Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is growing evidence that endogenous nitric oxide (NO) regulates mucosal barrier integrity under physiological conditions and counters the increase in mucosal permeability associated with acute pathophysiological states. The potential mechanisms of action for the protective effects of NO are discussed. These include maintenance of blood flow, inhibition of platelet and leukocyte adhesion and/or aggregation within the vasculature, modulation of mast cell reactivity, and scavenging of reactive oxygen metabolites such as superoxide. On the basis of the data presented, we conclude that both constitutive nitric oxide synthase (cNOS)-derived endogenous NO and exogenous NO (from NO donors) appear to reduce the sequelae of acute inflammation. The second section of this review summarizes the data germane to prolonged (chronic) inflammatory conditions associated with the overproduction of NO from the inducible form of NOS (iNOS). Some emphasis is placed on the role of NO in sepsis and inflammatory bowel disease (IBD), and data to suggest that NO, or more specifically a NO-derived mediator, is involved in these disorders are summarized. These studies are compared with recent publications suggesting that inhibition of NO synthesis with nonspecific inhibitors of NOS or selective iNOS inhibitors may not protect in models of sepsis or IBD. Overall, the review highlights the potential importance of the type of NOS enzyme involved in the particular inflammatory process being studied.
 ...
PMID:A critical role for nitric oxide in intestinal barrier function and dysfunction. 877 63

Inflammation is a protective response of vascularized tissue normally elicited toward nonself-determinants or tissue injury. Inflammation functions as part of normal host surveillance mechanisms to destroy or quarantine both harmful agents and damaged tissue. Most forms of inflammation are exaggerated out of proportion to the stimulus, because humoral amplification systems recruit additional components of the immune system initiating the production of proinflammatory mediators, including cytokines synthesized by activated macrophages. These act as secondary messengers to induce synthesis and expression of specific adhesion molecules on endothelial cells and white cells. Polymorphonuclear leukocytes play a central role in the acute inflammatory response. Anaphylaxis, an immediate hypersensitivity reaction to substances administered in the perioperative period, serves as a useful model for some of the problems of acute inflammation because there are important interrelationships with the cardiovascular system, endothelium, and coagulation. Mast cells and basophils produce the acute inflammation associated with anaphylaxis mediated by immunoglobulin E (IgE) antibodies, whereas the immunoglobulin G (IgG)-antigen interaction activates the complement cascade to generate anaphylatoxins, specifically C5a. Activation of white cells causes release of proteolytic enzymes, production of oxygen-derived free radicals, and the synthesis of a variety of lipid mediators. Protamine sulfate is one of the most common causes of life-threatening anaphylactic reactions during cardiac surgery. Differing responses occur, dependent on the presence of either IgE or IgG antibodies with the activation of the mast cell or the complement system, respectively. The many different amplifying pathways that can be recruited during anaphylaxis and the array of mediators involved are important when therapeutic intervention is considered. The challenge for the future will be to identify a pharmacologic agent that will arrest the inflammatory cascade and thus prevent further amplification and resultant host injury.
 ...
PMID:The human inflammatory response. 893 81

Previous reports indicate that intestinal intraluminal ethanol increases mucosal permeability (an index of mucosal injury) and histamine release by mast cells, and that the released histamine plays a role in mediating the increased permeability. In the present study, we investigated whether reactive oxygen metabolites and their major sources (xanthine oxidase and leukocytes) were involved in these ethanol effects. In rabbits, segments of the jejunum were perfused with a control solution or with 6% ethanol. In these segments, mucosal permeability was assessed by determining jejunal clearance of i.v. administered 51Cr-ethylenediaminetetraacetate (51Cr-EDTA) and 125I-bovine serum albumin (125I-BSA), and mast cell histamine release was estimated from the histamine concentration of the gut effluent. Ethanol increased 51Cr-EDTA clearance, 125I-BSA clearance, and histamine release. These ethanol effects decreased when the animals were given superoxide dismutase plus catalase (scavenger of O2- and H2O2, respectively), allopurinol, or oxypurinol (xanthine oxidase inhibitors). Administration of a monoclonal antibody (R15.7) against leukocyte adhesion molecule, CD18, inhibited completely the ethanol-induced increased 51Cr-EDTA and 125I-BSA clearances and histamine release. These and supplementary data suggest that (a) ethanol-induced mucosal injury and mast cell histamine release are mediated primarily by leukocytes, and (b) oxy radicals, especially those generated by xanthine oxidase, mediate these ethanol effects mainly by promoting leukocyte infiltration.
 ...
PMID:Role of xanthine oxidase-derived oxidants and leukocytes in ethanol-induced jejunal mucosal injury. 901 59

The administration of mercuric chloride (HgCl2), gold compounds, or D-penicillamine to Brown Norway (BN) rats causes a T helper (Th)2 cell-associated autoimmune syndrome characterized by the production of a number of autoantibodies, marked elevation of serum IgE concentration, and tissue injury in the form of a vasculitis and arthritis. We have recently shown that the same compounds in vitro sensitize BN rat peritoneal mast cells for IgE-triggered mediator release and interleukin-4 mRNA production. We wished to test the hypothesis that these agents influence mast cell function via an effect on intracellular reactive oxygen species (ROS) production/redox balance. Mast cells were obtained from BN rats by peritoneal washout. Incubation with HgCl2, gold compounds or D-penicillamine (the latter only in the presence of copper ions) led to the intracellular production of ROS as shown by the oxidative production of the fluorescent compound 2',7'-dichlorofluorescein. Mast cells were more sensitive than splenocytes to this effect. Direct oxidative stress (exposure to H2O2) produced a similar sensitization for mediator release to that caused by HgCl2. Inhibition of ROS formation by desferrioxamine or catalase diminished the enhancement of IgE-mediated serotonin release caused by HgCl2, as did replenishment of intracellular glutathione. 2-Mercaptoethanol exacerbated the toxicity of HgCl2, perhaps due to the formation of a lipophilic complex that enhanced HgCl2 uptake. Blocking of glutathione synthesis increased the toxicity of HgCl2, but also abolished any sensitizing effect on mediator release. These results support three main predictions of our hypothesis: (1) the compounds known to influence mast cell function all lead to the generation of ROS within the mast cell; (2) direct oxidative stress causes sensitization for mediator release by the mast cell; and (3) modulation of ROS production/redox balance within the mast cell modulates the effects of these compounds on mast cell function. The balance of oxidative/antioxidative influences may play an important role in the modulation of mast cell function, particularly in the context of chemically induced autoimmunity.
 ...
PMID:Alterations in intracellular reactive oxygen species generation and redox potential modulate mast cell function. 902 32

3,3'-Diaminobenzidine, in the presence of manganese and cobalt ions, was applied for the detection of superoxide anions in unfixed cryostat sections of rat oesophagus, trachea, skin and intact mesenterium. In all connective tissues, a blue final reaction product was found in a granular form in mast cells. The amount of final reaction product formed after incubation with diaminobenzidine and cobalt ions was increased by the addition of manganese ions. Electron microscopical analysis revealed that the electron-dense final reaction product was exclusively present in the granules of mast cells and on elastin fibres. It was found that the constitutive spontaneous formation of final reaction product in mast cells was enzymatic and dependent on the presence of oxygen in the medium. Of all the enzyme inhibitors and free radical scavengers tested, only azide strongly reduced the amount of final reaction product. It was concluded that the reaction was partly caused by peroxidase activity, but that superoxide anions are also constitutively and spontaneously produced in mast cell granules. The exact enzymatic source could not be established. Whether this property of mast cell granules plays an antimicrobial role in connective tissues can only be speculated.
 ...
PMID:In situ detection of constitutive superoxide anion production in granules of mast cells. 918 43

The possibilities of treating male subfertility are still limited. Approaches at medical therapy include stimulation of spermatogenesis at the testicular level, improvement of epididymal function (sperm maturation), influence on sperm transport and activation of sperm metabolism with improvement of sperm motility. Causal therapy has been most successful in patients with hormonal insufficiency and male adnexitis, while microsurgical reconstructive measures have yielded best results in cases of occlusion within the efferent seminal ducts. New therapeutic approaches include the use of mast cell blockers and alpha blockers as well as vitamin C/E as an antioxidative treatment to reduce reactive oxygen species. If medical or surgical therapy has failed, methods for improvement of sperm quality in vitro must be considered (swim-up technique, glass wool filtration, migration/sedimentation technique, density gradient centrifugation). In cases of severe male sterility factor, intracytoplasmic sperm injection (ICSI) has been a breakthrough in the therapy of childlessness. A further progress is the collection of spermatozoa from the epididymis (MESA = microsurgical epididymal sperm aspiration) or testis (TESE = testicular sperm extraction). Finally, pressure in terms of time and organization can now be avoided by the use of cryopreserved spermatozoa from the ejaculate, epididymis or testicular tissue so that microinjection may be planned independently of the partner. In any case, a close cooperation between gynecologist and andrologist is of utmost importance.
 ...
PMID:[Therapy of male subfertility]. 919 Jul 68

The relationship between the changes of active oxygen metabolism and blood flow and the formation, progression, and recovery of lesions was examined in the gastric mucosa of rats treated once with compound 48/80, a mast cell degranulator. Gastric mucosal lesions appeared 0.5 hr after compound 48/80 treatment, became worst at 3 hr, and recovered fairly well at 12 hr. Increases in gastric mucosal lipid peroxide content and xanthine oxidase and myeloperoxidase activities and decreases in gastric mucosal vitamin E and hexosamine contents and Se-dependent glutathione peroxidase activity occurred with the formation and progression of gastric mucosal lesions. These changes were attenuated with the recovery of the lesion. Gastric mucosal nonprotein SH content decreased with the formation of gastric mucosal lesions, and this decreased SH content returned to near the original level with lesion progression. No changes in gastric mucosal superoxide dismutase and catalase activities occurred with the formation, progression, and recovery of gastric mucosal lesions. Gastric mucosal blood flow decreased with the formation of gastric mucosal lesions, and this decreased blood flow recovered with lesion progression. Serum serotonin concentration, an index of mast cell degranulation, increased with the formation of gastric mucosal lesions, and this increased serotonin level was attenuated with lesion progression and recovery. Pretreatment with ketotifen, a connective tissue mast cell stabilizer, prevented the formation of gastric mucosal lesions, the increases of gastric mucosal lipid peroxide content, xanthine oxidase and myeloperoxidase activities, and serum serotonin level; and the decreases of gastric mucosal nonprotein SH content, glutathione peroxidase activity, and blood flow found at 0.5 hr after compound 48/80 treatment. These results indicate that the changes of gastric mucosal active oxygen metabolism and blood flow are closely related to the formation, progression, and recovery of gastric mucosal lesions in rats with a single compound 48/80 treatment. The present results also suggest that this compound 48/80-induced gastric mucosal injury could be a kind of ischemia-reperfusion-induced injury occurring through degranulation of connective tissue mast cells.
 ...
PMID:Relationship between changes of active oxygen metabolism and blood flow and formation, progression, and recovery of lesions is gastric mucosa of rats with a single treatment of compound 48/80, a mast cell degranulator. 920 Oct 88

PAC spectra (perturbed angular correlation of gamma-rays) of cadmium-substituted carboxypeptidase A (CPD) show that the enzyme in solution imposes a flexible, pH- and chloride-dependent coordination structure on the metal site, in contrast to what is found in the crystalline state. A much more restricted coordination geometry occurs for the steady-state peptide intermediates of Bz-Gly-l-Phe and Bz-Gly-Gly-l-Phe in solution, suggesting that substrate binding locks the structure in a rigid conformation. The results further indicate that the peptide intermediate has a six-coordinated metal coordination geometry with an OH- ligand at the solvent site and a carbonyl oxygen at an additional ligand site. In marked contrast, conformational rigidity is not induced by the inhibitor/poor substrate Gly-L-Tyr nor by the products of high turnover substrates, Bz-Gly, Bz-Gly-Gly, and L-Phe. These results are consistent with an intact scissile peptide bond in the enzyme-substrate complex of Bz-Gly-L-Phe and Bz-Gly-Gly-L-Phe. A single nuclear quadrupole interaction (NQI) is observed for the crystalline state of the enzyme between pH 5.7 and pH 9.4. This NQI agrees with calculations based on the metal coordination geometry for cadmium in crystalline CPD derived from X-ray diffraction studies. A single broad distribution of NQIs is observed for CPD in sucrose solutions and 0.1 M NaCl at pH values below 6.5. This NQI (NQI-1') has parameters very close to those for the crystalline state. The enzyme metal site, characterized by this NQI, is converted into two new enzyme metal sites over the pH range of 6.5-8.3. The metal coordination sphere of one of these has a NQI (NQI-1) with parameters similar to those at lower pH values (NQI-1') while the other NQI (NQI-2) is characterized by markedly different NQI parameters. Angular overlap model (AOM) calculations indicate that the coordination sites giving NQI-1' and NQI-1 both have a metal-bound water molecule while the coordination site giving NQI-2 has a metal-bound hydroxide ion. PAC results at pH 8.3-10.5 indicate that in this pH range the two metal coordination geometries related to NQI-1 and NQI-2 occur in a pH independent ratio of 2:1, with the one with the water ligand being the most abundant species. The observed pH-independent equilibrium between the two different metal coordination geometries for cadmium can be explained by an equilibrium between tautomeric forms of a hydrogen bond between the Glu-270 carboxyl group and the metal-bound water (Glu-270 COO-...(HOH)M <==> Glu-270 COOH...(OH-)M) being slow on the time scale of a PAC experiment, i.e., slower than 0.5 micros. We finally suggest that NQI-1' observed at low pH reflects an enzyme species containing a metal-coordinated water molecule and the protonated carboxyl group of Glu-270.
 ...
PMID:Structure and dynamics of the metal site of cadmium-substituted carboxypeptidase A in solution and crystalline states and under steady-state peptide hydrolysis. 929 72

1. The mechanisms involved in mediating bacterial endotoxin lipopolysaccharide (LPS)-induced injury in the colon of neonatal rat pups aged 10-12 days was examined. 2. Administration of LPS (3 mg kg(-1), i.p.) caused a time-related increase in the plasma concentration of rat mast cell protease-II (RMCP-II) which was attenuated dose-dependently, by the non-selective mast cell stabilizer doxantrazole (0.05-5 mg kg(-1), i.p.). The selective connective tissue mast cell stabilizer ketotifen (5-25 mg kg(-1), i.p.) was without effect at the lower dose and had only a limited inhibitory effect at the higher dose. 3. In addition, doxantrazole (5 mg kg(-1), i.p.) inhibited mast cell degranulation in response to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg(-1), i.p.) was without effect. 4. The increase in plasma RMCP-II concentration in response to LPS treatment preceded increases in tissue myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg(-1), i.p.), antineutrophil serum (100 microl kg(-1), i.p.), dexamethasone (2 mg kg(-1), i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg(-1), i.p.). 5. In addition, lipid peroxidation was inhibited by pre-administration of the antioxidant enzymes superoxide dismutase (2000 u kg(-1), i.p.) and catalase (2000 u kg(-1), i.p.), the xanthine oxidase inhibitor allopurinol (100 mg kg(-1), i.p.) and the peroxyl scavenger deferoxamine (10 mg kg(-1), i.p.), suggesting the involvement of reactive oxygen metabolites in the colonic injury. 6. These findings suggest that the sequence of events resulting in colonic damage in the neonatal rat following administration of LPS include mast cell degranulation, neutrophil infiltration, elevation in iNOS activity and subsequent lipid peroxidation.
 ...
PMID:Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon. 948 51

This study investigated whether short-term exposure to Escherichia coli lipopolysaccharide (LPS) elicits vasomotor dysfunction in skeletal muscle in vivo and, if so, whether perivascular mast cell proteases partly modulate this response. With intravital microscopy, we found that suffusion of E. coli LPS on the in situ hamster spinotrapezius muscle for 60 min elicits immediate vasoconstriction followed by vasodilation. Vasoconstriction is abrogated by SK&F 108566, a selective, nonpeptide angiotensin II (AT II) subtype 1 receptor antagonist, chymostatin and soybean trypsin inhibitor. These compounds also attenuate E. coli LPS-induced vasodilation. By contrast, superoxide dismutase, catalase and indomethacin attenuate only E. coli LPS-induced vasodilation. Endothelin receptor antagonists, lisinopril, leupeptin, Bestatin and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid are ineffective. Histochemical analysis of the spinotrapezius muscle reveals abundant perivascular mast cells with chymostatin-inhibitable chymase-like activity. Pretreatment of hamsters with compound 48/80 for 4 days curtails E. coli LPS-induced vasoconstriction and converts vasodilation to vasoconstriction. On balance, these data indicate that E. coli LPS stimulates perivascular mast cells in the in situ hamster spinotrapezius muscle to release an AT II-producing chymase-like protease(s). AT II thus produced elicits local vasoconstriction and elaborates reactive oxygen species which, in turn, generate vasodilator prostaglandins.
 ...
PMID:Mast cell chymase-like protease(s) modulates Escherichia coli lipopolysaccharide-induced vasomotor dysfunction in skeletal muscle in vivo. 949 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>