Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to search for microbial modulators of the activity of neuropeptide, we established a screen based on substance P (SP)-induced myeloperoxidase (MPO) release from human polymorphonuclear leukocytes (PMN). SP induced MPO release in a dose-dependent manner at concentrations ranging from 1 approximately 10 x 10(-4) M. In comparison at 1 x 10(-4) M, induction was also observed with SP derivatives but not with other neuropeptides such as neurokinin and enkephalin. Based on this, we searched for microbial inhibitors against SP-induced MPO release. An actinomycete metabolite designated HS3, which turned out to be identical with dioxapyrrolomycin or A1-R2081, and structurally related pyrrolomycins were found to inhibit SP-induced MPO release. In addition, these compounds inhibited the f-Met-Leu-Phe (FMLP)-induced MPO release from PMN. Pyrrolomycin derivatives with an N-methylated pyrrole ring showed, however, a selective inhibition of the SP-induced MPO release. This was in contrast to results with aseanostatin P5 which selectively inhibited FMLP-induced MPO release.
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PMID:Pyrrolomycin group antibiotics inhibit substance P-induced release of myeloperoxidase from human polymorphonuclear leukocytes. 171 7

Many inflammatory mediators trigger the adhesion of leukocytes to the vascular endothelium. We sought to determine whether the beta 2-adrenergic receptor agonist formoterol can inhibit the adhesion of neutrophils and eosinophils to the endothelium of venules in the rat airway mucosa. We also tested whether this action is mediated by beta 2-adrenergic receptors. Inflammation was induced in the airways of anesthetized pathogen-free F344 rats by injecting substance P (5 micrograms/kg) or bradykinin (10 mg/kg) intravenously. The rats were perfused with fixative 5 min later, and the tracheas were removed. Adherent intravascular neutrophils and eosinophils, stained by a histochemical reaction for myeloperoxidase, were counted in tracheal whole mounts. We found that, after the injection of substance P, formoterol (0.1, 1.0, or 10.0 micrograms/kg i.v.) reduced the number of adherent neutrophils by 8, 59, or 56% and reduced the number of eosinophils by 59, 90, or 86%, respectively. The three doses of formoterol reduced the amount of substance P-induced extravasation of Monastral blue by 21, 66, or 80%, respectively. Both effects of formoterol were blocked by the beta 2-adrenergic receptor antagonist ICI-118,551, which by itself produced neither leukocyte adhesion nor plasma extravasation. After the injection of bradykinin, the three doses of formoterol reduced the number of adherent neutrophils by 28, 67, or 62% and reduced the number of eosinophils by 17, 38, or 57%, respectively. We conclude that formoterol, acting via beta 2-adrenergic receptors, not only can reduce the amount of plasma leakage but also can reduce the number of neutrophils and eosinophils that adhere to the vascular endothelium at sites of inflammation.
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PMID:Inhibition of neutrophil and eosinophil adhesion to venules of rat trachea by beta 2-adrenergic agonist formoterol. 752 29

We investigated the effects of an enteric infection with the parasitic nematode, Trichinella spiralis, on peptidergic and cholinergic neural pathways of the guinea pig jejunum. The content of the enteric neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), and the activities of the key cholinergic enzymes, acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), were measured and compared in extracts of jejunal muscularis externa (ME) obtained from uninfected jejunum and T. spiralis-inflamed jejunum. Significant decreases were detected in both SP immunoreactivity and AChE activity on days 6 and 10 postinfection (PI) in nematode-infected guinea pig jejunum compared to uninfected controls. The maximum changes observed for SP and AChE both occurred on day 10 PI and were evident as decreases of 37% and 48%, respectively, from the mean uninfected control values for SP and AChE. In contrast, VIP immunoreactivity and ChAT activity showed no significant changes during the enteric phase of T. spiralis infection. Nematode-evoked histopathological changes in jejunal tissues from infected animals were associated with significant increases in myeloperoxidase (MPO) activity, an index of inflammation intensity, which occurred on day 6 PI (885% of mean control) and day 10 PI (469% of mean control) coinciding temporally with the significant decrease in SP content and AChE activity during infection. Thus, intestinal motor disturbances observed in mammalian hosts during enteric nematode infections involve inflammation-generated changes in the neurohumoral control of smooth muscle function.
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PMID:Altered neuropeptide content and cholinergic enzymatic activity in the inflamed guinea pig jejunum during parasitism. 754 15

The proinflammatory peptide substance P (SP) has been shown to be intimately involved in the local inflammatory processes of Trichinella-spiralis-induced murine intestinal inflammation. Significant increases in SP, increased myeloperoxidase levels coupled with local morphological deterioration of the jejunum and impaired lymphocyte responses to exogenous SP in vitro have been associated with the model. We have recently determined that the elimination of increased levels of SP via anti-SP antibody therapy can spare the murine gastrointestinal tract much of the pathologies associated with the parasitic infection. Here we further demonstrate that the somatostatin analogue SMS 201-995 as well as the SP receptor antagonist CP 96,345 can effectively decrease the inflammation and lost lymphocyte function seen in the jejunum of T. spiralis-infected mice. Again, both intestinal morphology and myeloperoxidase levels were shown to return to normal values upon treatment. The above results suggest that SP is an important modulator of gastrointestinal inflammation.
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PMID:Substance-P-mediated intestinal inflammation: inhibitory effects of CP 96,345 and SMS 201-995. 754 31

Substance P, a neuropeptide mediator of inflammation, was quantified during the evolution of trinitrobenzene sulfonic acid (TNBS)-induced ileitis in guinea pigs. Ileitis was induced by a single intraluminal injection of TNBS (30 mg/kg in 50% ethanol). Misoprostol, a prostaglandin E1 analogue, was administered parenterally (30 mg/kg sc twice daily) in a group of TNBS-treated animals. Control guinea pigs received intraluminal saline (sham) or 50% ethanol (TNBS vehicle). Guinea pigs were evaluated at day 1, 3, 7, 14, or 30 after ileitis induction for substance P content (radioimmunoassay) and distribution (immunohistochemistry), morphology, myeloperoxidase (MPO) activity, and protein leak into the gut lumen. TNBS administration caused an increase in ileal MPO activity that peaked at day 7 and increased mucosal leak of protein. Misoprostol attenuated the granulocyte infiltration (MPO) response to TNBS but exacerbated the mucosal leak of protein. Substance P levels in whole ileal segments were unaltered from baseline on day 1 in all groups. On day 3 a marked decrease in ileal substance P content was evident in the TNBS and TNBS + misoprostol groups. As early as day 1, immunohistochemistry suggested that the decreased substance P content was confined to the mucosa and submucosa, because myenteric plexus staining was not reduced. Loss of staining in the perivascular nerves was particularly marked. Substance P content and distribution returned to baseline by day 30 post-TNBS, although MPO activity remained slightly elevated. We concluded that TNBS ileitis is associated with a marked reduction in mucosal and submucosal substance P content in parallel with the inflammatory response. Although misoprostol attenuated granulocyte infiltration in this model, it did not prevent the disturbances in enteric substance P or mucosal protein leak.
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PMID:Substance P levels in experimental ileitis in guinea pigs: effects of misoprostol. 769 Jan 87

Our aim was to characterize and quantitate changes in two key neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), that are involved in governing neurally-mediated gastrointestinal (GI) reflex activity during enteric inflammation in the ferret. Neuropeptide content was determined by radioimmunoassay of extracts of jejunal, ileal and colonic muscularis externa from uninfected ferrets and ferrets infected with enteric stages of the parasitic nematode, Trichinella spiralis. Increased myeloperoxidase activity (MPO), an enzymatic marker of inflammation, occurred in all three gut regions. Histopathological changes were present only in the small intestine. Significant reductions were detected in both SP (72% decrease) and VIP (62% decrease) in the inflamed jejunum. Ileal concentrations of both SP (77% decrease) and VIP (46% decrease) were also decreased during T. spiralis infection compared to uninfected ferrets. Only SP (58% decrease) concentration showed a significant change in colonic tissues from infected ferrets; colonic VIP was unaltered. Parasite-induced inflammation caused significant changes in peptide-containing enteric neural pathways and might contribute to functional GI motor disturbances that occur during nematode infections in mammalian hosts.
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PMID:Regional content of enteric substance P and vasoactive intestinal peptide during intestinal inflammation in the parasitized ferret. 769 45

Jejunal motility measured manometrically and coupled fluctuations in electrogenic ion transport measured as transmural potential differences (PD) were simultaneously studied in ferrets infected with enteric stages of the parasitic nematode, Trichinella spiralis. Vagotomy in uninfected ferrets abolished jejunal motility clusters and associated PD oscillations. Conversely, in infected ferrets on days 8-12 postinfection (PI), vagotomy did not abolish jejunal motility and PD. Calculated motility indexes (MI) indicated that postvagotomy MI decreased to 12% of prevagotomy MI in uninfected ferrets, whereas, in T.spiralis-infected ferrets, postvagotomy MI declined only to 48% of prevagotomy MI. Atropine abolished all vagotomy-resistant residual jejunal motility clusters and PD oscillations in T. spiralis-infected ferrets. Decreased intestinal content of substance P (27% of control) and vasoactive intestinal peptide (41% of control) and increased myeloperoxidase activity (262% of control) were detected in T. spiralis-infected ferrets. Our results suggest that integrated neural control of muscular and epithelial effectors in the small bowel is altered by nematode-induced inflammation.
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PMID:Neural integration of jejunal motility and ion transport in nematode-infected ferrets. 876 Jan 6

Toxin A, a 308,000-Mr enterotoxin from Clostridium difficile, mediates antibiotic-associated diarrhea and colitis in humans. Injection of toxin A into animal intestine triggers an acute inflammatory response characterized by activation of sensory neurons and immune cells of the intestinal lamina propria, including mast cells and macrophages, and migration of circulating neutrophils in the involved intestinal segment. In this study we show that mice genetically deficient in the neurokinin-1 receptor are protected from the secretory and inflammatory changes as well as from epithelial cell damage induced by toxin A. The protective effect of neurokinin-1R deletion correlates with diminished intestinal levels of the cytokine TNF-alpha and its mRNA and the leukocyte enzyme myeloperoxidase. These results demonstrate a major requirement for substance P receptors in the pathogenesis of acute inflammatory diarrhea.
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PMID:Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis. 954 82

Recently we demonstrated that sensory denervation with the neurotoxin capsaicin worsened the inflammation in an acute and chronic model of experimental colitis, which suggests a protective role of sensory nerve fibers during gut inflammation. Because we could demonstrate that sensory neuropeptides like Calcitonin gene-related peptide (CGRP) and substance P (SP) are released from sensory nerve fibers during intestinal inflammation, both are strong candidates as mediators for the protective effect of sensory neurons. In this study we investigate the role of CGRP and SP during experimental colitis in the rat by use of receptor antagonists against CGRP (CGRP 8-37, 1 microg/h continuous subcutaneous infusion), SP (RP67580, a NK-1 receptor antagonist, 3 mg/kg i.p.) and an immunoneutralizing CGRP-antibody. A mild colitis was induced by a rectal enema containing trinitrobenzenesulfonic acid. The severity of inflammation increased markedly after 7 days in the CGRP receptor antagonist and CGRP-antibody group compared with the vehicle group as determined by a macroscopic damage score (10.4 +/- 1.2 and 9.6 +/- 1.6 vs. 6.2 +/- 2.1) by a histologic ulceration score (82 +/- 8% and 73 +/- 6% vs. 42 +/- 23%) and by myeloperoxidase activity (19.2 +/- 6.8 and 18.1 +/- 5.9 vs. 8.6 +/- 5.3 U/mg tissue protein), respectively. Treatment with the specific SP receptor antagonist did not significantly alter the severity of colitis at 7 days compared with the control group. These data suggest that CGRP exerts mucosal protection during chronic experimental colitis.
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PMID:Calcitonin gene-related peptide mediates the protective effect of sensory nerves in a model of colonic injury. 969 17

Previous studies have shown tachykinins implicated in gut inflammation. The aim of this work was to evaluate the effect of treatments with tachykinin NK1, NK2, and NK3 selective receptor antagonists on the development of gut inflammation induced by trinitrobenzenesulfonic acid (TNBS) in rats and guinea-pigs. On day 0, rats and guinea-pigs received an intraluminal instillation of TNBS/ethanol (40 mg/kg). Each group was daily treated with intraperitoneally injected NK1 (SR 140333; 0.3 mg/kg/day), NK2 (SR 48968; 5 mg/kg/day), or NK3 (SR 142801; 1, 5, or 10 mg/kg/day) receptor antagonists or their vehicle. On day 4, inflammatory levels were evaluated by measuring gut permeability, myeloperoxidase activity, macro- and microscopic damage scores. In TNBS treated rats, daily administration of SR 140333 (0.3 mg/kg/day) and SR 48968 (5 mg/kg/day) reduced colonic inflammation. In TNBS treated guinea-pigs, daily administration of SR 48968 (5 mg/kg/day) and SR 142801 (at 5 and 10 mg/kg/day) attenuated significantly ileal injury. These results suggest that non-peptide tachykinin receptor antagonists are potent anti-inflammatory agents on gut inflammation in rats and guinea-pigs. However, their activity depends upon the animal species and type of receptor considered.
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PMID:Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs. 969 38


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