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)

Stimulation of primary sensory neurons produces local vasodilation, plasma extravasation, and pain and is due largely to the release of the tachykinins substance P and calcitonin-gene-related peptide. Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation and appear to be important in many organ systems, including the pancreas. Factors that stimulate primary sensory neurons include hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, bradykinin, and proteases such as trypsin, all of which may participate in the generation of acute pancreatitis. The current review examines the cellular and molecular mechanisms involved in sensory nerve activation within the pancreas and the potential contribution of neurogenic inflammation to the pathogenesis of pancreatitis.
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PMID:Neurogenic inflammation and pancreatitis. 1555 Jul 64

Earlier studies have shown that mice deficient in NK1 receptors or its ligand, substance P, are protected against acute pancreatitis and associated lung injury. In the current study, the protective effect of NK1 receptor blockage against acute pancreatitis and associated lung injury was investigated, using a specific receptor antagonist, CP-96345. Acute pancreatitis was induced in mice by intraperitoneal (i.p.) injections of caerulein. Substance P levels in plasma, pancreas, and lungs were found to be elevated in a caerulein dose-dependent manner. Mice treated with CP-96345, either prophylactically, or therapeutically, were protected against acute pancreatitis and associated lung injury as evident by attenuation in plasma amylase, pancreatic and pulmonary myeloperoxidase activities, and histological evidence of pancreatic and pulmonary injuries. Pulmonary microvascular permeability was also reduced as a result of CP-96345 treatment. These results point to a key role of NK1 receptors in acute pancreatitis and associated lung injury.
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PMID:A key role of neurokinin 1 receptors in acute pancreatitis and associated lung injury. 1562 43

Acute pancreatitis is an inflammatory disorder, and inflammation not only affects the pathogenesis but also the course of the disease. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction; if marked this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies by us and other investigators have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, CINC/GRO-alpha, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, MIP1-alpha, RANTES, substance P, and hydrogen sulfide in acute pancreatitis and the resultant MODS. This review intends to present an overview of the inflammatory response that takes place following pancreatic acinar cell injury.
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PMID:Inflammatory response on the pancreatic acinar cell injury. 1611 Oct 89

Patients with acute pancreatitis often suffer from intestinal motility disturbances but the mechanism of this dysfunction is largely unknown. We studied the effect of acute necrotising pancreatitis (ANP) on in vivo gastrointestinal motility and in vitro intestinal contractility in mice. ANP was induced non-invasively by feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet during 72 h. Gastric emptying and intestinal transit were measured in vivo 15 min after intragastric gavage of a semiliquid Evans blue bolus. Gastric and intestinal neuromuscular function was determined in vitro on isolated muscle strips. ANP significantly decreased gastric emptying from 61.2 +/- 9.8 to 34.9 +/- 7.1% and intestinal transit from 63.4 +/- 5.6 to 32.5 +/- 5.4%. ANP did not affect receptor-dependent and receptor-independent gastric muscle contractions except the contractions to substance P, which were slightly inhibited. In intestinal muscle strips, ANP significantly decreased contractions to EFS, carbachol, PGF(2alpha), substance P and KCl. Our results show that ANP delays gastric emptying in vivo, associated with a specific reduction in substance P contractility in vitro. ANP also impairs intestinal transit in vivo, associated with a non-specific reduction of intestinal contractility in vitro. We conclude that ANP impairs gastrointestinal motility in mice with underlying regional differences in the pathogenic mechanisms.
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PMID:Regional differences in gastrointestinal motility disturbances during acute necrotising pancreatitis. 1618 5

Acute pancreatitis is a clinical condition whose incidence has increased over the past few years. The exact mechanism of its development is not yet clear. Substance P, the proinflammatory neuropeptide, has a role in the initiation of neurogenic inflammation. Substance P and its receptor neurokinin-1 receptor (NK-1R) are involved in the development of local as well as systemic inflammation in acute pancreatitis. This editorial focuses on the role of substance P and its receptors in the development of acute pancreatitis.
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PMID:Neurogenic inflammation in acute pancreatitis. 1618 61

Acute pancreatitis (AP) is a life-threatening condition that involves an acute inflammatory process in the pancreas. The involvement of tachykinins and neurokinin receptors in acute pancreatitis has been described only recently, despite their long-established role in inflammatory conditions. Among these, substance P (SP) is believed to play a central role in exacerbating the inflammatory process by acting through neurokinin-1 receptor (NK1R). Treatment with the NK1R antagonist, CP96,345, results in protection against caerulein-induced acute pancreatitis in mice. However, the mechanism by which NK1R and SP worsen the condition is still unclear. In the present study, we have investigated the effect of NK1R blockage on the expression of preprotachykinin genes and neurokinin receptors in acute pancreatitis. In the pancreas, CP96,345 treatment resulted in suppression of the elevation of SP concentration, preprotachykinin-A gene (PPT-A) mRNA expression, and NK1R mRNA and protein expression. In the lungs, the antagonist was found to suppress the increase in SP concentration, PPT-A mRNA expression and preprotachykinin-C gene (PPT-C) mRNA expression. However, the antagonist treatment further promoted the accumulation of pulmonary NK1R mRNA and protein expression. Neurokinin-2 receptor (NK2R) mRNA expression was not detected in normal pancreas. However, up-regulated expression of the mRNA for this receptor was observed during acute pancreatitis and treatment with CP96,345 further increased this expression. Pulmonary NK2R mRNA expression was found to be reduced during acute pancreatitis and CP96,345 treatment normalized this reduction. Neurokinin-3 receptor (NK3R) mRNA expression was absent in both pancreas and lung. These data have provided valuable information regarding the regulation of tachykinins and neurokinin receptors during acute pancreatitis.
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PMID:The effect of CP96,345 on the expression of tachykinins and neurokinin receptors in acute pancreatitis. 1636 13

Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.
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PMID:Acute pancreatitis: models, markers, and mediators. 1637 72

Activation of neurokinin (NK)-1 receptors but not of NK-3 stimulates amylase release from isolated pancreatic acini of the rat. Immunofluorescence studies show that NK-1 receptors are more strongly expressed than NK-3 receptors on pancreatic acinar cells under basal conditions. No studies have examined the expression of the two NK receptor populations in pancreatic acini during pancreatitis in rats. We therefore investigated the relationships between expression of these two tachykinin receptors and experimental acute pancreatitis induced by stimulating pancreatic amylase with caerulein (CK) in rats. Hyperstimulation of the pancreas by CK caused an increase in plasma amylase and pancreatic water content and resulted in morphological evidence of cytoplasmic vacuolization. Immunofluorescence analysis revealed a similar percentage of NK-1 receptor antibody immunoreactive acinar cells in rats with pancreatitis and in normal rat tissue but a larger percentage of NK-3 receptor immunoreactive cells in acute pancreatitis than in normal pancreas. Western blot analysis of NK-1 and NK-3 receptor protein levels after CK-induced pancreatitis showed no change in NK-1 receptors but a stronger increase in NK-3 receptor expression in pancreatic acini compared with normal rats thus confirming the immunofluorescence data. These new findings support previous evidence that substance P-mediated functions within the pancreas go beyond sensory signal transduction contributing to neurogenic inflammation, and they suggest that substance P plays a role in regulating pancreatic exocrine secretion via acinar NK-1 receptors. The significant increase in NK-3 receptors during pancreatic stimulation suggests that NK-3 receptors also intervene in the pathogenesis of mild acute pancreatitis in rats.
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PMID:Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats. 1678 1

Accumulating evidence suggests the neuropeptide substance P (SP) and its receptor neurokinin-1 receptor (NK-1R) play a pivotal role in the pathogenesis of acute pancreatitis (AP). However, the mechanisms remain unclear. The present study investigated whether chemokines as proinflammatory molecules are involved in SP-NK-1R-related pathogenesis of this condition. We observed temporally and spatially selective chemokine responses in secretagogue caerulein-induced AP in mice. CC chemokines monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein-1alpha (MIP-1alpha) and CXC chemokine MIP-2 were elevated after AP induction. Time-dependent, tissue-specific analysis of their mRNA and protein expression suggested that they are early mediators in the condition and mediate local as well as systemic inflammatory responses. In contrast, another CC chemokine regulated on activation, T cells expressed and secreted (RANTES) was only involved in local pancreatic inflammation at a later stage of the disease. Either prophylactic or therapeutic treatment with a potent selective NK-1R antagonist CP-96,345 significantly suppressed caerulein-induced increase in MCP-1, MIP-1alpha, and MIP-2 expression but had no apparent effect on RANTES expression. The suppression effect of CP-96,345 on MCP-1, MIP-1alpha, and MIP-2 expression was concordantly demonstrated by immunohistochemistry, which, additionally, suggested that chemokine immunoreactivity was localized to acinar cells and the infiltrating leukocytes in the pancreas and alveolar macrophages, epithelial cells, and endothelial cells in the lungs. Our data suggest that SP, probably by acting via NK-1R on various chemokine-secreting cells in the pancreas and lungs, stimulates the release of chemokines that aggravate local AP and the development of its systemic sequelae.
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PMID:Blockade of neurokinin-1 receptor attenuates CC and CXC chemokine production in experimental acute pancreatitis and associated lung injury. 1687 93

Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1alpha (MIP-1alpha), as well as MIP-2. Furthermore, SP also increased NF-kappaB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-kappaB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-kappaB inhibitor NF-kappaB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-kappaB dependent.
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PMID:Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-kappaB. 1687 95


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