Substance P mediates inflammatory oedema in acute pancreatitis <i>via</i> activation of the neurokinin‐1 receptor in rats and mice

Grady, Eileen F.; Yoshimi, Shandra K.; Maa, John; Valeroso, Dahlia; Vartanian, Robert K.; Rahim, Shamila; Kim, Edward H.; Gérard, Craig; Gerard, Norma P.; Bunnett, Nigel W.; Kirkwood, Kimberly S.

doi:10.1038/sj.bjp.0703343

Cited by 96 publications

(75 citation statements)

References 20 publications

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“…Based on the pathological changes such as intestinal mucosa injury and mucosa exuviation, it is presumed that the linkage between cell and cell or cell and matrix of the intestinal epithelium as well as the recovery of the intestinal epithelial layer were affected by a decrease of CD44 expression after SAP, while the role of growth hormone (GH) in maintaining the integrity of epithelial structures and immune functions of the intestinal mucosa might be related to the increase of CD44 mRNA expression. P substance and its receptor such as neurokinin-1 receptor (NK-1R) and neurokinin-2 receptor (NK-2R) have played important roles in the onset and progression of AP Grady et al, 2000). The action of neurokinin has been disturbed and the intestinal mucosa injury has been aggravated due to the significant increase of expressions of NK-1R and NK-2R in the colon during SAP (Zheng et al, 2002).…”

Section: Influence Of Enteral Nutrition Deficiency On Injury Of Intesmentioning

confidence: 99%

“…The early enteral nutuition (EN) might be indispensable to the protection of intestinal mucosa barrier of rats (Al-Omran et al, 2003;Marik and Zaloga, 2004). Grady et al(2000) found that PAF played an important role in the progression of pancreatitis complicated with functional disturbance of intestinal mucosa barrier. Its antagonist might be a potential therapy.…”

Section: Influence Of Enteral Nutrition Deficiency On Injury Of Intesmentioning

confidence: 99%

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Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier

Zhang

Song

et al. 2007

J. Zhejiang Univ. - Sci. B

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Acute pancreatitis (AP) is a common acute abdomen in clinic with a rapid onset and dangerous pathogenetic condition.AP can cause an injury of intestinal mucosa barrier, leading to translocation of bacteria or endotoxin through multiple routes, bacterial translocation (BT), gutorigin endotoxaemia, and secondary infection of pancreatic tissue, and then cause systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS), which are important factors influencing AP's severity and mortality. Meanwhile, the injury of intestinal mucosa barrier plays a key role in AP's process. Therefore, it is clinically important to study the relationship between the injury of intestinal mucosa barrier and AP. In addition, many factors such as microcirculation disturbance, ischemical reperfusion injury, excessive release of inflammatory mediators and apoptosis may also play important roles in the damage of intestinal mucosa barrier. In this review, we summarize studies on mechanisms of AP.

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Section: Influence Of Enteral Nutrition Deficiency On Injury Of Intesmentioning

confidence: 99%

Section: Influence Of Enteral Nutrition Deficiency On Injury Of Intesmentioning

confidence: 99%

Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier

Zhang

Song

et al. 2007

J. Zhejiang Univ. - Sci. B

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“…The present study demonstrates that NEP is protective against the damaging effects of caerulein-induced AP by modulating physiological SP levels. Pancreatic edema, increased plasma amylase activity, and infiltration of neutrophils into the inflamed tissue are well-known characteristics of caerulein-induced AP (7,27,33,39). In AP, plasma amylase level is markedly increased due to this enzyme escaping into the blood from damaged pancreatic tissues (40).…”

Section: Discussionmentioning

confidence: 99%

“…SP-NK1R interaction plays an early and important role in the inflammatory cascade and promotes excessive activation of inflammatory cells. Proinflammatory mechanisms of SP are thought to be its effects on plasma extravasation, neutrophil recruitment, and inflammatory mediator synthesis upon exogenous stimuli (7,8). SP is encoded by the preprotachykinin-A (PPTA) gene, produced primarily by sensory nociceptive neurons, but it can also be produced by inflammatory cells and pancreatic acinar cells (9)(10)(11).…”

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confidence: 99%

The Role of Neutral Endopeptidase in Caerulein-Induced Acute Pancreatitis

Koh

Moochhala²,

Bhatia³

2011

The Journal of Immunology

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Substance P (SP) is well known to promote inflammation in acute pancreatitis (AP) by interacting with neurokinin-1 receptor. However, mechanisms that terminate SP-mediated responses are unclear. Neutral endopeptidase (NEP) is a cell-surface enzyme that degrades SP in the extracellular fluid. In this study, we examined the expression and the role of NEP in caerulein-induced AP. Male BALB/c mice (20–25 g) subjected to 3–10 hourly injections of caerulein (50 μg/kg) exhibited reduced NEP activity and protein expression in the pancreas and lungs. Additionally, caerulein (10−7 M) also downregulated NEP activity and mRNA expression in isolated pancreatic acinar cells. The role of NEP in AP was examined in two opposite ways: inhibition of NEP (phosphoramidon [5 mg/kg] or thiorphan [10 mg/kg]) followed by 6 hourly caerulein injections) or supplementation with exogenous NEP (10 hourly caerulein injections, treatment of recombinant mouse NEP [1 mg/kg] during second caerulein injection). Inhibition of NEP raised SP levels and exacerbated inflammatory conditions in mice. Meanwhile, the severity of AP, determined by histological examination, tissue water content, myeloperoxidase activity, and plasma amylase activity, was markedly better in mice that received exogenous NEP treatment. Our results suggest that NEP is anti-inflammatory in caerulein-induced AP. Acute inhibition of NEP contributes to increased SP levels in caerulein-induced AP, which leads to augmented inflammatory responses in the pancreas and associated lung injury.

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“…Previous data (2) show that SP levels and NK-1 receptors in pancreatic acinar cells are upregulated during experimental pancreatitis in mice. In addition, NK-1 receptor deletion or antagonism protects mice against pancreatitis (3,9,15). SP-induced activation of the NK-1 receptor is an important proinflammatory step also in rat acute pancreatitis.…”

mentioning

confidence: 99%

Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats

Broccardo

Linari²,

Agostini³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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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. isolated pancreatic acini; tachykinin receptor distribution; immunofluorescence; Western blot analysis THE NEUROPEPTIDES substance P (SP), neurokinin (NK)-A, and NK-B are primary mammalian tachykinins (TKs) involved in a wide-ranging control of peripheral and central functional activities. Each TK preferentially binds to a specific cell surface receptor subtype belonging to the superfamily of G proteincoupled receptors: SP binds to the NK-1 receptor, NK-A to the NK-2 receptor, and NK-B to the NK-3 receptor. TKs and their receptors are diffusely distributed in the mammalian gastrointestinal tract where they mediate motor, secretory, and circulatory responses (10).To date, few reports exist on the role of the TKs in regulating exocrine pancreatic secretion. TKs acting on NK-1 and NK-2 receptors have been reported to stimulate in vitro pancreatic amylase secretion (12-14, 16, 20, 33), and NK-1 and NK-2 receptors have been detected in the pancreatic acinar cells of guinea pig and mouse (6,11,29,30,32). No information is available on whether acinar cells in the pancreas of these and other animal species express the NK-3 receptor, and little is known on the effects of NK-3 receptor agonists on pancreatic exocrine secretion (7,12,18,20,33). In our recent stud...

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Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin‐1 receptor in rats and mice

Cited by 96 publications

References 20 publications

Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier

Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier

The Role of Neutral Endopeptidase in Caerulein-Induced Acute Pancreatitis

Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats

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