Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elastase anti-elastase imbalance theory is most important in the pathogenesis of COPD (pulmonary emphysema). Proteolytic activity of neutrophil elastase (NE) plays an important role because of the detachment of cells through proteolysis of extracellular matrix. In addition to proteolytic activity of NE, NE-induced activation of intracellular signaling (MAPK(Erk), Rho and MLCK) participates in NE-induced morphological changes in airway epithelial cells.
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PMID:[Elastase anti-elastase imbalance in the pathogenesis of COPD]. 1049 94

There is a driving need to develop new and effective treatments for COPD. Bronchodilators are now the mainstay of symptomatic therapy and a new long-acting anticholinergic bronchodilator, tiotropium bromide, is now in advanced clinical trials as a once daily dry powder inhaler. Several inflammatory mediators are involved in the chronic neutrophilic inflammation that typifies COPD, including leukotriene B(4) and interleukin 8, for which specific receptor antagonists have been developed. Since the inflammatory process in COPD is essentially steroid resistant, new antiinflammatory treatments are needed. Drugs that may be effective include phosphodiesterase 4 inhibitors, NF-kappaB inhibitors, and interleukin 10. Inhibition of proteases is another approach and inhibitors of neutrophil elastase, cathepsins, and matrix metalloproteases are now in clinical development. Supply of endogenous antiproteases, such as alpha(1)-antitrypsin and secretory leukocyte protease inhibitors as recombinant proteins or by gene transfer, is also being explored. In future drugs that may stimulate alveolar repair might be developed, including retinoid receptor agonists and hepatic growth factor. Future directions will include earlier detection of disease, gene profiling to identify which smokers are at risk of COPD, and the development of noninvasive surrogate markers to monitor disease activity in order to monitor new therapies. Identification of genes that confer a risk for COPD in smokers may identify novel targets for drug development. Barnes PJ. Novel approaches and targets for treatment of chronic obstructive pulmonary disease.
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PMID:Novel approaches and targets for treatment of chronic obstructive pulmonary disease. 1055 74

Airflow limitation in COPD is a result partially of bronchospasm, but it is also caused by a reduction in airway caliber, the number of small airways, airway collapse because of loss of connective tissue support, excess mucus in the airways, and edema of the airway wall. Structural changes also occur because of long-term destruction of interstitial connective tissue, including elastin. Therefore, in addition to the traditional aim of reversing bronchospasm with bronchodilators, disease-modifying approaches are being investigated. The enzyme neutrophil elastase is implicated in the induction of bronchial disease causing structural changes in lungs, impairment of mucociliary clearance, and impairment of host defenses. The precise mechanism pathway of neutrophil elastase is uncertain, but the effects of influencing the pathway in order to slow disease progression are being investigated. Oxidants may also have a role in the development of COPD, with increased levels activating airway cells and cytokine production.
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PMID:New approaches to the management of COPD. 1067 77

Systemic corticosteroids have been recommended as a therapeutic option in patients with moderate to severe COPD. In an early stage of the disease, i.e. chronic bronchitis with mild or no airflow obstruction, a trial with inhaled steroids could reveal potential benefits, particularly in terms of a modulation of airway inflammation. We therefore investigated the effect of inhaled fluticasone (1000 microg day(-1)) on markers of airway inflammation in 19 patients with chronic bronchitis (mean+/-SEM FEV1, 83.4+/-3.0% predicted; FEV1/VC, 67.5+/-2.4%) in a double-blind, cross-over, placebo-controlled manner. Visits were performed before and after two 4-week treatment periods. separated by a 4-week washout period. Lung function, the concentration of exhaled nitric oxide, differential cell counts in induced sputum and the number of cells positive for iNOS, as well as the levels of LDH, ECP, neutrophil elastase and IL-8 in sputum supernatants were determined. Although the total cell number decreased significantly after fluticasone (geometric mean 12.3 vs. 7.7 x 10(6)/ml; P<0.05) it was not significantly different from the change observed after placebo (14.2 vs. 10.6 x 10(6)/ml; n.s.). None of the other parameters showed statistically significant changes after fluticasone or placebo and the results did not depend on the presence of airway hyperresponsiveness. We conclude that in patients with chronic bronchitis short-term treatment with inhaled corticosterids did not improve lung function or inflammatory parameters to an extent which was statistically significant as compared to spontaneous variability.
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PMID:In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. 1121 7

There is a pressing need for more effective drug treatments for COPD. New bronchodilators include a long-acting anticholinergic tiotropium bromide and a dual beta2-dopamine2-receptor agonist. But no treatments prevent the progression of COPD. Mediator antagonists in development include leukotriene B4 antagonists, chemokine receptor antagonists and more potent antioxidants. The inflammation of COPD is resistant to corticosteroids, so new anti-inflammatory drugs need to be developed. These include phosphodiesterase-4 inhibitors, nuclear factor-kappaB inhibitors and p38 MAP kinase inhibitors. Small molecule protease inhibitors, including neutrophil elastase inhibitors and selective matrix metalloproteinase inhibitors are also in development. Future drug targets may be identified by gene array and proteomics.
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PMID:Future Advances in COPD Therapy. 1169 2

Airway mucus hypersecretion is a serious and presently untreatable symptom of COPD. Over the past several years, emerging evidence has implicated epidermal growth factor receptor (EGFR) expression and activation in mucin production by airway epithelial (goblet) cells. Activated neutrophils recruited to the airways (and their secreted products) play several key roles in EGFR-dependent mucus hypersecretion: (i) activated neutrophils secrete tumor necrosis factor (TNF)-alpha, which induces EGFR expression in airway epithelial cells; (ii) activated neutrophils release reactive oxygen species, which activate EGFR; (iii) neutrophil elastase cleaves the EGFR proligand, pro-transforming growth factor (TGF)-alpha, releasing mature TGF alpha which activates EGFR in a ligand-dependent fashion; and (iv) neutrophil elastase causes potent goblet cell degranulation. The secretion of active products by neutrophils appears carefully regulated. The local release of neutrophil elastase requires close contact between the neutrophil and another cell, mediated by surface adhesion molecules, thus limiting proteolysis to the immediate pericellular environment. In the airway lumen, neutrophils undergo apoptosis and are cleared by macrophages without releasing their intracellular contents. In contrast, neutrophils that die by necrosis disgorge proteases and reactive oxygen species into the lumen. In COPD, conditions within the airway lumen promote neutrophil necrosis. It is concluded that neutrophil death via necrosis leads to the high concentrations of free neutrophil elastase and reactive oxygen species in the sputum of patients with airway neutrophilia and mucus hypersecretion. Inflammatory cells (neutrophils), molecules (neutrophil elastase and reactive oxygen species), signaling pathways (EGFR), and cellular processes (neutrophil necrosis) contribute to mucus hypersecretion in COPD, and are potential targets for therapy. Interventions that target EGFR, neutrophil elastase, and reactive oxygen species exist and can be evaluated as treatments for neutrophil-dependent mucus hypersecretion.
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PMID:Role of neutrophils in mucus hypersecretion in COPD and implications for therapy. 1521 74

The potential therapeutic use of inhibitors of neutrophil elastase (NE) is reviewed with emphasis on diseases of the airway. In addition to its proteolytic properties, NE is a potent secretagogue and may be pro-inflammatory. The properties of natural occurring inhibitors of NE such as alpha-one antitrypsin and secretory leukoprotease inhibitor are reviewed. In addition, recombinant versions of naturally occurring inhibitors and synthetic small molecule inhibitors are potential therapies for respiratory diseases. For recombinant proteins, aerosol administration has been the preferred method of delivery. The inhaled mode of delivery can complicate the determination of dose responsiveness and thus the evaluation of safety and efficacy of these agents. In addition to the aerosolization issue, there remain other significant barriers to the successful deployment of these agents in clinical trials. These include the need for high standards for purification of recombinant proteins, the lack of understanding of interaction with airway secretions, the controversy over role of NE in the pathogenesis of nonhereditary COPD, and asthma, while the need for the safety of new classes of systemically delivered small molecules will need to be established.
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PMID:Potential role of inhibitors of neutrophil elastase in treating diseases of the airway. 1568 29

It is unclear how chronic expectoration influences airway inflammation in patients with chronic lung disease. The aim of this study was to investigate factors influencing inflammation in induced sputum samples, including, in particular, chronic sputum production. Myeloperoxidase, interleukin-8, leukotriene B4 (LTB4), neutrophil elastase, secretory leukoprotease inhibitor (SLPI) and protein leakage were compared in induced sputum samples from 48 patients (36 with chronic expectoration) with COPD (with and without alpha-1-antitrypsin deficiency; AATD), 9 individuals with AATD but without lung disease and 14 healthy controls. There were no differences in inflammation in induced sputum samples from healthy control subjects and from AATD deficient patients with normal lung function but without chronic expectoration (P>0.05). Inflammation in induced sputum from AATD patients with airflow obstruction and chronic sputum expectoration was significantly greater than for similar patients who did not expectorate: Interleukin-8 (P<0.01), elastase activity (P=0.01), and protein leakage (P<0.01). The presence of spontaneous sputum expectoration in AATD patients with airflow obstruction was associated with increased neutrophilic airway inflammation in induced sputum samples. The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified.
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PMID:Effect of expectoration on inflammation in induced sputum in alpha-1-antitrypsin deficiency. 1625 94

Alpha-1 antitrypsin (AAT) deficiency is a common but under-recognized disease. This hereditary disorder is characterized by low levels of AAT, and increased risks of panacinar emphysema at an early age, liver disease, vasculitis and panniculitis. Destruction of lung parenchyma and consequent emphysema result from an imbalance between different inflammatory proteases (in particular, leukocyte elastase), and the major natural antiprotease, AAT. To offer a review of key aspects of this important condition, we present the epidemiology, natural history, and pathogenesis of AAT deficiency and, in the context of recent data and the publication of an international standards document regarding the diagnosis and management of individuals with AAT deficiency, review current therapy of AAT deficiency.
COPD 2005 Jun
PMID:A review of alpha-1 antitrypsin deficiency. 1713 53

Recent years have seen an explosion of animal models of cigarette smoke-induced chronic obstructive lung disease (COPD). Almost all of these have concentrated on the induction and prevention of emphysema. Neutrophils and neutrophil elastase, macrophages and macrophage-derived metalloproteases, lymphocytes, TNF-alpha, and oxidants have all been shown to play a role in the pathogenesis of emphysema in animal models, and interventions using either knockout mice or drugs have indicated possible preventive/therapeutic avenues. There is less in the way of models of smoke-induced small airway remodeling and almost nothing is known of its pathogenesis. Cigarette smoke has been shown to induce vascular remodeling and pulmonary hypertension in laboratory animals, and these mechanisms are beginning to be understood. A major limitation of existing animal models is that most produce relatively mild disease (no more severe than corresponding to the GOLD 2 stage of human COPD), and none of the models show the smoke-independent progressive disease seen in humans with GOLD 3 or 4 COPD. There are no models of cigarette smoke-induced chronic bronchitis in animals and there are no models of acute exacerbations of COPD.
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PMID:Animal models of cigarette smoke-induced chronic obstructive lung disease. 1768 36


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