated in the development of emphysema for several decades, only relatively recently has a pathogenetic function been ascribed to this serine proteinase in situations where excessive extracellular matrix deposition occurs. The use of genetically manipulated animal models is starting to uncover the potential ways in which its actions might influence fibrotic lung repair. Emerging evidence suggests that the engagement of cellular pathways with more direct effects on fibrogenic mediator generation and collagen synthesis appears to underpin the actions of neutrophil elastase in promoting lung matrix accumulation.

Key Words: emphysema • pulmonary fibrosis • transforming growth factor-ß

A growing sense that emphysematous and fibrotic lung changes can comanifest in the same lung has been consolidated over the past decade or so. The hypothesis goes, quite reasonably, that because lung repair usually follows one of a limited number of stereotypical responses, macroscopic evidence of coexistent extracellular matrix (ECM) breakdown (emphysema) and overaccumulation (fibrosis) should not be that unusual. Cumulative observations would further suggest the possibility that these two disorders share elemental pathogenetic mechanisms that overlap within the wider spectrum of pathologic ECM remodeling. After all, aberrant matrix degradation has long been believed to be an integral part of the fibrotic process (1, 2).

EMPHYSEMA AND PULMONARY FIBROSIS: COINCIDING OR COINCIDENTAL?

One early finding that emphysema and fibrosis often coexist came from computed tomography studies of individuals with so-called cryptogenic fibrosing alveolitis (3). Although clinicians now accept that the cryptogenic fibrosing alveolitis label probably encompassed different subtypes of fibrotic interstitial pneumonia, the presence of such opposing tissue reactions in the same individual suggested that emphysema and pulmonary fibrosis were not mutually exclusive at the phenotype level. Similarly, when patients with chronic emphysema are evaluated, established centrilobular alveolar destruction often has adjacent features of fibrosis (4). As such, with growing knowledge of the spectrum of smoking-related lung diseases, the combination of emphysema and pulmonary fibrosis is no longer believed to reflect coincidental occurrence of two unrelated clinical entities (5).

As the lung remodels from normal to either an emphysematous or fibrotic phenotype, the ECM undergoes significant physical and biochemical modification. In smokers with emphysema, topographic changes in the relative abundance of collagen and elastin take place, resulting in regions of lung parenchyma where loss of alveolar wall tissue may be accompanied by increased collagen content (6). Likewise, animal models of interstitial fibrosis that result from treatment with exogenous agents may also express changes indicating both ECM accumulation and degradation. Administration of bleomycin or cadmium chloride to animals has been shown to induce a diffuse fibrotic reaction followed, after a variable interval, by evidence of alveolar wall breakdown and airspace enlargement (7, 8). Although the underlying mechanisms responsible for such alterations are still unclear, they implicate a pathogenic role for molecules whose action can ultimately reshape the ECM. Of the numerous proteinases that operate within the alveolar environment, neutrophil elastase is perhaps the most closely scrutinized.

CLINICALLY IMPORTANT NEUTROPHIL ELASTASE EFFECTS

The early notion of neutrophil elastase as a mediator of alveolar destruction has its roots in studies of hereditary {alpha}1-antitrypsin ({alpha}1-AT) deficiency; affected individuals were shown to have significantly increased predisposition to panacinar emphysema, particularly if they smoked (9). Over time, unopposed neutrophil elastase activity has come to be implicated in the pathobiology of many other lung diseases. Appreciation of its matrix-degrading capacity and broad substrate repertoire has led to the hypothesis that enhanced neutrophil elastase predominance over its natural inhibitors may result in, or at least intensify, these pathologic states (Figure 1). Even so, the elastase–anti-elastase hypothesis, while popular for a time, is no longer believed to solely account for the pathogenesis of emphysema, in the same way that neutrophils are not believed to represent the only cellular source of elastolytic enzymes in the lung (10).


Figure 1
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  		Figure 1. Extracellular effects of neutrophil elastase can modulate pulmonary matrix remodeling after lung injury.

 
Clinical and experimental studies have begun to question the prevailing view that tissue manifestations of neutrophil elastase are exclusively degradative. Idell and colleagues first reported that neutrophil elastase–releasing factors were present in bronchoalveolar lavage (BAL) fluid of patients with adult (or acute) respiratory distress syndrome, a condition frequently terminating in fatal fibroproliferative consequences (11). Another study reported elevated elastase activity in the lungs of patients with sarcoidosis who had a stage III (fibrotic or cystic) radiologic pattern (12). Not long after, elevated serum neutrophil elastase activity was correlated to increased disease severity (and diminished lung function) in a small group of individuals with idiopathic pulmonary fibrosis (IPF) (13). A separate group observed that the release of neutrophil granule enzymes, including elastase, was greater in IPF compared with fibrosing alveolitis associated with systemic sclerosis (14). Within the lung, raised levels of neutrophil elastase–alpha-1-proteinase inhibitor ({alpha}1-PI) complexes in BAL fluid (15, 16) and extracellular neutrophil elastase in areas of established interstitial and honeycomb fibrosis (15, 17) have been described. Although these observations postulate a role for neutrophil elastase in enhancing pathologic ECM accumulation, the nature of its involvement remains unclear. At the tissue level, increased numbers of neutrophils in BAL fluid and lung tissue are commonly found in individuals with progressive pulmonary fibrosis due to a number of different etiologies (18). More precise correlation of neutrophil prevalence to in situ neutrophil elastase activity and its downstream effects on fibrotic ECM remodeling is not possible at this time.

NEUTROPHIL ELASTASE: FUNCTIONAL CONSIDERATIONS

Leukoprotease activity was first described early in the 20th century, but human neutrophil elastase (EC 3.4.21.37 [EC] , International Union of Biochemistry and Molecular Biology) was only identified relatively recently (19). Most early studies concentrated on defining the structure and function of serum-derived pancreas-secreted elastase, whose amino acid sequence was reported (20) a full 14 years before that of neutrophil elastase (21). In humans, expression of the neutrophil elastase gene (ELA2, chromosome 19p) occurs within a narrow period during promyelocytic differentiation. The active enzyme is subsequently stored within cytoplasmic azurophilic granules for the remaining life of the neutrophil until extruded into phagolysosomes or out of the cell.

Intracellular neutrophil elastase is a key effector molecule of the innate immune system, with potent antimicrobial activity against gram-negative bacteria (22), spirochaetes (23), and fungi (24). In contrast, connective tissue digestion is its best-known extracellular manifestation. Apart from targeting components of the ECM, a variety of cell surface ligands, soluble proteins, and a number of important adhesion molecules are also susceptible to its activity (25, 26). In general, neutrophil elastase is capable of digesting virtually every type of matrix protein, including several types of collagen, fibronectin, proteoglycans, heparin, and cross-linked fibrin (27). The biological roles of neutrophil elastase also include acting as a secretagogue for cytokines (28), glycosaminoglycans (29), and mucin (30), in addition to acting as a modulator of inflammation (31).

The ability to evade tissue antiproteinases is key to the success of neutrophil elastase in the extracellular environment. Catalytically active neutrophil elastase has been localized to the plasma membrane of mature neutrophils after release from intracellular stores (32). Based on in vitro estimations, as much as 12% of stored human neutrophil elastase may be expressed on the cell surface after neutrophil priming by either tumor necrosis factor-{alpha} or activation by interleukin-8 (33). In the lungs and other organs, the existence of neutrophil elastase in shielded pericellular microenvironments may explain why substantial tissue breakdown can occur despite an apparently low intensity of inflammation (34). More recently, Brinkmann and colleagues showed that activated neutrophils could secrete discrete webs of extracellular fibers that contain DNA, histones, and granule proteinases, such as neutrophil elastase and cathepsin G (35). These so-called neutrophil extracellular traps (NETs) are dispersed to trap bacteria that are then digested by the activity of neutrophil elastase protected within them. This specialized function/phenomenon may also help target the activity of neutrophil elastase against ECM tissue remodeling.

POTENTIAL NEUTROPHIL ELASTASE–MEDIATED MECHANISMS OF FIBROPROLIFERATION

Neutrophil elastase is likely to operate at different levels, both directly and indirectly, in modulating fibrotic ECM regulation. Some years ago, it was shown that in vitro treatment of collagen and elastin with neutrophil elastase could generate breakdown products with stimulatory activity for collagen synthesis in fibroblasts (36). Instillation of these peptides into rabbit lungs had previously led to the induction of pulmonary fibrosis (37). Neutrophil elastase has also been shown to activate proteinase-activated receptor (PAR)-1, the cellular receptor for thrombin (38). PAR-1–deficient mice are resistant to bleomycin-induced pulmonary fibrosis and have decreased lung immunostaining of transforming growth factor (TGF)-ß (39). However, neutrophil elastase–mediated activation of PAR-1 as a mechanism of fibrosis in vivo remains speculative at this juncture.

The integrin {alpha}vß6 is an epithelial-restricted integrin whose increased expression after lung injury has been implicated in the activation of TGF-ß. Mice lacking {alpha}vß6 are protected from bleomycin-induced pulmonary fibrosis (40). Molecular cooperation between {alpha}vß6 and tissue proteinases might exist; for example, it is now known that {alpha}vß6-deficient mice express increased levels of matrix metalloproteinase (MMP)-12 and demonstrate increased susceptibility to age-related emphysema (41). Increased {alpha}vß6 expression also occurs at sites of neutrophilic inflammation (42), although the significance of this to fibroproliferative lung damage has not been established. Evidence from in vitro studies have implicated a role for neutrophil elastase in mobilizing matrix-sequestered latent TGF-ß, a phenomenon that results in enhanced activation of the cytokine (43). Whether neutrophil elastase interacts with {alpha}vß6 in a profibrotic manner remains unclear.

Counterregulation between neutrophil elastase and MMPs might also be important. For example, neutrophil elastase can activate MMP-9 (44). In turn, MMP-9 recognizes {alpha}1-AT as a degradative substrate, cleavage of which will indirectly enhance neutrophil elastase activity (45). Degradation of {alpha}1-AT also generates peptide fragments that have neutrophil chemotactic activity. Furthermore, MMP-9 itself has been implicated in activating latent TGF-ß in transformed keratinocytes in vitro (46).

In bleomycin-induced pulmonary fibrosis, administration of neutrophil elastase inhibitors ({alpha}1-PI, secretory leukoprotease inhibitor [SLPI] and ONO-5046) has been associated with reductions in BAL fluid neutrophil numbers, extent of lung tissue neutrophil inflammation, and the degree of pulmonary fibrosis (47–49). Furthermore, in this model, neutrophil elastase gene–deleted mice fail to increase lung collagen content or develop obvious histologic lesions of parenchymal fibrosis (Figure 2) (50), despite developing lung injury and alveolitis. Further analysis has revealed that the capacity to activate pulmonary TGF-ß is diminished in these neutrophil elastase–null animals (F. Chua and colleagues, unpublished data).


Figure 2
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  		Figure 2. Total lung collagen is not increased in neutrophil elastase–deficient (NE–/–) mice treated with either 0.05 or 0.10 U bleomycin, as measured 30 days after injection by high performance liquid chromatography, compared with wild type (WT) mice. *p < 0.001. Reproduced by permission from Reference 50.

 
These potential mechanisms postulate that the participation of neutrophil elastase in promoting fibrotic lung remodeling is not simply an epiphenomenon of overwhelming neutrophilic inflammation. Neutrophil elastase appears to play a focused role in targeting the conversion of latent/activatable TGF-ß into the biologically active form. Extensive studies from Taipale and colleagues and Hyytiäinin and colleagues have previously shown that neutrophil elastase can cleave latent TGF-ß binding protein (LTBP) at putative proteinase-sensitive sites located within its hinge region, adjacent to its matrix-binding N-terminus (43, 51). In the proposed model, neutrophil elastase processes LTBP contained within ECM-bound, large, latent TGF-ß complexes (likely in a sequential manner), leading to the release of TGF-ß that is susceptible to activation by both proteolytic and nonproteolytic mechanisms. Preliminary studies using lung tissue from neutrophil elastase–deficient mice have demonstrated that heat-activatable TGF-ß can be mobilized from matrix stores after treatment with exogenous neutrophil elastase (F. Chua, unpublished data). The realization now that the total pool of latent TGF-ß in repairing tissue likely consists of a bound (matrix) reservoir as well as a soluble component indicates complex regulation of its activity.

CONCLUSIONS

Neutrophils, with their battery of potent proteinases and oxidant species, play vital roles in host defense. Accumulating data suggest that defects in these effector pathways may also contribute to the development of pulmonary disorders in which aberrant matrix remodeling is a pathologic hallmark. In particular, the actions of neutrophil elastase may govern just how such tissue injury is ultimately expressed. For example, in fibrosis, the ability of neutrophil elastase to enhance unwanted matrix accumulation might depend on the availability of prestored latent TGF-ß in the ECM. Increased generation of active TGF-ß can then drive both fibrogenesis as well as exacerbate lung injury (52). In emphysema, neutrophilic inflammation as a consequence of cigarette constituent exposure likely compounds lung ECM cleavage mediated by other proteolytic pathways as well as oxidant-mediated damage, resulting in uncontrolled alveolar wall destruction. It is hoped that future research will define the interplay between neutrophil elastase and other molecules that embody these pathways. In pulmonary fibrosis, at least, interference of the active TGF-ß generation pathway might allow excessive ECM accumulation to be curtailed.

FOOTNOTES

Supported by a Wellcome Trust Program Grant (G.J.L.) and a Wellcome Trust Research Training Fellowship (F.C.).

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 18, 2006; accepted in final form April 17, 2006)

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