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)

Although the absence of Substance P (SP), a neurotransmitter in the trigeminal nerve, has been speculated as a cause for developing neurotrophic keratitis, its exact pathogenesis is still not clarified. In a previous report, we showed with electron microscopic examination that epithelial cell attachment was weakened in denervated corneas. In this study, SV40-transformed human corneal epithelial cells (HCE-Ts) were used to explore the molecular mechanisms responsible for mediating regulation of E-cadherin expression in response to Substance P receptor stimulation. Expression of the mRNAs for specific SP receptors, neurokinin (NK)-1R, NK-2R, and NK-3R, was demonstrated with RT-PCR. The cells were treated with various concentrations of SP in vitro, and the expression of an adhesion molecule E-cadherin was analyzed by immunofluorescence, immunoblotting, and enzyme-linked immunosorbent assay (ELISA) using an anti-E-cadherin antibody. E-cadherin expression was increased by SP in a dose-dependent manner both in the cytosolic fraction and in the cell membrane fraction. This increase in E-cadherin expression was completely inhibited by Calphostin C (PKC inhibitor) and KN-62 (CaMK inhibitor), but not by H-89 (PKA inhibitor), indicating that SP-induced E-cadherin expression involves the activation of protein kinase C (PKC) and calmodulin kinase (CaMK). SP did not affect cell proliferation at all. All these findings indicate that SP induced E-cadherin expression through PKC and CaMK activation and suggest that a lack of SP may account in part for the pathogenesis of neurotrophic keratitis.
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PMID:Substance P-induced cadherin expression and its signal transduction in a cloned human corneal epithelial cell line. 1062 82

There is increasing evidence that the cutaneous neurosensory system can directly modulate inflammatory responses in the skin by the release of neuropeptides such as substance P (SP). Dermal microvascular endothelial cell (DMEC) cellular adhesion molecule (CAM) expression plays a key role in directing leukocyte trafficking during cutaneous inflammatory responses. In recent studies, our laboratory examined the direct effect of SP on DMEC CAM expression and function in vitro and in vivo. Our studies indicate that DMEC express high affinity functional receptors for SP. After exposure to SP, DMEC expressed significant levels of both intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which was accompanied by increased binding to leukocytes expressing the appropriate integrin counter receptors for these CAM. We then determined the in vivo effect of released neuropeptides on DMEC CAM expression. Our results indicate that the topical cutaneous application of the neuropeptide-releasing agent capsaicin resulted in increased ICAM-1 and VCAM-1 immunostaining of microvascular cells in the skin of human volunteers. Little is known regarding the cellular regulatory events by which SP modulates DMEC CAM expression. Our studies indicate that SP-induced cellular Ca+2 signals led to the activation of the NF-kappaB pathway, resulting in nuclear translocation of p65/p50 heterodimers that bind to high-affinity tandem kappaB sites on the VCAM-1 promoter, whereas SP activation induced NF-AT activation and ICAM-1 DNA binding. Thus, these studies further support the role of the cutaneous neurologic system in modulating inflammatory processes in the skin.
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PMID:Neural regulation of endothelial cell-mediated inflammation. 1114 79

Increased vagal reflexes contribute to bronchoconstriction in asthma. Antigen challenge of sensitized animals induces vagal hyperresponsiveness. This review will discuss the evidence that eosinophils increase release of acetylcholine from the parasympathetic nerves. After antigen challenge, eosinophils are actively recruited to the airway nerves, possibly through expression of chemotactic substances and adhesion molecules by the nerves. Tachykinins acting on neurokinin 1 receptors activate the eosinophils. Activated eosinophils release eosinophil major basic protein (MBP), which is an endogenous antagonist for M2 muscarinic receptors. The M2 muscarinic receptors on the parasympathetic nerves in the lungs normally inhibit release of acetylcholine. When M2 receptors are blocked by MBP, acetylcholine release is increased, resulting in hyperresponsiveness. Neutralization of MBP with polyanionic substances restores M2 receptor function and eliminates hyperresponsiveness. Antibodies to MBP prevent M2 receptor dysfunction and hyperresponsiveness, as do antibodies to the adhesion molecule very late antigen 4, which prevent eosinophil migration. A low dose of dexamethasone, which does not affect total eosinophil influx into the lungs and airways, prevents eosinophils from clustering around the nerves and prevents antigen-induced M2 dysfunction and hyperresponsiveness. Furthermore, animal studies show that viral infections, which are important precipitants of asthma attacks, and exposure to air pollutants such as ozone can also activate airway eosinophils, leading to a chain of events similar to that seen after antigen challenge. Finally, a similar clustering of eosinophils around airway nerves, as well as release of MBP onto the nerves, is seen in fatal asthma, suggesting that similar mechanisms may be involved in human airway hyperresponsiveness.
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PMID:Eosinophil recruitment to the airway nerves. 1117 83

Patients with acute pancreatitis may develop acute lung injury, manifest clinically as the adult respiratory distress syndrome. Most patients who die during the early stages of severe acute pancreatitis die either with or as a result of this lung injury. To explore the events which couple acute pancreatitis to lung injury, a number of recent studies have been performed in the author's laboratory using a variety of experimental models and interventions including gene-targeted deletion of chemokines, cytokines, specific receptors, and adhesion molecules. These studies have indicated that adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), neutrophils, platelet activating factor (PAF), substance P, and chemokines acting via the CCR-1 chemokine receptor play a pro-inflammatory role while complement factor C5a plays an anti-inflammatory role in pancreatitis and lung injury. Future studies will build on these observations to expand the list of pro- and anti-inflammatory coupling factors and explore the mechanisms by which they act to cause or prevent lung injury in acute pancreatitis.
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PMID:Relationship between pancreatitis and lung diseases. 1153 57

We recently demonstrated that substance P mediates increased permeability of brain endothelium exposed to HIV-1 gp120. To test whether substance P is involved in immune processes at the blood-brain barrier (BBB), we stimulated rat brain endothelial cultures prepared from cerebral microvessels with Interferon-gamma (IFN-gamma) and Tumor necrosis factor-alpha (TNF-alpha), two proinflammatory cytokines that alter the BBB and measured permeability to albumin and expression of adhesion molecule ICAM-1 and MHC class II antigen in the presence and absence of spantide, a powerful substance P antagonist. In a dose-dependent manner, spantide completely neutralized increased permeability induced by TNF-alpha and IFN-gamma and expression of MHC class II molecule induced by IFN-gamma and prevented associated cell morphological changes as revealed by scanning electron microscope. Spantide also reduced expression of ICAM-1 induced by TNF-alpha and IFN-gamma by 35% and 30%, respectively. Substance P mRNA was found in unstimulated brain endothelial cells and was upregulated after stimulation with TNF-alpha and IFN-gamma. These in vitro findings demonstrate that substance P plays a major pathogenetic role in damaging and activating the BBB vascular component in the presence of proinflammatory cytokines.
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PMID:Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium. 1245 35

We explored whether substance P (SP) via neurokinin (NK) receptor facilitates bladder afferent signaling and reactive oxygen species (ROS) formation in bladder in association with neurogenic inflammation. We evaluated ROS activity and cystometrograms as well as pelvic nervous activity in anesthetized rat bladder with SP stimulation. Our results showed that endogenous SP via NK(1), not NK(2), receptor mediated a micturition reflex. An increase in SP by electrical stimulation of the pelvic nerve or an increase in exogenous SP by intra-arterial or intrathecal administration can facilitate myogenic and neurogenic bladder contractions. Furthermore, exaggerated SP release increased ROS in the bladder and whole blood via increased mast cell degranulation, intercellular adhesion molecule expression, and leukocyte adhesion, a primary source of ROS in the inflamed bladder. Treatment with NK(1)-receptor antagonists or ROS scavengers reduced bladder intercellular adhesion molecule expression and ROS and ameliorated the hyperactive bladder response. Our study indicates that the mechanism by which SP participates in the neurogenic bladder may be complicated by its proinflammatory activity and its ability to stimulate ROS generation.
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PMID:Substance P via NK1 receptor facilitates hyperactive bladder afferent signaling via action of ROS. 1262 Sep 25

Inflammatory response leading to organ dysfunction and failure continues to be the major problem after injury in many clinical conditions such as sepsis, severe burns, acute pancreatitis, haemorrhagic shock, and trauma. In general terms, systemic inflammatory response syndrome (SIRS) is an entirely normal response to injury. Systemic leukocyte activation, however, is a direct consequence of a SIRS and if excessive, can lead to distant organ damage and multiple organ dysfunction syndrome (MODS). When SIRS leads to MODS and organ failure, the mortality becomes high and can be more than 50%. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is a major component of MODS of various aetiologies. Inflammatory mediators play a key role in the pathogenesis of ARDS, which is the primary cause of death in these conditions. This review summarizes recent studies that demonstrate the critical role played by inflammatory mediators such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, platelet activating factor (PAF), IL-10, granulocyte macrophage-colony stimulating factor (GM-CSF), C5a, intercellular adhesion molecule (ICAM)-1, substance P, chemokines, VEGF, IGF-I, KGF, reactive oxygen species (ROS), and reactive nitrogen species (RNS) in the pathogenesis of ARDS. It is reasonable to speculate that elucidation of the key mediators in ARDS coupled with the discovery of specific inhibitors would make it possible to develop clinically effective anti-inflammatory therapy.
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PMID:Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. 1474 96

Elevated plasma levels of the neuropeptide substance P (SP) precede the perivascular inflammatory infiltrate seen in hearts of Mg(2+)-deficient (MgD) animals. The N-methyl-d-aspartate (NMDA) receptor is found in neurons, and activation of this receptor participates in SP release; under normal circumstances, this release can be blocked by Mg(2+). Therefore, we reasoned that blockade of the NMDA receptor with dizolcipine maleate (a noncompetitive NMDA receptor antagonist) would prevent SP release from C-fibers due to MgD. In this study, animals were implanted with slow-release pellets containing dizolcipine or placebo and were fed with diet sufficient in Mg(2+) or deficient with only 9% of USDA-recommended Mg(2+). SP immunostaining of dorsal root ganglia showed a time-dependent depletion of SP in the MgD animals, with a dramatic decrease of SP by week 2; this depletion was prevented by pretreatment with dizolcipine maleate. The significant increase in plasma prostaglandin E(2) levels during MgD was prevented by dizolcipine, and the loss of total red blood cell glutathione content was significantly attenuated by NMDA blockade after 3 weeks of MgD (p < 0.01 versus controls). Immunohistochemical and Western blot analyses of ventricular tissue demonstrated that NMDA receptor blockade abolished MgD-related increase of endothelium adhesion molecule CD54 (weeks 1 and 2; p < 0.05), and of monocyte/macrophage surface protein CD11b expression (week 3; p < 0.05). We conclude that NMDA receptor blockade with dizolcipine maleate prevented SP depletion and reduced perivascular inflammatory infiltrates, thus decreasing cardiac injury due to Mg(2+) deficiency.
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PMID:N-methyl-D-aspartate receptor blockade inhibits cardiac inflammation in the Mg2+-deficient rat. 1516 28

We previously reported substance P (SP) via neurokinin type 1 receptor facilitates bladder afferent signaling and reactive oxygen species (ROS) formation in bladder connected with neurogenic inflammation [Am. J. Physiol. Renal Physiol. 284 (2003) F840]. Increased intercellular adhesion molecule expression and subsequent leukocyte adhesion in the inflamed bladder contribute to SP-induced oxidative injury. Here we investigate the effect of green tea extract (catechins) on SP-induced bladder hyperactivity. We evaluated isovolumetric cystometrogram, adhesion molecular expression, and ROS activity in anesthetized rat bladder with SP stimulation. Our results showed that SP increased the amount of leukocyte ROS production in vitro in a dose-dependent manner and the enhanced ROS can be inhibited by catechins treatment. Exogenous SP increased ROS in vivo in the bladder via increased intercellular adhesion molecule expression and subsequent leukocyte adhesion, a primary source of ROS in the inflamed bladder. Two weeks of catechins pretreatment reduced SP-induced bladder intercellular adhesion molecule expression and ROS amount and ameliorated the hyperactive bladder response. These results indicate that catechins pretreatment can ameliorate SP-induced neurogenic inflammation via the action of antioxidant, anti-adhesion, and anti-inflammatory activity.
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PMID:Catechins prevents substance P-induced hyperactive bladder in rats via the downregulation of ICAM and ROS. 1533 Nov 56

Soft tissue injury accounts for approximately 44% of all wounds in both the military and civilian populations. Following injury to soft tissue, Substance P (SP) and other neuropeptides are released by cutaneous neurons and modulate the function of immunocompetent and inflammatory cells, as well as epithelial and endothelial cells. The interaction between these components of the nervous system and multiple target cells affecting cutaneous repair is of increasing interest. In this report, we describe the effects of SP on wound repair in a novel, laser-induced, skin-wound model. Gross and histologic examination of laser-induced injury revealed that exogenously administered SP affects wound healing via neurite outgrowth, in addition to adhesion molecule and neurokinin-1 receptor involvement in vivo. All SP effects were decreased by pretreatment with Spantide II, an SP antagonist. The elucidation of SP-mediating mechanisms is crucial to firmly establishing the involvement and interaction of the peripheral nervous system and the immune system in cutaneous repair. Findings presented here suggest that SP participates in the complex network of mediators involved in cutaneous inflammation and wound healing.
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PMID:Exogenous administration of Substance P enhances wound healing in a novel skin-injury model. 1579 49


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