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)

To evaluate the inflammatory response to the cardiopulmonary bypass, we investigated the serum levels of tumor necrosis factor alpha (TNF alpha), interleukin 8 (IL-8), and the expression of leukocyte adhesion molecule CD18. Six patients who underwent elective coronary artery bypass grafting were studied. TNF alpha was elevated significantly 30 minutes after the start of CPB and returned to the baseline 60 minutes after CPB. IL-8 increased significantly after the start of CPB and reached a peak at 10 minutes after release of the aortic cross-clamp, remaining significantly elevated until 10 minutes after the end of CPB (P < 0.05). Circulating neutrophil count and granulocyte elastase increased significantly 10 minutes after release of the aortic-cross clamp and remained high until the first postoperative day. The increase of the neutrophil CD18 expression was not observed. This study demonstrates elevated TNF alpha and IL-8 levels during CPB followed by increases of the neutrophil and the granulocyte elastase, which may be of importance in the systemic inflammatory response to CPB, especially in the development of postperfusion lung injury.
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PMID:[Responses of TNF alpha, IL-8, and leukocyte adhesion molecule CD18 to cardiopulmonary bypass]. 769 21

Chronic lung disease of prematurity (CLD) is a common respiratory disorder of preterm infants. At autopsy, fibroblast proliferation, and components of the extracellular matrix, including collagen and fibronectin, are markedly increased in the lungs of infants who die from CLD. Examination of broncho-alveolar fluid suggests that the persistence of neutrophils is associated with the development of CLD. In our studies, the pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and interleukin-6, (IL-6) and mediators which reflect neutrophil recruitment and activation, including soluble intercellular adhesion molecule, interleukin-8 (IL-8) and neutrophil elastase, were increased in lavage fluid obtained from infants who developed CLD when compared to infants who did not. Furthermore, semiquantitative reverse transcriptase-polymerase chain reaction of mRNA extracted from lavage cells suggested that luminal cells may be the source of IL-6 detected in lavage fluid but non-luminal cells may be the sources of IL-1 beta and IL-8. Fibrosis is thought to be mediated by the pro-fibrotic cytokines including transforming growth factor-beta1 (TGF-beta 1). Both active and total TGF-beta 1 were increased in lavage fluid from infants who developed CLD. Furthermore, both type I procollagen and TGF-beta were increased qualitatively in lung tissue obtained at autopsy from infants who died from respiratory failure. The increase in inflammatory mediators was maximal at 10 days of age. By contrast, the increase in TGF-beta 1 was maximal at 4 days of age. This suggests that the interaction between inflammation and fibrosis in CLD is complex, and that prenatal factors may be important in the pathogenesis of CLD.
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PMID:Cytokines in chronic lung disease of prematurity. 883 40

Pulmonary injury may result from the use of cardiopulmonary bypass (CPB). We investigated changes in the haemostatic system in the pulmonary vein during CPB compared with blood that circulated through the bypass circuit. Paired samples were taken from the pulmonary vein and central venous pressure (CVP) line during the peri-operative period from ten patients. Plasma levels of factor VII (P < 0.001), prekallikrein (P < 0.05), antithrombin III (P < 0.001) and heparin cofactor II (P < 0.005) were decreased in the pulmonary vein after 20 min of bypass compared with pre-operative levels. In the pulmonary vein there was a significant increase in neutrophil expressed CD11b (P < 0.001), neutrophil elastase: alpha 1-antitrypsin complexes (P < 0.001), endothelin-1(P < 0.001) and thrombin-antithrombin complexes (P < 0.001) by the end of bypass compared with pre-operative levels. There was no significant change in monocyte expressed CD11b, factor XII or C1-esterase inhibitor in the pulmonary vein for the study period. None of these variables were significantly different in the pulmonary vein compared with CVP line. In the pulmonary vein plasma levels of activated factor VII decreased following heparin administration (P < 0.001) in the majority of patients which was coincidental to an increase (P < 0.001) in tissue factor pathway inhibitor (TFPI). This increase in TFPI was significantly higher in the pulmonary vein compared with CVP line (P < 0.05) There was a decrease in neutrophil count by 20 min on CPB in both the pulmonary vein and CVP line (P < 0.001) and this did not return to pre-operative levels in the pulmonary vein. Soluble thrombomodulin levels decreased by 20 min on CPB in the CVP line (P < 0.05) but tended to increase in the pulmonary vein, although this was not statistically significant. In conclusion we found evidence of thrombin generation and possible endothelial damage together with increased neutrophil activation and adhesion molecule expression in the pulmonary vein during CPB which may play an important role in the development of post-CPB pulmonary injury.
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PMID:Haemostatic changes in the pulmonary blood during cardiopulmonary bypass. 887 68

We have assessed the pattern of dermal endothelial adhesion molecule expression following broadband UVB irradiation in vivo and in vitro. Skin biopsies were taken from 4 human volunteers at baseline and at 4, 8 and 24 h post-irradiation with 2.5 minimal erythema doses of UVB. Sections were stained immunohistochemically for E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1). CD31 and neutrophil elastase. The effect of direct UVB irradiation on E-selectin, ICAM-1 and VCAM-1 was examined in a human dermal microvascular endothelial cell line, HMEC-1. Cultured HMEC-1 were irradiated with 2.5-40 mJ/cm2 of UVB, and assessed for adhesion molecule expression by immunofluorescence microscopy and fluorescence-activated cell sorter analysis. In vivo, E-selectin was minimally expressed on EC at baseline and was induced by 4 h following irradiation, P < 0.01. ICAM-1 was moderately expressed at baseline and appeared mildly induced at 24 h, although this did not reach statistical significance. VCAM-1 was weakly expressed in unirradiated skin while CD31 was moderately expressed, but neither was induced by UVB irradiation. A significant neutrophilic infiltrate appeared by 8 h and was maximal at 24 h, P < 0.05. Neutrophil infiltration correlated with E-selectin expression, r = 0.96. In HMEC-1, ICAM-1 was upregulated at 24 h post-irradiation, with an increase in mean channel fluorescence from 100% at baseline to 145 (SD12)% at 24 h, P < 0.05. No change was seen in expression of E-selectin, VCAM-1 or CD31. These studies support the involvement of endothelial adhesion molecules E-selectin and ICAM-1 in UVB-induced inflammation. Whereas ICAM-1 is upregulated by direct irradiation of endothelial cells, E-selectin stimulation appears to be an indirect effect.
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PMID:Comparison of changes in endothelial adhesion molecule expression following UVB irradiation of skin and a human dermal microvascular cell line (HMEC-1). 895 61

Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion. Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell's intercellular adhesion molecule (ICAM-1) through the leukocyte integrin, CD11/CD18. We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11/CD18 integrin in a rabbit model of transient focal ischemia. Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral, anterior cerebral, and internal carotid arteries using aneurysm clips for 2 h, followed by 6 h of reperfusion. Treatment with a maximally saturating dose (4 mg/kg) of a humanized CD11/CD18 monoclonal antibody (Hu23F2G, ICOS Corp., Bothell, WA) (n = 8) or placebo (n = 7) was administered 20 min after occlusion and given as a single intravenous bolus. Hemispheric ischemic neuronal damage (IND) as seen on hematoxylin- and eosin-stained sections was significantly reduced in Hu23F2G-treated animals by 57% (Hu23F2G: 15 +/- 6.9%; placebo: 35 +/- 5%; mean +/- SEM, P < 0.05, t-test). Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains. Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration. (No. of neutrophils/IND area: Hu23F2G 36.1 +/- 36.7 cm-2, placebo 460.6 +/- 101.8 cm-2, P = 0.001. ) Antagonism of neutrophil migration at the level of the CD11/CD18 integrin reduces ischemic injury in experimental stroke.
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PMID:Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. 978 82

Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion. Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cells via interactions with various adhesion molecules. One adhesion molecule, L-selectin, is found on the surface of leukocytes, and is shed prior to leukocyte infiltration. We studied whether a humanized antibody to L-selectin (HuDREG200) might limit ischemic injury in an experimental stroke model. New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral, anterior cerebral and internal carotid arteries using aneurysm clips for 2 h followed by 6 h of reperfusion. Treatment with a saturating dose (4 mg kg-1) of HuDREG200 (n = 8) or vehicle (n = 8) was administered 20 min after occlusion and given as a single i.v. bolus. Hemispheric ischemic neuronal damage (IND) as seen on hematoxylin and eosin stained sections was no different between groups (HuDREG200, 23.3% +/- 6%; vehicle, 19.6% +/- 6%; mean +/- SEM, n.s., t-test). Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains, but treatment did not alter their numbers within ischemic tissue. We conclude that antagonism of neutrophil adhesion at the level of L-selectin does not alter ischemic injury in experimental stroke.
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PMID:L-selectin inhibition does not reduce injury in a rabbit model of transient focal cerebral ischemia. 1121 Apr 35

The clinical presentation of pre-eclampsia suggests that microvascular dysfunction may play a role in the maternal manifestations of the disease. Isovolumetric venous pressure ( P V(i)) is an index of microvascular function, reflecting local plasma colloid osmotic (oncotic) pressure, and is abnormal in clinical conditions with microvascular dysfunction. We hypothesized that, in pre-eclampsia, post-capillary margination of neutrophils would increase post-capillary resistance, and therefore P V(i). A small cumulative step strain-gauge plethysmography protocol was used to compare P V(i) in 18 women with pre-eclampsia, 16 normal pregnant women and 17 non-pregnant controls. Circulating levels of vascular cell-adhesion molecule-1 (VCAM-1), intercellular cell-adhesion molecule-1 (ICAM-1) and E-selectin, and neutrophil elastase, were measured to assess endothelial and neutrophil activation respectively. P V(i) was significantly greater in the pre-eclampsia group, relative to the normal pregnant and non-pregnant controls ( P <0.001, ANOVA, for both comparisons). P V(i) was significantly lower during normal pregnancy compared with the non-pregnant controls ( P =0.001). Plasma levels of neutrophil elastase, VCAM-1, ICAM-1 and E-selectin ( P =0.001) were significantly greater in the pre-eclamptics than the controls. Significant positive correlations were observed between P V(i) and neutrophil elastase ( r =0.71, P =0.001), VCAM-1 ( r =0.52, P =0.03), ICAM-1 ( r =0.67, P =0.002), E-selectin ( r =0.69, P =0.001), uric acid levels ( r =0.54, P =0.02) and haematocrit ( r =0.64, P =0.004) in pre-eclampsia. The relationship with the platelet count was negative ( r =-0.65, P =0.003). No significant correlations were observed between P V(i) and maternal age, gestational age, total protein, albumin, diastolic blood pressures, age, body mass index and infant birth mass in the normal pregnant and non-pregnant controls. These data suggest that microvascular dysfunction occurs in pre-eclampsia, and that it is related to alterations in endothelial cell and neutrophil activation.
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PMID:Evidence of impaired microvascular function in pre-eclampsia: a non-invasive study. 1265 86

Chronic obstructive pulmonary disease (COPD) is a common, smoking-related, severe respiratory condition characterised by progressive, irreversible airflow limitation. Current treatment of COPD is symptomatic, with no drugs capable of halting the relentless progression of airflow obstruction. Better understanding of the airway inflammation, oxidative stress and alveolar destruction that characterise COPD has delineated new disease targets, with consequent identification of novel compounds with therapeutic potential. These new drugs include aids to smoking cessation (e.g. bupropion) and improvements to existing therapies, for example long-acting rather than short-acting bronchodilators, as well as combination therapy. New antiproteases include acyl-enzyme and transition state inhibitors of neutrophil elastase (e.g. sivelestat and ONO-6818), matrix metalloprotease inhibitors (e.g. batimastat), cathepsin inhibitors and peptide protease inhibitors (e.g. DX-890 [EPI-HNE-4] and trappin-2). New antioxidants include superoxide dismutase mimetics (e.g. AEOL-10113) and spin trap compounds (e.g. N-tert-butyl-alpha-phenylnitrone). New anti-inflammatory interventions include phosphodiesterase-4 inhibitors (e.g. cilomilast), inhibitors of tumour necrosis factor-alpha (e.g. humanised monoclonal antibodies), adenosine A(2a) receptor agonists (e.g. CGS-21680), adhesion molecule inhibitors (e.g. bimosiamose [TBC1269]), inhibitors of nuclear factor-kappaB (e.g. the naturally occurring compounds hypoestoxide and (-)-epigallocatechin-3-gallate) and activators of histone deacetylase (e.g. theophylline). There are also selective inhibitors of specific extracellular mediators such as chemokines (e.g. CXCR2 and CCR2 antagonists) and leukotriene B(4) (e.g. SB201146), and of intracellular signal transduction molecules such as p38 mitogen activated protein kinase (e.g. RWJ67657) and phosphoinositide 3-kinase. Retinoids may be one of the few potential treatments capable of reversing alveolar destruction in COPD, and a number of compounds are in clinical trial (e.g. all-trans-retinoic acid). Talniflumate (MSI-1995), an inhibitor of human calcium-activated chloride channels, has been developed to treat mucous hypersecretion. In addition, the purinoceptor P2Y(2) receptor agonist diquafosol (INS365) is undergoing clinical trials to increase mucus clearance. The challenge to transferral of these new compounds from preclinical research to disease management is the design of effective clinical trials. The current scarcity of well characterised surrogate markers predicts that long-term studies in large numbers of patients will be needed to monitor changes in disease progression.
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PMID:Therapy for chronic obstructive pulmonary disease in the 21st century. 1296 14

For 50 years, macrolide antibiotics have been used to treat community acquired pneumonia and atypical infections such as Chlamydia pneumonia and Mycoplasma. In the late 1960s it was noted that when the 14-member ring macrolide antibiotic troleandomycin was given to asthma patients who required large doses of systemic corticosteroids, they could often reduce their steroid dose or even stop steroids completely without exacerbation of their asthma. Because of this experience, Prof. S. Kodoh and colleagues first used erythromycin as an immunomodulatory agent to treat diffuse panbronchiolitis (DPB). DPB is a cystic fibrosis (CF)-like condition seen predominantly in young, nonsmoking adults in Japan and Korea. The introduction of erythromycin profoundly improved survival, and in many of these very ill patients the illness disappeared. Since then, research has focused attention on many non-antibacterial, disease modifying effects of this class of compounds. These include downregulation of proinflammatory cytokines via an effect on nuclear transcription factors, reduction in adhesion molecule expression, suppression of inducible nitric oxide synthase (iNOS), reduced neutrophil chemotaxis and degranulation, inhibition of neutrophil elastase, cytoprotection against bioactive phospholipids, improvement in the rheological properties of mucus, reduction in bronchial hyperreactivity, and, perhaps, modulation of neutrophil death by apoptosis pathways, and in the end, airway remodeling. Additionally, they have unconventional effects on microorganisms, including inhibiting Pseudomonas aeruginosa twitching motility and thus biofilm formation. There are small case series and three large randomized controlled trials that have established unequivocal evidence of benefit in CF. There is less evidence for an immunomodulatory effect in bronchiectasis. Future work is likely to focus on the development of macrolides with disease-specific modes of action.
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PMID:Macrolides as biological response modifiers in cystic fibrosis and bronchiectasis. 1608 89

Hyperforin (Hyp), a polyphenol-derivative of St. John's wort (Hypericum perforatum), has emerged as key player not only in the antidepressant activity of the plant but also as an inhibitor of bacteria lymphocyte and tumor cell proliferation, and matrix proteinases. We tested whether as well as inhibiting leukocyte elastase (LE) activity, Hyp might be effective in containing both polymorphonuclear neutrophil (PMN) leukocyte recruitment and unfavorable eventual tissue responses. The results show that, without affecting in vitro human PMN viability and chemokine-receptor expression, Hyp (as stable dicyclohexylammonium salt) was able to inhibit in a dose-dependent manner their chemotaxis and chemoinvasion (IC50=1 microM for both); this effect was associated with a reduced expression of the adhesion molecule CD11b by formyl-Met-Leu-Phe-stimulated neutrophils and block of LE-triggered activation of the gelatinase matrix metalloproteinase-9. PMN-triggered angiogenesis is also blocked by both local injection and daily i.p. administration of the Hyp salt in an interleukin-8-induced murine model. Furthermore, i.p. treatment with Hyp reduces acute PMN recruitment and enhances resolution in a pulmonary bleomycin-induced inflammation model, significantly reducing consequent fibrosis. These results indicate that Hyp is a powerful anti-inflammatory compound with therapeutic potential, and they elucidate mechanistic keys.
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PMID:Hyperforin blocks neutrophil activation of matrix metalloproteinase-9, motility and recruitment, and restrains inflammation-triggered angiogenesis and lung fibrosis. 1728 34


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