Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Cigarette smoke induces plasma exudation in the airways of rodents by activation of capsaicin-sensitive 'sensory-efferent' nerves. The response is mediated predominantly by substance P (SP) and the magnitude of exudation is regulated by neutral endopeptidase (NEP). The component(s) of the smoke responsible for the activation of the nerves may be reactive oxygen radicals. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea (DMTU), a regulator of superoxide anion, superoxide dismutase (SOD), and a regulator of hydrogen peroxide, catalase, on plasma exudation (measured using Evans blue dye) induced by cigarette smoke in guinea-pig main bronchi in vivo. The effect of DMTU on plasma exudation and non-cholinergic bronchoconstriction (measured as pulmonary insufflation pressure, PIP) induced by electrical stimulation of the vagus nerves was also assessed. Interaction between hydroxyl radicals and NEP was assessed with the NEP inhibitor phosphoramidon. 2. In each of the experiments, cigarette smoke increased plasma exudation by approximately 200% above air-exposed controls. Acute administration of DMTU (1.5 g kg-1, i.v. for 20 min) significantly reduced cigarette smoke-induced plasma exudation by 69%. In contrast, neither SOD (240,000 u kg-1, i.v.) nor catalase (400,000 u kg-1, i.v.) significantly affected the exudative response. 3. Chronic pretreatment with DMTU (1.25 g kg-1 over 4 days) significantly reduced bronchial plasma exudation induced by cigarette smoke by 72%. Phosphoramidon (1.5 mg kg-1, i.v.) completely reversed the inhibition by DMTU of cigarette smoke-induced plasma exudation. 4. Vagal stimulation increased plasma exudation by approximately 200% and PIP by approximately 250%. Acute treatment with DMTU had no significant inhibitory effect on these responses, whereas chronic pretreatment inhibited them by approximately 80%. Phosphoramidon reversed the inhibition by chronic DMTU. 5. SP (1 nmol kg-1) increased plasma exudation by approximately 250%, a response which was not inhibited by either acute or chronic DMTU. 6. We conclude that hydroxyl radicals, rather than superoxide anion or hydrogen peroxide, are involved in the induction of neurogenic plasma exudation and bronchoconstriction induced by cigarette smoke or by electrical stimulation of the vagus nerves. These radicals also affect the activity of NEP. Acute DMTU may affect directly the neural actions of hydroxyl radicals contained in the cigarette smoke. Chronic pretreatment with DMTU may inhibit the neurogenic airway responses by effects on tachykinin biosynthesis and/or axonal transport.
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PMID:Involvement of hydroxyl radicals in neurogenic airway plasma exudation and bronchoconstriction in guinea-pigs in vivo. 882 33

1. We have studied the conversion of big endothelin-1 (big ET-1), big endothelin-2 (big ET-2) and big endothelin-3 (big ET-3) and characterized the enzyme involved in the conversion of the three peptides in guinea-pig lung parenchyma (GPLP). 2. Endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3) (10 nM to 100 nM) caused similar concentration-dependent contractions of strips of GPLP. 3. Big ET-1 and big ET-2 also elicited concentration-dependent contractions of GPLP strips. In contrast, big ET-3, up to a concentration of 100 nM, failed to induce a contraction of the GPLP. 4. Incubation of strips of GPLP with the dual endothelin converting enzyme (ECE) and neutral endopeptidase (NEP) inhibitor, phosphoramidon (10 microM), as well as two other NEP inhibitors thiorphan (10 microM) or SQ 28,603 (10 microM) decreased by 43% (P < 0.05), 42% (P < 0.05) and 40% (P < 0.05) the contractions induced by 30 nM of big ET-1 respectively. Captopril (10 microM), an angiotensin-converting enzyme inhibitor, had no effect on the contractions induced by big ET-1. 5. The incubation of strips of GPLP with phosphoramidon (10 microM), thiorphan (10 microM) or SQ 28,603 (10 microM) also decreased by 74% (P < 0.05), 34% and 50% (P < 0.05) the contractions induced by 30 nM big ET-2 respectively. As for the contractions induced by big ET-1, captopril (10 microM) had no effect on the concentration-dependent contractions induced by big ET-2. 6. Phosphoramidon (10 microM), thiorphan (10 microM) and SQ 28,603 (10 microM) significantly potentiated the contractions of strips of GPLP induced by both ET-1 (30 nM) and ET-3 (30 nM). However, the enzymatic inhibitors did not significantly affect the contractions induced by ET-2 (30 nM) in this tissue. 7. These results suggest that the effects of big ET-1 and big ET-2 result from the conversion to ET-1 and ET-2 by at least one enzyme sensitive to phosphoramidon, thiorphan and SQ 28,603. This enzyme corresponds possibly to EC 3.4.24.11 (NEP 24.11) and could also be responsible for the degradation of ETs in the GPLP.
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PMID:Role of the neutral endopeptidase 24.11 in the conversion of big endothelins in guinea-pig lung parenchyma. 882 61

In the present study, we explored whether or not a neutral endopeptidase inhibitor provokes cough in awake guinea-pigs. Inhalation of phosphoramidon at a concentration of 10(-6) M did not cause cough, but increasing the concentration to 10(-5) M caused cough with a latency of about 10 to 12 min. Inhalation of enalapril, an angiotensin-converting enzyme inhibitor, did not cause cough, even at high concentrations of 10(-5) M and 10(-4) M. Pretreatment with phosphoramidon (10(-5) M) significantly increased the number of coughs caused by substance P and capsaicin. Capsaicin-induced coughs were more easily produced in bronchitic guinea-pigs than in normal guinea-pigs. However, there was no significant difference in the number of phosphoramidon-induced coughs between normal and bronchitic guinea-pigs. Phosphoramidon-induced coughs were significantly depressed by codeine (20 mg/kg, p.o.) and CP96345 (2 mg/kg, i.v.). The present results provide new evidence for the proposed idea that neutral endopeptidase may regulate the occurrence of cough.
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PMID:Inhalation of phosphoramidon, a neutral endopeptidase inhibitor, induces cough in awake guinea-pigs. 886 15

Endothelin-1 (ET-1) by itself was not an effective stimulus for inducing superoxide (O2.) generation in human resting or DMSO-differentiated neutrophil-like HL-60 cells. ET-1 (0.01-100 nM) was not able to modulate O2. generation stimulated by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP, EC50 = 4.24 +/- 1.63 nM in the absence and 3.16 +/- 1.95 nM in the presence of ET-1). Neither did ET-1 (0.01-100 nM) promote the mobilization of intracellular calcium ions or modulate fMLP-induced [Ca(2+)]i increase in this model of human neutrophils. Phosphoramidon, a neutral endopeptidase inhibitor, was not able to reveal any biological (O2.) or biochemical ([Ca(2+)]i response to ET-1 in the absence or in the presence of fMLP in these cells. These results indicate that DMSO-differentiated neutrophil-like HL-60 cells are not sensitive to ET-1 in terms of O2. generation or [Ca(2+)]i variations.
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PMID:Endothelin-1 does not modulate O2.release and [Ca(2+)]i variations in resting or differentiated HL-60 cells. 890 Apr 97

The intratracheal (i.t.) instillation of Sephadex beads into rat induced inflammation and a 30-fold increase in the endothelin-1-like immunoreactivity (ET-1-LI) of broncho-alveolar lavage fluid. The levels were highest 24 h after the instillation and had declined significantly after 48 h. At a dose of 1 mg kg-1 i.t., the glucocorticosteroid budesonide almost abolished this response. Phosphoramidon, which inhibits neutral endopeptidase, an enzyme reported to degrade ET-1 and also to inhibit the endothelin-converting enzyme, potentiated the Sephadex-induced rise in ET-1-LI. Chymostatin and heparin, which are reported to reduce the formation of ET-1, did not affect the increase in ET-1-LI. The present model represents a very reactive system for analyzing the changes in ET-1 levels during inflammation.
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PMID:Release of endothelin-1 into rat airways following Sephadex-induced inflammation; modulation by enzyme inhibitors and budesonide. 896 64

To investigate whether tachykinins are released in the airways in response to stimulation of the esophagus, we studied the airway plasma extravasation induced by intraesophageal HCl in the presence or absence of neutral endopeptidase inhibitor phosphoramidon and NK1-receptor antagonist FK-888 in anesthetized guinea pigs. The airway plasma leakage was evaluated by measuring extravasated Evans blue dye in the animals pretreated with propranolol and atropine. Infusion of 1 N HCl into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation in the trachea and main bronchi, whereas FK-888 significantly inhibited that extravasation in a dose-related manner. In the capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilateral vagotomized animals. These results suggest that 1) tachykinin-like substances are released to cause plasma extravasation in the airways as a result of intraesophageal HCl stimulation and 2) there are neural pathways communicating between the esophagus and airways, including the vagus nerve.
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PMID:Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs. 907 57

The formation of endothelins (ET) from exogenous big-ET-1, -2 and -3 was investigated in cultured guinea pig Clara cells. When Clara cells were incubated with 10(-9) or 10(-8) M human big-ET-1 (1-38), the release of ET was 69.9 +/- 7.6 and 221.6 +/- 25 fmol/ml respectively, after 1 h incubation period. Treatment of Clara cells with 1 mM phosphoramidon strongly suppressed (80%) the conversion of big-ET-1 to ET-1 during 1, 2 and 6 h incubation periods. Treatment of Clara cells with thiorphan (1 mM), an inhibitor of neutral endopeptidase, decreased by 44 and 26% the levels of immunoreactive endothelin (ir-ET) in the cell supernatant respectively, after 1 and 2 h incubation periods. When Clara cells were incubated with 10(-8) M human big-ET-2 (1-38), the release of ir-ET was 287.6 +/- 8.9 fmol/ml after a 1 h incubation period. Phosphoramidon and thiorphan (1 mM) reduced the amount of ir-ET generated from exogenous human big-ET-2 (10(-8) M) by 69 and 56%, respectively. When Clara cells were incubated with 10(-8) M human big-ET-3 (1-41), the release of ET was not increased after a 1 h incubation period. Our results suggest that guinea pig Clara cells convert exogenous big-ET-1 and -2 but not big-ET-3 into ET-1 and ET-2, respectively, through metalloproteinases sensitive to both phosphoramidon and thiorphan.
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PMID:Phosphoramidon and thiorphan suppress the generation of endothelin (ET) from exogenous big-endothelin by guinea pig Clara cells. 911 Mar 81

Thymic hormones such as thymopoietin (TP) have been shown to regulate thymocyte differentiation and lymphocyte activation. However, it is not known whether thymopoietin affects thymic epithelial cell (TEC) functions. In this study we have examined the effect of a five amino acid active peptide (TP5), corresponding to amino acids 32-36 of TP, on the proliferation of nontransformed clones of human TEC. Our results indicate that TP5 induced reinitiation of DNA synthesis and potentiated fetal calf serum (FCS)-induced cell growth in postnatal and fetal-derived human TEC. We also found that TEC lines express high levels of endopeptidase 24.11, a cell-surface metallopeptidase also known as the CD10 antigen. We show that TP5 is cleaved by CD10 at the surface of TEC lines, indicating that this endopeptidase may regulate TP5-induced TEC proliferation. Phosphoramidon, a specific endopeptidase 24.11 inhibitor, consistently acts in synergy with TP5 to enhance FCS-induced TEC growth. Hence, we conclude that 1) TP5 alone or in combination with FCS supports the growth of TEC lines, and 2) TEC lines express high levels of CD10, which regulates TP5-induced TEC proliferation by acting as a thymic peptide degrading enzyme.
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PMID:CD10 is expressed on human thymic epithelial cell lines and modulates thymopentin-induced cell proliferation. 933 53

Endothelin-1 (ET-1) is produced from inactive precursor big ET-1 by endothelin-converting enzyme-1 (ECE-1), a membrane-bound metalloprotease, structurally similar to another metalloprotease, neutral endopeptidase 24.11 (NEP). Although both phosphoramidon and thiorphan are metalloprotease inhibitors, the ECE activity is inhibited by phosphoramidon but not by thiorphan, a specific inhibitor of NEP. Therefore, to investigate whether an ECE inhibitor can prevent indomethacin-induced gastric mucosal damage in rats, we compared the effects between the two metalloprotease inhibitors on both gastric mucosal integrity and the levels of ET-1 and big ET-1 in gastric tissue. Phosphoramidon significantly decreased ET-1 levels, causing a concomitant big ET-1 increase and dose-dependently attenuated indomethacin-induced gastric mucosal damage. By contrast, thiorphan neither changed the ratio of ET-1/big ET-1 nor attenuated the damage. In conclusion, the prevention of gastric mucosal damage by an ECE inhibitor indicates that endogenous ET-1 may play an important role in the pathogenesis of indomethacin-induced gastric mucosal damage.
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PMID:Phosphoramidon, an inhibitor of endothelin-converting enzyme, prevents indomethacin-induced gastric mucosal damage in rats. 947 29

The formation and processing of neurotensin (NT) by three prostate cancer cell lines was investigated. Neurotensin (NT) immunoreactivity was detected in conditioned media and extracts of LNCaP cells. Using HPLC techniques, the immunoreactivity extracted from LNCaP cells coeluted with synthetic NT standard. Metalloendopeptidase 3.4.24.15 activity was detected in PC-3, DU-145 and LNCaP cells, whereas high levels of neutral endopeptidase 3.4.24.1 1 activity was detected only in LNCaP cells. NT was relatively stable when incubated with PC-3 or D-145 cells but was rapidly degraded by LNCaP cells to NT1-11 and NT1-10. Phosphoramidon inhibited the metabolism of NT by LNCaP cells. These data suggest that NT is present in and metabolized by LNCaP cellular enzymes.
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PMID:Neurotensin is metabolized by endogenous proteases in prostate cancer cell lines. 949 57


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