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)

While considerable progress has been made in development of drugs for asthma, there have been few advances in the treatment of chronic obstructive pulmonary disease (COPD). New therapeutic approaches to prevent disease progression are urgently needed and these will arise out of better understanding of the disease process at a cell and molecular level. The inflammatory response in COPD differs markedly from that of asthma, with differences in inflammatory cells, mediators and response to therapy. The neutrophilic inflammation is orchestrated by chemotactic factors, such as interleukin (IL)-8, other CXC chemokines and leukotriene B4; receptor blockers (CXCR1, CXCR2, BLT antagonists) or synthesis inhibitors (5'-lipoxygenase inhibitors) might be effective. Tumour necrosis factor (TNF) alpha may be an important amplifying cytokine and there are several strategies for blocking it (antibodies, soluble receptors, TACE inhibitors). IL-10 is effective in blocking the synthesis of IL-8 and TNF alpha as well as proteases. Oxidative stress and peroxynitrite may be important in COPD; more effective antioxidants are now in development. The inflammatory response in COPD is essentially steroid-resistant so that alternative anti-inflammatory treatments are needed. Phosphodiesterase 4 inhibitors look promising in early clinical studies. Nuclear factor-kappa B inhibitors and p38 MAP kinase inhibitors may also be effective. Several protease inhibitors are in development including those for neutrophil elastase, selective matrix metalloproteinase and cathepsin.
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PMID:Potential novel therapies for chronic obstructive pulmonary disease. 1119

Status asthmaticus (SA) is a sudden respiratory failure characterized by an acute bronchospasm with a severe inflammation, requiring in some cases mechanical ventilation (MV). Initial postmortem studies emphasized the presence of eosinophils in the bronchial wall and of mucus plugs filling the bronchi. More recently a prominent neutrophil influx was observed in patients with fatal or near fatal asthma. The aim of our study was to evaluate characteristics of bronchial inflammation in terms of cellular influx, mediators, cytokines and chemokines. Ten patients with SA were compared with 11 patients with chronic asthma, 4 without preexisting pulmonary disease requiring MV and 8 healthy subjects. Bronchial lavages in SA were indicated to remove bronchial plugs in case of atelectasis and/or refractory SA. The main findings in patients with SA were a massive influx of neutrophils (81.5 +/- 4.5%) with a dramatic increase of neutrophil elastase. Although more limited than the neutrophil influx, eosinophils were present and associated with high levels of eosinophil cationic protein (ECP), which suggested that a part of the eosinophils were activated and degranulated. In parallel to the neutrophil and eosinophil influx, we observed elevated amounts of proinflammatory (IL-1beta, IL-5, IL-6, TNFalpha) and anti-inflammatory (IL-10, IL-1 receptor antagonist, soluble TNF receptors) cytokines with a balance in favor of a net proinflammatory activity. Chemokines were also present in large quantities with a predominance of MCP-1, MIP-alpha and RANTES with a significant correlation between MCP-1, RANTES, IL-5 and both eosinophil and ECP values. In addition an acute 10- to 160-fold increase of 92-kD gelatinase (MMP9) was detected in bronchial lavage fluid from patients with SA associated with a free metallogelatinolytic activity, suggesting an imbalance in the local production of proteases and antiproteases. Therefore, our results indicate that the bronchi in SA are the site of an intense production of pro- and anti-inflammatory cytokines and chemokines that are implicated in the influx of eosinophils and neutrophils. The inflammatory pattern in SA clearly differs from the usual profile observed in chronic asthma.
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PMID:Characteristics of the Inflammatory response in bronchial lavage fluids from patients with status asthmaticus. 1130 87

Acute respiratory distress syndrome (ARDS), is characterised by capillary permeability and pulmonary oedema formation and may complicate a variety of medical and surgical illnesses. As a self-perpetuating state of inflammatory derangement, acute lung injury (ALI)/ARDS is manifest clinically as rapid development of radiographic infiltrates, severe hypoxaemia and reduced lung compliance. Over the years, researchers have made significant progress in elucidating the pathophysiology of this complex syndrome. Therapies targeting specific pathophysiologic steps in the development or persistence of this syndrome are in various stages of laboratory and clinical testing. Results to date have shown nitric oxide (NO) to improve oxygenation in the majority of patients but fail to improve mortality. Surfactant replacement has had limited success in adults, but new formulations and delivery methods may prove beneficial. Several inflammatory mediator-targeted therapies have progressed successfully through early clinical evaluation. Among these, neutrophil elastase inhibitors have shown the most promise and are currently undergoing Phase III trials. Other mediator-targeted therapies, such as prostaglandin E1, IL-10 and platelet activating factor antagonists, have not been found efficacious in large clinical trials of ARDS. However, these therapies, along with coagulation modulators, may have a favourable impact on ARDS by improving outcomes in sepsis, the greatest risk factor for developing this condition. In the interim, supportive care through improvements in mechanical ventilation are beneficial, while specific fluid balance and nutrition strategies may prove advantageous.
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PMID:Clinical developments for treating ARDS. 1177 19

Exposure to an erythemal dose of ultraviolet B (UVB) is known to induce interleukin (IL-10) expression in human skin. It is generally believed that this IL-10 is predominantly expressed by CD11b+ HLA-DR+ macrophages that infiltrate the UVB-exposed skin. This cytokine is presumed to contribute to the immunosuppressive effects of UVB by inhibiting cell-mediated immune responses. We recently demonstrated that neutrophils, which also invade UVB-irradiated skin, express CD11b and HLA-DR as well. In addition, we showed that the presence of these neutrophils affects T-cell responses in primary T-cell cultures derived from UVB-exposed skin. Since neutrophils invade UVB-exposed skin and, like macrophages, express CD11b and HLA-DR, we sought to determine whether neutrophils represent another source of IL-10. Skin biopsies were obtained from four healthy volunteers before and 2 days after exposure to four minimal erythema doses of UVB. A series of immunohistochemical double-staining procedures using the following markers was performed: IL-10, CD11b, HLA-DR, CD36, neutrophil elastase, and CD66b. As expected IL-10 could be detected in CD11b+ HLA-DR+ CD36+ macrophages in the epidermis and dermis of UVB-exposed skin. Surprisingly, the majority of the abundant IL-10 expression was found in CD11b+ HLA-DR+ elastase+ CD66b+ neutrophils. Cytospin preparations from dermal cell suspensions confirmed the IL-10 expression by neutrophils displaying characteristic multilobular nuclei. Thus, neutrophils in UVB-exposed skin express IL-10 and should be recognized as active coplayers in the creation of the UVB-induced immunosuppressive microenvironment.
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PMID:Neutrophils infiltrating ultraviolet B-irradiated normal human skin display high IL-10 expression. 1555 Nov 42

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
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PMID:Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. 1620 20

Controversy exists over whether the lower airway inflammation that characterizes cystic fibrosis (CF) is initiated primarily by the genetic defect. To determine if inflammation precedes infection, we examined bronchoalveolar lavage (BAL) fluid cytology, cytokines (interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha), and free neutrophil elastase activity from 70 CF (aged 1.5-71 months) children detected by newborn screening and 19 (aged 2.0-48 months) controls with chronic stridor. CF subjects were selected and categorized as pristine (13 aged </= 6 months, lacking prior respiratory symptoms and exposure to antibiotics, and without respiratory pathogens on BAL), infected (42 with viruses or >/= 10(5) colony-forming units/ml of pathogenic bacteria in BAL), and uninfected (15 aged > 6 months, asymptomatic, not taking antibiotics at bronchoscopy, and free of pathogens in their BAL). To further resolve if inflammation develops without infection, inflammatory mediators in paired annual BAL samples from 38 CF subjects were measured, and results were grouped according to whether BAL showed persistence (n = 6), acquisition (n = 8), clearance (n = 13), or absence (n = 11) of infection. While pristine, uninfected, and control subjects had similar BAL profiles, infected patients showed elevated inflammatory indices, including increased IL-10 (P < 0.001). Pristine subjects had the fewest signs of inflammation. Analysis of BAL pairs found differences between the four infection groups for changes in neutrophil percentages, IL-8 (P < 0.001), and free neutrophil elastase (P = 0.009). Infection was associated with elevated inflammatory mediators in BAL fluid. In contrast, minimal or reduced signs of inflammation accompanied absence of eradication of infection from BAL fluid. We conclude that in CF, infection initiates and sustains airway inflammation.
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PMID:Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. 1620 79

This study was performed to investigate the relationships between markers of inflammation in serum (interleukin-6 [IL-6], interleukin-10 [IL-10], and granulocyte elastase [GE]), severity of injury, and clinical outcomes, and to evaluate the predictive value of these markers for major complications and mortality. This study, which was conducted between August 2003 and May 2005, examined patients older than 16 y who were admitted to the Emergency Unit of the Uludag University Medical School within 12 h after trauma, and who had traumatic hemorrhagic shock (THS) at admission. Three groups were established: the THS group (n=20), the pure hemorrhagic shock (PHS) group (n=20), and the healthy control group (n=20). Demographic data were recorded for all subjects, and blood samples were taken for lactate, base excess, GE, IL-6, and IL-10 measurements. The Glasgow Coma Score, the Revised Trauma Score, the Injury Severity Score, the New Injury Severity Score, and the Trauma Score-Injury Severity Score were calculated; complications and final clinical outcomes were monitored. A total of 35 men and 25 women were included in the study; mean patient age was 41+/-17 y. In the THS group, scores were as follows: Revised Trauma Score, 10.2+/-2.2; Trauma Score-Injury Severity Score, 0.86+/-0.2; Injury Severity Score, 24.8+/-9.0; and New Injury Severity Score, 32.7+/-9.0. IL-6, IL-10, lactate, and base excess levels in the THS group were significantly higher than those in the PHS and healthy control groups. The serum GE level of the THS group was significantly higher than that of the healthy control group, but it did not differ significantly from that of the PHS group. Complications such as sepsis, acute respiratory distress syndrome, and multiple organ failure occurred in 50% of the THS group and in 20% of the PHS group. Mortality was 30% in the THS group and 10% in the PHS group. In the THS group, no significant differences were noted between markers of inflammation and trauma scores of patients who died and those who survived. The investigators concluded that although the levels of markers of inflammation increased in THS patients, they were inadequate for predicting mortality and the development of complications such as acute respiratory distress syndrome, multiple organ failure, and sepsis. A larger study based on the use of serial marker measurements is warranted.
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PMID:Relationships between markers of inflammation, severity of injury, and clinical outcomes in hemorrhagic shock. 1802 20

The Toxoplasma gondii serin protease inhibitor-1 (TgPI-1) is a dense granule antigen that showed to specifically inhibit trypsin, chymotrypsin and neutrophil elastase, suggesting a possible modulatory role during the parasite invasion process and on the development of the innate immune response. To study the immune-protective value of TgPI-1, C3H/HeN mice were immunized with a recombinant form of the antigen rTgPI-1 combined with alum. All immunized mice produced specific anti-rTgPI-1 immunoglobulins, with high IgG antibody titers and a mixed IgG(1)/IgG(2a) response, with predominance of IgG(1) production. The cellular immune response was associated with the production of IFN-gamma and IL-10 cytokines. Vaccinated mice displayed significant protection against an oral challenge either after a lethal infection with Me49 cysts (90% survival vs. 50%) and also after a non-lethal infection (58% reduction in brain parasite load) compared to the non-vaccinated control group. In conclusion, rTgPI-1 elicits a strong specific immune response providing partial protection against both T. gondii acute and chronic infection, so it would be a good candidate in a vaccine against toxoplasmosis, which could be combined with other relevant parasite antigens.
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PMID:Toxoplasma gondii protease inhibitor-1 (TgPI-1) is a novel vaccine candidate against toxoplasmosis. 1867 73

Endodontic infections are polymicrobial infections resulting in bone destruction and tooth loss. The host response to these infections is complex, including both innate and adaptive mechanisms. Osteopontin (OPN), a secreted, integrin-binding protein, functions in the regulation of immune responses and enhancement of leucocyte migration. We have assessed the role of OPN in the host response to endodontic infection using a well-characterized mouse model. Periapical bone loss associated with endodontic infection was significantly more severe in OPN-deficient mice compared with wild-type 3 weeks after infection, and was associated with increased areas of inflammation. Expression of cytokines associated with bone loss, interleukin-1alpha (IL-1alpha) and RANKL, was increased 3 days after infection. There was little effect of OPN deficiency on the adaptive immune response to these infections, as there was no effect of genotype on the ratio of bacteria-specific immunoglobulin G1 and G2a in the serum of infected mice. Furthermore, there was no difference in the expression of cytokines associated with T helper type 1/type2 balance: IL-12, IL-10 and interferon-gamma. In infected tissues, neutrophil infiltration into the lesion area was slightly increased in OPN-deficient animals 3 days after infection: this was confirmed by a significant increase in expression of neutrophil elastase in OPN-deficient samples at this time-point. We conclude that OPN has a protective effect on polymicrobial infection, at least partially because of alterations in phagocyte recruitment and/or persistence at the sites of infection, and that this molecule has a potential therapeutic role in polymicrobial infections.
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PMID:Protective role of osteopontin in endodontic infection. 1982 20

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.
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PMID:Neutrophil elastase inhibitor improves survival of rats with clinically relevant sepsis. 1995 5


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