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

Improvements in neonatal intensive care have resulted in more extremely low birthweight babies surviving who are at risk of developing chronic lung disease. The preterm lung is vulnerable as it is both structurally immature and deficient in surfactant and antioxidant defences. Mechanical ventilation and high inspired oxygen concentrations are often necessary for preterm babies to survive but they can cause pulmonary inflammation which leads to lung damage. Abnormal healing in the presence of ongoing inflammation leads to airways remodelling which can result in protracted respiratory problems in these babies. A commonly used definition for chronic lung disease is the requirement for supplemental oxygen beyond 36 weeks' postconception. Many drugs that are commonly used for chronic lung disease have not been subjected to proper randomised controlled trials but are widely used on the basis of small studies showing short term benefits. They can be broadly divided into 2 groups. First, there are preventative drugs that are administered early to reduce oxygen toxicity and pulmonary inflammation. Secondly, there are those administered in established chronic lung disease, designed to reduce respiratory morbidity. Pulmonary inflammation in the neonate is reduced by systemic corticosteroids. Corticosteroid therapy within the first 2 weeks of life enables earlier extubation of preterm babies with subsequent reduced chronic lung disease and improved neonatal survival when given between 7 and 14 days. However, there is an increased risk of gastrointestinal haemorrhage, metabolic derangement, ventricular hypertrophy and potential effects on long term growth and brain development. Diuretics and inhaled bronchodilators improve pulmonary compliance and reduce oxygen requirements in established chronic lung disease but probably have little effect in reducing the incidence. In babies with established chronic lung disease, home oxygen therapy enables earlier discharge and prophylaxis against respiratory syncytial virus can reduce morbidity from bronchiolitis. All of the above therapies have adverse effects that need to be considered before initiating treatment. Recently, new drugs have become available which may be beneficial. These include inhaled nitric oxide for reduction of ventilation-perfusion mismatching, recombinant human superoxide dismutase for protection against oxidative stress and alpha-1 proteinase inhibitor which may reduce airways remodelling. At present these therapies are undergoing clinical trials. Exogenous surfactant is beneficial in respiratory distress syndrome and may reduce the risk of chronic lung disease but there have been no randomised controlled trials of its use in established chronic lung disease. Drugs which have been tried unsuccessfully include erythromycin, ambroxol and mast cell stabilisers.
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PMID:A risk-benefit assessment of drugs used for neonatal chronic lung disease. 1083 Feb 55

Chronic ingestion of xenobiotics could be pathogenic in the gastrointestinal tract. Recently, we showed that acute low administration of a food contaminant (diquat) induced intestinal secretion involving mast cells and nitric oxide. This work aimed to determine in rats: (1) the influence of a low level (0.1 mg/kg/day per os) chronic ingestion of diquat on gastrointestinal immune cells, and (2) the participation of nitric oxide synthases (NOS) in these effects. Diquat increased both gastric and jejunal myeloperoxidase activities, tissue histamine in vitro release after stimulation by 48/80, and mast cell numbers. Diquat did not alter gastric NOS but increased intestinal inducible NOS (iNOS) activity. L-NAME prevented diquat-induced gastric and intestinal mastocytosis and gastric but not intestinal inflammation. L-NAME reduced gastric constitutive NOS (cNOS) activity and reestablished control iNOS activity. Chronic low level ingestion of diquat induces a low-grade gastric and intestinal inflammation with mastocytosis and enhancement of intestinal iNOS activity.
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PMID:Chronic ingestion of a potential food contaminant induces gastrointestinal inflammation in rats: role of nitric oxide and mast cells. 1105 29

The role of nitric oxide (NO) in precipitating pulmonary oedema in acute lung injury remains unclear. We have investigated the mechanism of involvement of NO in the maintenance of liquid balance in the isolated rabbit lung. Thirty pairs of lungs were perfused with colloid for up to 6 h, during which pulmonary vascular resistance (PVR) and capillary pressure (PCP) were measured frequently, and time to gain 5 g in weight (t5) was recorded. Four protocols with different perfusate additives were studied: (i) none (control, n = 11); (ii) 10 mmol NG-nitro-L-arginine methyl ester (L-NAME) (n = 6); (iii) 10 mmol L-NAME with 100 mumol lodoxamide, an inhibitor of mast cell degranulation (n = 7); (iv) 10 mmol L-NAME with 10 mumol 8-bromo-3',5'-cyclic guanosine monophosphate (8Br-cGMP), an analogue of cGMP that may reduce vascular permeability by relaxing contractile elements in endothelial cells (n = 6). Neither PVR nor PCP differed between protocols. L-NAME markedly reduced t5 from 248 (27) min (mean (SEM)) in protocol (i) to 144 (5) min in protocol (ii) (P < 0.05). Both lodoxamide (t5 = 178 (7) min) and 8Br-cGMP (t5 = 204 (10) min) substantially corrected the effect of L-NAME (P < 0.005). Results suggest that maintenance of a low permeability by NO may involve mast cell stabilization and endothelial cell relaxation.
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PMID:Inhibition of nitric oxide synthesis augments pulmonary oedema in isolated perfused rabbit lung. 1106 16

The study of the mechanisms of action of the triptan group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine. In this context, two discoveries have been especially important: 1) these anti-migraine drugs are specifically recognized by three main types of serotonin receptors (5-HT1B, 5-HT1D, and 5-HT1F); and 2) these receptors are present in the meninges, where they are expressed by both smooth muscle cells and/or endothelial cells of the vascular wall and/or the perivascular trigeminal to be deleted axon terminals. These two findings have led to the most currently accepted physiopathogenic hypothesis, whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers, which would then trigger the release of vasoactive peptides (substance P, calcitonin gene-related peptide/CGRP) within the dura mater. Locally, i.e., in the dura mater in particular, these substances can provoke vasodilatation (CGRP) and plasmatic extravasation (substance P) with platelet lysis and mast cell degranulation, thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers, and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole. This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex, where it is integrated and expressed as migraine pain. The aim of this article was to report the main findings on endogenous substances (serotonin, peptides, nitric oxide [NO], etc.) which appear to play a key role in this physiopathogenic sequence.
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PMID:[Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine. Current hypotheses]. 1107 40

We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 microM ET-1 (1.43 +/- 0.64 microM, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 +/- 0.38 microM) whilst that in the flare increased to reach a peak value of 2.28 +/- 0.61 microM at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52% at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ET(A)/ET(B) antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26%, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo.
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PMID:The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo. 1118 78

The present study is designed to investigate the role of nitric oxide (NO) and cardiac mast cells in the cardioprotective effect of endotoxin in isolated rat heart subjected to 30 min of global ischaemia and 30 min of reperfusion. Endotoxin (2.5 mg kg(-1); i.p.) was administered 8 h before subjecting the heart to global ischaemia. Endotoxin pretreatment markedly reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK), markers of cardiac injury, in coronary effluent and the percentage incidence of ventricular premature beats (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during the reperfusion phase. Endotoxin pretreatment significantly increased the release of nitrite prior to and after global ischaemia. On the other hand, endotoxin pretreatment decreased the release of mast cell peroxidase (MPO) during the reperfusion phase. The cardioprotective and antiarrhythmic effect of endotoxin pretreatment was abolished by dexamethasone (3 mg kg(-1); i.p.) or l -canavanine (20 mg kg(-1); i.p.) given 1 h before the administration of endotoxin. It is proposed that the cardioprotective and antiarrhythmic effect of the endotoxin may be ascribed to the induction of nitric oxide synthase (NOS) and subsequent increase in the release of NO. NO may stabilize cardiac mast cells and consequently decrease the release of cytotoxic mediators from these cells. Prevention of degranulation of cardiac mast cells may be responsible for the cardioprotective and antiarrhythmic effects of the endotoxin.
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PMID:Possible role of nitric oxide and mast cells in endotoxin-induced cardioprotection. 1120 64

Cutaneous antidromic vasodilatation and plasma extravasation, two phenomena that occur in neurogenic inflammation, are partially blocked by substance P (SP) receptor antagonists and are known to be mediated in part by mast cell-released substances, such as histamine, serotonin, and nitric oxide. In an attempt to provide a morphological substrate for the above phenomena, we applied light and electron microscopic immunocytochemistry to investigate the pattern of SP innervation of blood vessels and its relationship to mast cells in the skin of the rat lower lip. Furthermore, we examined the distribution of SP (neurokinin-1) receptors and their relationship to SP-immunoreactive (IR) fibers. Our results confirmed that SP-IR fibers are found in cutaneous nerves and that terminal branches are observed around blood vessels and penetrating the epidermis. SP-IR fibers also innervated hair follicles and sebaceous glands. At the ultrastructural level, SP-IR varicosities were observed adjacent to arterioles, capillaries, venules, and mast cells. The varicosities possessed both dense core vesicles and agranular synaptic vesicles. We quantified the distance between SP-IR varicosities and blood vessel endothelial cells. SP-IR terminals were located within 0.23-5.99 microm from the endothelial cell layer in 82.7% of arterioles, in 90.2% of capillaries, and in 86.9% of venules. Although there was a trend for SP-IR fibers to be located closer to the endothelium of venules, this difference was not significant. Neurokinin-1 receptor (NK-1r) immunoreactivity was most abundant in the upper dermis and was associated with the wall of blood vessels. NK-1r were located in equal amounts on the walls of arterioles, capillaries, and venules that were innervated by SP-IR fibers. The present results favor the concept of a participation of SP in cutaneous neurogenic vasodilatation and plasma extravasation both by an action on blood vessels after binding to the NK-1r and by causing the release of substances from mast cells after diffusion through the connective tissue.
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PMID:Light and electron microscopic study of the distribution of substance P-immunoreactive fibers and neurokinin-1 receptors in the skin of the rat lower lip. 1126 9

The expression of a primary initiator of tumor angiogenic responses, vascular endothelial growth factor (VEGF), may be induced by nitric oxide (NO) in carcinoma cells. However, the net impact of NO on carcinogenesis remains unclear, because manipulation of NO levels has been shown to either stimulate or inhibit tumor growth. We have investigated the relationship between inducible NO synthase (NOS II), VEGF expression, and growth of B16-F1 melanoma over 14 days in wild-type (NOS II+/+) mice and in those in which the gene for NOS II has been deleted (NOS II-/-). B16-F1 tumor growth was measured as wet weight of the excised tissue. Tumor NOS II and VEGF localization were evaluated by immunohistochemistry, and VEGF mRNA levels were measured by Northern blot analysis. In NOS II+/+ mice inoculated with B16-F1 melanoma cells, macroscopic tumors were always observed at 14 days; however, 22% of NOS II-/- mice had no detectable tumor mass. Immunoreactive NOS II was detected in tumor cells of tumors grown in NOS II+/+ but not in NOS II-/- mice. Although immunoreactive VEGF was detected in the granules of tumor-associated mast cells from both NOS II+/+ and NOS II-/- mice, VEGF mRNA expression in tumors from NOS II-/- was half that in NOS II+/+ mice. Neither NOS II inhibition, exogenous NO, nor peroxynitrite influenced DNA synthesis in culture B16-F1 melanoma cells. The NO donor did not alter either VEGF mRNA levels or degranulation in cultures of the mast cell line RBL-2H3, but peroxynitrite increased both VEGF mRNA expression and degranulation. We conclude that host expression of NOS II contributes to induction of NOS II in the tumor and to melanoma growth in vivo, possibly by regulating the amount and availability of VEGF.
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PMID:Nitric oxide synthase II gene disruption: implications for tumor growth and vascular endothelial growth factor production. 1130 6

A significant role of nitric oxide (NO) is being acknowledged gastroduodenal mucosa defense mechanism(s) against the injurious effect of NSAIDs. Many of the NO effects recall those of prostaglandins, such as direct protection of epithelial cells, mucus release, repair of mucosal erosions or ulcerations, mast cell degranulation. Other co-effects prove to be the inhibition of neutrophil adherence to the vascular endothelium, also associated with an improved mucosal blood flow. NO may also act by scavenging oxygen-derivedfree radicals. Consequently, in order to reduce the NSAID gastrotoxicity has been proposed: a) the linking of a NO-releasing mojety to these agents (NSAID NO-donors); b) the use of amtolmetin guacyl (AMG), a drug which induces an increase in the gastric mucosa NO concentration via direct stimulation of the local endogenous synthesis of this gas. Clinical studies on the efficacy and tolerability have been carried out with AMG versus other NSAIDs (diclofenac, indomethacin, piroxicam, naproxen) in patients with osteoarthritis, rheumatoid arthritis and a number of post-traumatic arthropathies. As far as clinical symptoms are concerned AMG proves to be equally effective, but significantly better as far as gastroscopic lesions are concerned. NONSAIDs and AMG may play an important role among the long-term treatment of chronic inflammatory osteoarticular and rheumatic diseases.
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PMID:[Nitric oxide and gastroduodenal damage caused by NSAIDs. Recent findings and clinical implications]. 1132 Aug 58

1. The influence of lipopolysaccharide (LPS)-induced sepsis on the various mast cell phenotypes of rat dura mater were examined both by immunohistochemical and biochemical methods. 2. Three different populations of mast cells were identified in control rats: connective tissue type mast cells (CTMC) which contain rat mast cell protease1 (RMCP1), histamine, serotonin and heparin, mucosal type mast cells (MMC) which contain RMCP2, histamine and serotonin, and intermediate type which contains both RMCP1 and RMCP2 and probably various proportions of amines and heparin. 3. LPS (25 mg kg(-1) i.p.) caused changes in the proportions of the various types of mast cells. The number of MMC and intermediate type mast cells significantly increased and the number of mast cells immunopositive for both heparin and serotonin significantly decreased. Biochemical analysis showed that the histamine concentration of dura increased while its serotonin concentration decreased. 4. While vasoactive intestinal peptide (VIP) (25 ng kg(-1) i.p.) appears to potentiate LPS effects on dura mater mast cells, non-selective inhibition of nitric oxide (NO) synthase by N(g)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(-1) i.p.) did not influence sepsis-induced mast cell changes. 5. These findings suggest that mast cells of dura mater may play a role in brain protection during sepsis.
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PMID:Effects of sepsis on mast cells in rat dura mater: influence of L-NAME and VIP. 1172 41


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