Substance-P-like levels in inflammatory exudates

Tissot, M.; Pradelles, Philippe; Jp, Giroud

doi:10.1007/bf00915889

Cited by 41 publications

(12 citation statements)

References 33 publications

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“…Recent studies have suggested that the ultimate severity of the resulting pancreatitis may be determined by events that occur subsequent to acinar cell injury including inflammatory cell recruitment and activation and the generation and release of cytokines and other chemical mediators of inflammation (19)(20)(21). Although neurogenic factors have been shown to play an important role in a variety of other inflammatory processes (1,2,6,(22)(23)(24)(25)(26), the potential role of neurogenic factors as regulators of the severity of acute pancreatitis has not been previously evaluated.…”

Section: Discussionmentioning

confidence: 99%

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Bhatia

Saluja

Hofbauer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

277

271

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Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inf lammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R؊͞؊ mice when compared with wild-type NK1R؉͞؉ animals. Similarly, pancreatitisassociated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R؊͞؊ animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinf lammatory role in regulating the severity of acute pancreatitis and pancreatitisassociated lung injury.The neuropeptide substance P has been shown to play an important role in asthma, inflammatory bowel disease, arthritis, and other inflammatory processes (1, 2). Subsequent to its release from nerve endings, substance P binds to neurokinin 1 receptors (NK1R) on effector cells, increases microvascular permeability, and promotes plasma extravasation from the intravascular to the extravascular space. Although pancreatic acinar cells are known to express NK1R and substance P has been detected within the pancreas (3-5), apparently no studies have been reported that have examined the possibility that this neuropeptide might play a role in the evolution of a pancreatic inflammatory disease such as acute pancreatitis. We have found that pancreatic levels of substance P and the expression of NK1R on pancreatic acinar cells are increased during experimental acute pancreatitis. We have also found that genetic deletion of NK1R reduces the severity of pancreatitis and pancreatitis-associated lung injury. These observations indicate that substance P, acting through NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and associated lung injury. MATERIALS AND METHODSAll experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of the Beth Israel Hospital. Breeding pairs of NK1R-deficient mice were generated as described (6), and the identity of their offspring as NK1R-deficient (Ϫ͞Ϫ) homozygotes was confirmed by Southern blotting (6). Animals were bred and housed in standard shoe box cages in a climate-controlled room with an ambient temperature of 23 Ϯ 2°C and a 12-h light͞12-h dark cycle. They were fed standard laboratory chow, given water ad libitum, randomly assigned to control or experimental groups, and...

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Section: Discussionmentioning

confidence: 99%

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Bhatia

Saluja

Hofbauer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

277

271

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“…These results provide evidence that LPMs must be considered as a source of SP in C. difficile toxin A-mediated enteritis. Several other studies show that immune and inflammatory cells synthesize and release SP, including rat peritoneal macrophages (30), the murine macrophage cell line P388D1 (44), mouse granuloma eosinophils (16), and human eosinophils (45). Moreover, Bost et al (30) demonstrated that stimulation of rat peritoneal macrophages with LPS increased the abundance of SP mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Mast cells (10), polymorphonuclear leukocytes (11), T lymphocytes (12,13), and macrophages (14) can respond to SP, indicating that the effects of SP during inflammation may be mediated by direct activation of these cells. SP levels are also elevated in inflamed tissues (15)(16)(17), and increased binding sites for SP have been demonstrated at sites of inflammation in conditions such as arthritis (18) and Crohn disease (19). In regard to intestinal inflammation, studies from our laboratory indicate that SPcontaining sensory neurons are involved in the enterotoxic effects of Clostridium difficile toxin A, the causative agent of antibiotic-associated enterocolitis in animals and humans (20).…”

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confidence: 99%

Increased substance P responses in dorsal root ganglia and intestinal macrophages duringClostridium difficiletoxin A enteritis in rats

Castagliuolo

Keates

Qiu

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

153

124

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Previously we reported that pretreatment of rats with the substance P (SP) antagonist CP-96,345 inhibits the enterotoxic responses following administration of toxin A from Clostridium difficile into ileal loops, indicating that SP participates in the intestinal responses to this toxin. We now report that injection of toxin A into rat ileum causes a rapid increase in SP content in lumbar dorsal root ganglia (DRG) and mucosal scrapings 30-60 min after toxin A administration. Toxin A-mediated f luid secretion, mannitol permeability, and ileal histologic damage is significantly increased only after 2 hr. Toxin A also causes an increase in the abundance of SP mRNA in lumbar DRG and ileal mucosa as measured by reverse transcription-PCR. Lamina propria macrophages (LPMs) obtained from toxin A-injected loops release greater amounts of tumor necrosis factor ␣ (TNF␣) and SP as compared with LPMs isolated from buffer-injected loops (P < 0.01). Pretreatment of rats with the SP antagonist CP-96,345 inhibits toxin A-mediated TNF␣ release from isolated LPMs, whereas an inactive enantiomer (CP-96,344) of the SP antagonist has no effect. LPMs obtained from toxin A-injected ileal loops incubated in vitro with SP (10 ؊8 to 10 ؊9 M) show enhanced TNF␣ secretion, whereas LPMs isolated from buffer-injected loops do not respond to SP. In addition, LPMs obtained from toxin A-injected ileal loops incubated in vitro with CP-96,345 showed a diminished TNF␣ release. Our results indicate that activated LPMs secrete SP during toxin A enteritis that can lead to secretion of cytokines, suggesting an autocrine͞paracrine regulation of cytokine secretion by SP from LPMs during intestinal inf lammation.Substance P (SP), an 11-aa peptide member of the tachykinin family originally isolated by Chang and Leeman (1), is a peptide distributed throughout the central and peripheral nervous system. In the intestine, SP has been found in capsaicin-sensitive sensory neurons (2), enteric neurons (3), as well as intestinal enteroendocrine cells (4). SP is also synthesized in the cell bodies of the dorsal root ganglia (DRG) (5), and evidence indicates that release of SP from DRG to spinal cord mediates nociceptive and inflammatory stimuli (6-8). Recently, Reinshagen et al. (9) reported decreased levels of SP in the DRG of rabbits 48 hr after induction of colitis, suggesting that SP may be released from sensory neurons during the acute phase of inflammation. However, there are no studies specifically evaluating the SP content in the DRG during acute intestinal inflammation mediated by bacterial enterotoxins.In addition to its role as a neurotransmitter, SP also participates in immune and inflammatory responses. Mast cells (10), polymorphonuclear leukocytes (11), T lymphocytes (12, 13), and macrophages (14) can respond to SP, indicating that the effects of SP during inflammation may be mediated by direct activation of these cells. SP levels are also elevated in inflamed tissues (15-17), and increased binding sites for SP have been demonstrated at sites o...

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“…The peptidergic sensory nerve fibers take part in nociception and peptide-mediated neurogenic inflammation, both in normal and injured tissue (Heyeraas et al, 1994;McMahon and Koltzenburg, 1990;Kruger, 1988;Jancs6 et al, 1967). The sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) are released after sensory nerve stimulation (Heyeraas et al, 1994;Olgart et al, 1977) and at local sites of inflammation (Tissot et al, 1988).…”

Section: Troductionmentioning

confidence: 99%

Recruitment of immunocompetent cells after dentinal injuries in innervated and denervated young rat molars: an immunohistochemical study.

Fristad¹,

Heyeraas²,

Kvinnsland³

et al. 1995

J Histochem Cytochem.

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The dental pulp represents a peripheral end-organ deprived of a collateral nerve supply. After inferior alveolar nerve (IAN) axotomy, rat molar pulp is denervated over a period of at least 6 days. Therefore, rat molar pulp was used as an experimental model to study the effect of sensory nerve fibers on influx of immunocompetent cells after dentinal injury. In the present study we performed a quantitative analysis of CD43+, CD4+, CD11b+, and I-A antigen-expressing cells subjacent to dentinal cavities in denervated and innervated first mandibular molars. For visualization of nerve fibers, antibodies to protein gene product (PGP) 9.5, the sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), and the sympathetic neuropeptide Y (NPY) were used. Immunohistochemistry was performed by the avidin-biotin-peroxidase method. In the innervated teeth, a correlation between increased sensory nerve density and influx of immunocompetent cells was found. Compared to the contralateral innervated molars, a significant reduction in recruitment of immunocompetent cells was found in the denervated pulp tissue subjacent to the dentinal cavities. The rat molar represents a unique model to illustrate the influence of sensory nerves and neuropeptides on inflammation and recruitment of immunocompetent cells.

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Substance-P-like levels in inflammatory exudates

Cited by 41 publications

References 33 publications

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Increased substance P responses in dorsal root ganglia and intestinal macrophages duringClostridium difficiletoxin A enteritis in rats

Recruitment of immunocompetent cells after dentinal injuries in innervated and denervated young rat molars: an immunohistochemical study.

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