1 Department of Pharmacology, National University of Singapore, Singapore 117597; 2 Department of Surgery, University of Liverpool, L69 3GA Liverpool, United Kingdom; and 3 Department of Anatomy, University of California, San Francisco, California 94143
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ABSTRACT |
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Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Preprotachykinin-A (PPT-A) gene products substance P and neurokinin (NK)-A have been shown to play important roles in neurogenic inflammation. Substance P acts primarily (but not exclusively) via the NK1 receptor. NKA acts primarily via the NK2 receptor. Earlier work has shown that knockout mice deficient in NK1 receptors are protected against acute pancreatitis and associated lung injury. NK1 receptors, however, bind other peptides in addition to substance P, not all of which are derived from the PPT-A gene. To examine the role of PPT-A gene products in acute pancreatitis, the effect of PPT-A gene deletion on the severity of acute pancreatitis and the associated lung injury was investigated. Deletion of PPT-A almost completely protected against acute pancreatitis-associated lung injury, with a partial protection against local pancreatic damage. These results show that PPT-A gene products are critical proinflammatory mediators in acute pancreatitis and the associated lung injury.
multiple organ dysfunction syndrome; caerulein; substance P; neurogenic inflammation; systemic inflammatory response syndrome
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INTRODUCTION |
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ACUTE PANCREATITIS IS A COMMON clinical condition, whose incidence has been increasing over recent years (1, 3, 22, 26). In the majority of patients, the condition is mild, but up to 25% of patients suffer a severe attack, and between 30 and 50% of these will die (1, 3). Most cases are secondary to biliary disease or excess alcohol consumption. The exact mechanisms by which diverse etiological factors induce an attack are still unclear, but once the disease process is initiated, common inflammatory and repair pathways are invoked. If this inflammatory reaction is very strong, it leads to a systemic inflammatory response syndrome (SIRS), and it is this systemic response that is ultimately responsible for the majority of the morbidity and mortality (1, 3). Systemic leukocyte activation is a direct consequence of SIRS, and if excessive, it can lead to distant organ damage and multiple organ dysfunction syndrome (MODS) (1, 3). Lung injury that manifests itself clinically as adult respiratory distress syndrome is a major component of MODS associated with acute pancreatitis.
Substance P and neurokinin (NK)-A are neuropeptide products of the
preprotachykinin-A (PPT-A) gene. The primary RNA transcript of the
PPT-A gene is spliced to yield three different forms of mRNA termed
-,
-, and
-forms. The
-,
-, and
-PPT-A mRNAs code for
the synthesis of substance P, whereas
- and
-PPT-A mRNAs code for
the synthesis of both substance P and NKA. Substance P is released from
nerve endings in many tissues. Subsequent to its release, substance P
binds primarily, but not exclusively, to NK1 receptors on the surface
of effector cells and, in addition to being a mediator of pain, acts as
a proinflammatory mediator in many inflammatory states
(20) including asthma (15, 27), immune-complex-mediated lung injury (7), experimental
arthritis (40), and inflammatory bowel disease
(41). NKA binds primarily to NK2 receptors. Substance P
and NKA bind to NK3 receptors as well, although with a lower affinity.
Substance P has been detected within the pancreas, and it has been
suggested that substance P may act as a neurotransmitter for sensory
afferent nerves in the pancreas. Receptors for substance P have also
been detected on guinea pig pancreatic acinar cells and the
neuropeptide acts as a secretagogue, stimulating amylase secretion from
acinar cells via a G protein, phospholipase-, inositol phosphate-, and
calcium-mediated mechanisms in that species (37-39).
Rat pancreatic acinar cells apparently do not express receptors for
substance P, and the neuropeptide does not stimulate enzyme secretion
from rat acinar cells. By contrast, recent work (4) has
shown the presence of substance P in the mouse pancreas and of NK1
receptors on mouse pancreatic acinar cells. On induction of
pancreatitis in mice, there is a severalfold upregulation of pancreatic
substance P levels and of NK1 receptors on pancreatic acinar cells
(4). Moreover, knockout mice deficient in NK1 receptors
are protected against pancreatitis and associated lung injury (4,
18). These results suggest an important proinflammatory role for
neurogenic inflammation and NK1 receptors in acute pancreatitis and
associated lung injury. These results are further substantiated by the
observation that knockout mice deficient in neutral endopeptidase, the
enzyme that hydrolyzes substance P, thereby terminating its action, are
more susceptible to acute pancreatitis and associated lung injury
(5, 24).
NK1 receptors, however, bind other peptides in addition to substance P, and not all of these are products of the PPT-A gene. Also, the PPT-A gene products substance P and NKA bind to other receptors, albeit with a lower affinity, in addition to NK1 and NK2 receptors (8, 19, 20, 33). The present study, therefore, aims to investigate the contribution of the PPT-A gene products on the pathogenesis of acute pancreatitis and associated lung injury by using mice deficient in PPT-A gene.
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MATERIALS AND METHODS |
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Induction of acute pancreatitis.
All experiments were performed under a current Home Office Project
License within the regulations of the Animals (Scientific Procedures)
Act 1986. PPT-A knockout mice were generated and bred as described
previously (10). Caerulein was obtained from Research Plus
(Bayonne, NJ). PPT-A/
mice with BALB/c background and
PPT-A+/+ BALB/c mice (16-18 g) were randomly assigned
to control or experimental groups by using eight animals for each
group. Animals were given hourly intraperitoneal injections of normal
saline or saline containing caerulein (50 µg/kg) for 3, 6, or 10 h. One hour after the last caerulein injection, animals were killed by
an intraperitoneal injection of a lethal dose of pentabarbitone, and
samples were prepared for storage.
Preparation of pancreatic acini.
Pancreatic acini were obtained from mouse pancreas by collagenase
treatment as described previously (4). Briefly, pancreata from PPT-A/
and PPT-A
/
mice were
removed under aseptic conditions, infused with collegenase buffer
A (in mM: 140 NaCl, 4.7 KCl, 1.13 MgCl2, 1 CaCl2, 10 glucose, and 10 HEPES, pH 7.2) containing 200 IU/ml collagenase and 0.5 mg/ml soybean trypsin inhibitor, and
incubated in a shaking water bath for 10 min at 37°C.
Digested tissue was passed through 50 mg/ml BSA and washed twice with
buffer A (10% CO2-90% air) before further
experiments. Cell viability was assessed by trypan blue exclusion.
Acini were incubated with varying concentrations of caerulein (Research
Plus) for 30 min, and amylase secretion was determined as described in
Amylase estimation.
Amylase estimation. Amylase activity was measured by using a kinetic spectrophotometric assay. Plasma samples and acinar cell supernatants were incubated with the substrate, 4,6-ethylidene (G7)-p-nitrophenyl (G1)-1-D-maltoheptoside (Sigma, Dorset, UK) for 2 min at 37°C, and absorbance was measured every minute for the subsequent 2 min at 405 nm (4, 31). The change in absorbance was used to calculate the amylase activity.
MPO estimation. Neutrophil sequestration in pancreas and lung was quantified by measuring tissue MPO activity (2). Tissue samples were thawed, homogenized in 20 mM phosphate buffer (pH 7.4), centrifuged (10,000 g, 10 min, 4°C), and the resulting pellet was resuspended in 50 mM phosphate buffer (pH 6.0) containing 0.5% hexadecyltrimethylammonium bromide (Sigma). The suspension was subjected to four cycles of freezing and thawing and further disrupted by sonication (40 s). The sample was then centrifuged (10,000 g, 5 min, 4°C), and the supernatant was used for the MPO assay. The reaction mixture consisted of the supernatant, 1.6 mM tetramethylbenzidine (Sigma), 80 mM sodium phosphate buffer (pH 5.4), and 0.3 mM hydrogen peroxide. This mixture was incubated at 37°C for 110 s, the reaction was terminated with 0.18 M H2SO4, and the absorbance was measured at 450 nm. This absorbance was then corrected for the calculated dry weight of the tissue sample, and results were expressed as activity per unit of dry weight (fold increase over control).
Measurement of pulmonary microvascular permeability. Two hours before death, each animal received an intravenous bolus injection containing FITC-albumin (5 mg/kg, Sigma). Immediately after death, the trachea was exposed, and the lungs were lavaged three times with 1 ml of normal saline. The lavage fluid was combined, and FITC fluorescence was measured in the lavage fluid and plasma (excitation = 494 nm; emission = 520 nm). The ratio of fluorescence emission in lavage fluid to plasma was calculated and used as a measure of pulmonary microvascular permeability (4).
Morphological examination. Paraffin-embedded pancreas and lung samples were sectioned (4 µm), stained with hematoxylin and eosin, and examined with light microscopy.
Statistics. Data are expressed as the means ± SE. In all figures, vertical bars denote the SE, and the absence of such bars indicates that the SE is too small to illustrate. The significance of changes was evaluated by using Student's t-test when the data consisted of only two groups or by ANOVA when three or more groups were compared. If ANOVA indicated a significant difference, the data were analyzed by using Tukey's method as a post hoc test for the difference between groups. A P value of 0.05 was considered to indicate a significant difference.
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RESULTS |
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Effect of PPT-A gene deletion on caerulein-induced acute
pancreatitis.
Wild-type mice given intraperitoneal injections of supramaximally
stimulating doses of the secretagogue caerulein developed acute
necrotizing pancreatitis. As shown in Figs.
1-4, this was manifested by a dose
and time-dependent rise in plasma amylase activity, pancreatic water
content (a measure of pancreatic edema), pancreatic MPO activity (an
indicator of neutrophil sequestration in the pancreas), and
morphological evidence of extensive acinar cell necrosis.
PPT-A/
mice also showed evidence of pancreatic injury
in acute pancreatitis. Genetic deletion of PPT-A, however, markedly
reduced the severity of caerulein-induced pancreatitis. At induction of
acute pancreatitis, the rise in plasma amylase activity (Fig. 1),
pancreatic water content (Fig. 2), and
pancreatic MPO activity (Fig. 3) were
significantly subdued in PPT-A
/
mice compared with the
wild-type controls. Histological examination of pancreas sections
showed significant protective effect of PPT-A gene deletion on acinar
cell injury/necrosis in acute pancreatitis (Fig.
4).
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Effect of PPT-A gene deletion on caerulein-induced acute
pancreatitis-associated lung injury.
Acute pancreatitis in wild-type mice induced by 6 and 10 (but not 3)
hourly injections of caerulein 50 µg/kg was associated with lung
injury. As shown in Fig. 5,
caerulein-induced pancreatitis was associated with a rise in lung MPO
activity, indicating the presence of sequestered neutrophils.
Furthermore, leakage of intravenously administered FITC-labeled albumin
into the alveolar space, a measure of pulmonary microvascular
permeability, was increased during secretagogue-induced pancreatitis
(Fig. 6). Histological examination of
lung sections confirmed evidence of lung injury in acute pancreatitis (Fig. 7). Genetic deletion of PPT-A
resulted in a marked reduction in the severity of
pancreatitis-associated lung injury. Lung MPO activity, lung
microvascular permeability, and microscopic evidence of lung injury are
reduced in PPT-A/
mice when compared with the
PPT-A+/+ controls (Figs. 5-7). Indeed there was an
almost complete protection against acute pancreatitis-associated lung
injury in PPT-A
/
mice.
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Effect of PPT-A gene deletion on caerulein-stimulated enzyme
secretion from pancreatic acini.
In accordance with previously reported findings (4),
biphasic stimulation/inhibition of amylase secretion by increasing concentrations of caerulein was observed when freshly prepared pancreatic acini from wild-type PPT-A+/+ mice was evaluated
(Fig. 8). Similar changes were observed
when acini obtained from PPT-A/
mice were evaluated.
These findings indicate that the deletion of PPT-A does not alter
pancreatic cell responsiveness to the secretagogue caerulein.
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DISCUSSION |
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Substance P is a major mediator of neurogenic inflammation in several tissues including skin (20, 21), cardiovascular tissue (6, 9, 25), cephalic structures (13, 17, 26), respiratory tract (7, 15, 27), genitourinary tract (23, 30), and gastrointestinal tract (12, 16, 25, 32). NKA has also been shown to play an important role in neurogenic inflammation in several conditions. Indeed neurogenic inflammation likely underlies several disease conditions (20), such as asthma (15, 27), immune-complex-mediated lung injury (7), experimental arthritis (40), and inflammatory bowel disease (41). Based on our studies with NK1 receptor knockout mice, we previously proposed a proinflammatory contribution of substance P in the pathogenesis of acute pancreatitis and associated lung injury (8). In that study, mice genetically deficient in the NK1 receptor were protected against acute pancreatitis and associated lung injury. However, NK1 receptors bind other peptides in addition to substance P (and NKA), and not all of these are products of PPT-A gene. Also, substance P and NKA bind to other receptors, albeit with a lower affinity (8, 19, 20, 33).
This paper aims to investigate the contribution of PPT-A gene products to the pathogenesis of acute pancreatitis and associated lung injury, by using knockout mice deficient in the PPT-A gene. It has previously been shown that although the behavioral response to mildly painful stimuli is intact in these mice, the response to moderate-to-intense pain is significantly reduced. Neurogenic inflammation, evidenced by plasma extravasation and hindpaw edema induced by capsaicin treatment, which results from peripheral release of substance P, is almost absent in the mutant mice (10). By contrast, inflammation produced by complete Freund's adjuvant, which is nonneurogenic, is intact in these mice (10).
In PPT-A knockout mice, we induced acute pancreatitis by giving them
supramaximally stimulating doses of the secretagogue caerulein. This
secretagogue-induced model of acute pancreatitis is characterized by
hyperamylasemia, pancreatic edema (increased pancreatic water content),
sequestration of neutrophils within the pancreas (i.e., increased
pancreatic MPO activity), and morphological evidence of acinar cell
injury/necrosis. Severe, but not mild, acute pancreatitis is also
associated with lung injury characterized by sequestration of
neutrophils within the lung (increased lung MPO activity) and increased
pulmonary microvascular permeability (increased leakage of the
intravenously administered FITC-labeled albumin into the
bronchoalveolar lavage fluid). Our results show that deletion of PPT-A
results in a marked decrease in each of the parameters that
characterize the severity of secretagogue-induced acute pancreatitis.
The earliest events in acute pancreatitis are mediated by the action of
caerulein on the CCK receptors on pancreatic acinar cells, which may
account for the residual pancreatic injury in the mutant mice. A lack
of effect of PPT-A gene deletion on the biphasic caerulein
dose-response curve for amylase secretion indicates that the early
acinar cell responses to caerulein are unaltered in the PPT-A null mice
and that the deletion of PPT-A does not alter pancreatic cell
responsiveness to caerulein. Subsequently, however, PPT-A gene
products, acting via the NK1 receptors on pancreatic acinar cells, may
increase the severity of acinar cell injury in wild-type but not
PPT-A/
mice. Indeed, PPT-A gene deletion does not appear to have an
effect on mild, acute pancreatitis induced by three hourly injections
of caerulein (50 µg/kg), whereas the severity of more severe acute
pancreatitis induced by 6 and 10 hourly injections of caerulein is
significantly reduced.
Results presented in this paper show that mild acute pancreatitis is
not associated with lung injury, whereas severe pancreatitis is. Lung
injury in this model is unlikely to be due to a direct effect of
caerulein. In one of the earliest studies on this subject (14), it was shown that perfusion of isolated lungs with
caerulein did not lead to any evidence of lung injury or functional
alterations. A similar picture is observed in clinical acute
pancreatitis (1, 3). Significantly, there is an almost
complete protection against acute pancreatitis-associated lung injury
in PPT-A knockout mice. It has previously been shown (4)
that pancreatic levels of the PPT-A gene product substance P are
elevated within 3-4 h of starting caerulein administration before
any evidence of lung injury can be observed and remain elevated for
12 h, pointing to the pancreas being the primary site of action of
substance P. Results also indicate that leukocytes, particularly
neutrophils, are most likely to reflect the downstream lung injury,
because protection in the pancreas by plasma amylase and pancreatic
water content is minimal, whereas that in terms of pancreatic MPO
activity is more impressive. On the basis of these data,
however, we cannot conclusively say whether the protection
against lung injury in PPT-A/
mice is because acute
pancreatitis is not severe enough in PPT-A
/
mice or
because of a direct protective effect on lung injury (or both).
Nevertheless, the reduction in pancreatitis and lung injury severity
that is brought about by PPT-A deletion leads us to conclude that the
PPT-A gene product(s) substance P and/or NKA are important
proinflammatory mediators in the pathogenesis of acute pancreatitis and
associated lung injury.
A similar partial protection against local pancreatic injury in, and an almost complete protection against, lung injury in acute pancreatitis was observed in mice genetically deficient in the NK1 receptor (4, 18). The protective effect of the gene deletion is not limited to the caerulein model, because it has been shown (24) that NK1 receptor gene deletion protects mice against acute pancreatitis induced by the administration of a choline-deficient diet supplemented with ethionine. The question of the contribution of other NK1-receptor agonists and of individual contribution of substance P and NKA (possibly via the NK2 receptor) remains to be answered and will be the subject of future investigations.
Mechanisms by which PPT-A gene products act as proinflammatory mediators in acute pancreatitis are not very clear, although there are several possibilities. Of the PPT-A gene products, substance P (and possibly NKA) may act via NK1 receptors present on pancreatic acinar cells (4), contributing to acinar cell injury in acute pancreatitis. Other NK receptors, such as NK2 and NK3 receptors, have not yet been found on pancreatic acinar cells.
Alternatively, PPT-A gene products may act on endothelial cells to
increase vascular permeability and promote edema formation (16,
18). Interactions between different NK receptors are mediated by
-arrestin (35). It was previously shown (17a,
32a) that some cells, such as enteric neurons and microvascular
endothelial cells, coexpress NK1 and NK3 receptors. Schmidlin
et al. (35) reported that in cells coexpressing NK1 and
NK3 receptors, prior activation of the NK1 receptors inhibited
homologous desensitization of the NK3 receptors, but activation of NK3
receptors had no effect on NK1 receptor desensitization. PPT-A gene
products have been shown to act on both NK1 and NK3 receptors, and it
is likely that on activation of the NK1 receptor, the NK3 receptor
would become resistant to desensitization and be the major receptor
responding to the tachykinins.
Yet another possibility is that PPT-A gene products may act via the inflammatory cells, such as neutrophils (by inducing chemotaxis) or mast cells (11, 29, 34, 36). Further studies shall be directed at defining the mechanism of action of PPT-A gene products as proinflammatory mediators in the pathogenesis of acute pancreatitis and associated lung injury.
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ACKNOWLEDGEMENTS |
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This work was supported by Academic Research Fund Start-Up Grant R-184-000-048-112, Academic Research Fund Grant R-184-000-054-112, Biomedical Research Council Grant 02/1/21/19/110, and Wellcome Trust Project Grant 003393.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Bhatia, Dept. of Pharmacology, National University of Singapore, Faculty of Medicine, Bldg. MD2, 18 Medical Dr., Singapore 117597 (E-mail: mbhatia{at}nus.edu.sg).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00140.2002
Received 11 April 2002; accepted in final form 14 January 2003.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bhatia, M,
Brady M,
Shokuhi S,
Christmas S,
Neoptolemos JP,
and
Slavin J.
Inflammatory mediators in acute pancreatitis.
J Pathol
190:
117-125,
2000[ISI][Medline].
2.
Bhatia, M,
Brady M,
Zagorski J,
Christmas SE,
Campbell F,
Neoptolemos JP,
and
Slavin J.
Treatment with neutralising antibody against cytokine induced neutrophil chemoattractant (CINC) protects rats against acute pancreatitis associated lung injury.
Gut
47:
838-844,
2000
3.
Bhatia, M,
Neoptolemos JP,
and
Slavin J.
Inflammatory mediators as therapeutic targets in acute pancreatitis.
Curr Opin Investig Drugs
2:
496-501,
2001[Medline].
4.
Bhatia, M,
Saluja AK,
Hofbauer B,
Frossard JL,
Lee HS,
Castagliuolo I,
Wang CC,
Gerard N,
Pothoulakis C,
and
Steer ML.
Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury.
Proc Natl Acad Sci USA
95:
4760-4765,
1998
5.
Bhatia, M,
Saluja AK,
Hofbauer B,
Lee HS,
Frossard JL,
Lu B,
Gerard C,
and
Steer ML.
Neutral endopeptidase (NEP) plays an anti-inflammatory role in acute pancreatitis and pancreatitis-associated lung injury (Abstract).
Pancreas
15:
428,
1997.
6.
Bowden, JJ,
Garland AM,
Baluk P,
Lefevre P,
Grady EF,
Vigna SR,
Bunnett NW,
and
McDonald DM.
Direct observation of substance P-induced internalization of neurokinin 1 (NK1) receptors at sites of inflammation.
Proc Natl Acad Sci USA
91:
8964-8968,
1994[Abstract].
7.
Bozic, CR,
Lu B,
Hopken UE,
Gerard C,
and
Gerard NP.
Neurogenic amplification of immune complex inflammation.
Science
273:
1722-1725,
1996
8.
Bremer, AA,
Tansky MF,
Wu M,
Boyd ND,
and
Leeman SE.
Direct evidence for the interaction of neurokinin A with the tachykinin NK(1) receptor in tissue.
Eur J Pharmacol
423:
143-147,
2001[ISI][Medline].
9.
Brodin, E,
and
Nilsson G.
Concentration of substance P-like immunoreactivity (SPLI) in tissues of dog, rat and mouse.
Acta Physiol Scand
112:
305-312,
1981[ISI][Medline].
10.
Cao, YQ,
Mantyh PW,
Carlson EJ,
Gillespie AM,
Epstein CJ,
and
Basbaum AI.
Primary afferent tachykinins are required to experience moderate to intense pain.
Nature
392:
390-394,
1998[ISI][Medline].
11.
Carolan, EJ,
and
Casale TP.
Effects of neuropeptides on neutrophil migration through noncellular and endothelial barriers.
J Allergy Clin Immunol
92:
589-598,
1993[ISI][Medline].
12.
Castagliuolo, I,
Riegler M,
Pasha A,
Nikulasson S,
Lu B,
Gerard C,
Gerard NP,
and
Pothoulakis C.
Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis.
J Clin Invest
101:
1547-1550,
1998
13.
Edvinsson, L,
Rosendal-Helgesen S,
and
Uddman R.
Substance P: localization, concentration and release in cerebral arteries, choroid plexus and dura mater.
Cell Tissue Res
234:
1-7,
1983[ISI][Medline].
14.
Feddersen, CO,
Willemer S,
Karges W,
Puchner A,
Adler G,
and
Wichert PV.
Lung injury in acute experimental pancreatitis in rats. II. Functional studies.
Int J Pancreatol
8:
323-331,
1991[ISI][Medline].
15.
Figini, M,
Emanueli C,
Bertrand C,
Javdan P,
and
Geppetti P.
Evidence that tachykinins relax the guinea-pig trachea via nitric oxide release and by stimulation of a septide-insensitive NK1 receptor.
Br J Pharmacol
117:
1270-1276,
1996[Abstract].
16.
Figini, M,
Emanueli C,
Grady EF,
Kirkwood K,
Payan DG,
Ansel J,
Gerard C,
Geppetti P,
and
Bunnett N.
Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas.
Am J Physiol Gastrointest Liver Physiol
272:
G785-G793,
1997
17.
Figini, M,
Javdan P,
Cioncolini F,
and
Geppetti P.
Involvement of tachykinins in plasma extravasation induced by bradykinin and low pH medium in the guinea-pig conjunctiva.
Br J Pharmacol
115:
128-132,
1995[Abstract].
17a.
Grady, EF,
Baluk P,
Böhm S,
Gamp P,
Wong H,
Payan DG,
Ansel J,
Portbury AL,
Furness JB,
McDonald DM,
and
Bunnett NW.
Characterization of antisera specific to NK1, NK2, and NK3 neurokinin receptors and their utilization to localize receptors in the rat gastrointestinal tract.
J Neurosci
16:
6975-6986,
1996
18.
Grady, EF,
Yoshimi SK,
Maa J,
Valeroso D,
Vartanian RK,
Rahim S,
Kim EH,
Gerard C,
Gerard N,
Bunnett NW,
and
Kirkwood KS.
Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice.
Br J Pharmacol
130:
505-512,
2000
19.
Hardwick, JC,
Mawe GM,
and
Parsons RL.
Tachykinin-induced activation of non-specific cation conductance via NK3 neurokinin receptors in guinea-pig intracardiac neurones.
J Physiol
504:
65-74,
1997[Abstract].
20.
Harrison, S,
and
Geppetti P.
Substance P.
Int J Biochem Cell Biol
33:
555-576,
2001[ISI][Medline].
21.
Holzer, P.
Neurogenic vasodilatation and plasma leakage in the skin.
Gen Pharmacol
30:
5-11,
1998[Medline].
22.
Imrie, CW.
Acute pancreatitis: overview.
Eur J Gastroenterol Hepatol
9:
103-105,
1997[ISI][Medline].
23.
Kopp, UC,
and
Smith LA.
Effects of the substance P receptor antagonist CP-96,345 on renal sensory receptor activation.
Am J Physiol Regul Integr Comp Physiol
264:
R647-R653,
1993
24.
Maa, J,
Grady EF,
Yoshimi SK,
Drasin TE,
Kim EH,
Hutter MM,
Bunnett NW,
and
Kirkwood KS.
Substance P is a determinant of lethality in diet-induced hemorrhagic pancreatitis in mice.
Surgery
128:
232-239,
2000[ISI][Medline].
25.
Mantyh, CR,
Gates TS,
Zimmerman RP,
Welton ML,
Passaro EP, Jr,
Vigna SR,
Maggio JE,
Kruger L,
and
Mantyh PW.
Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease.
Proc Natl Acad Sci USA
85:
3235-3239,
1988[Abstract].
26.
Moskowitz, MA.
Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine.
Trends Pharmacol Sci
13:
307-311,
1992[ISI][Medline].
27.
Naline, E,
Molimard M,
Regoli D,
Emonds-Alt X,
Bellamy JF,
and
Advenier C.
Evidence for functional tachykinin NK1 receptors on human isolated small bronchi.
Am J Physiol Lung Cell Mol Physiol
271:
L763-L767,
1996
28.
Neoptolemos, JP,
Raraty M,
Finch M,
and
Sutton R.
Acute pancreatitis: the substantial human and financial costs.
Gut
42:
886-891,
1998
29.
Ogawa, K,
Nabe T,
Yamamura H,
and
Kohno S.
Nanomolar concentrations of neuropeptides induce histamine release from peritoneal mast cells of a substrain of Wistar rats.
Eur J Pharmacol
374:
285-291,
1999[ISI][Medline].
30.
Parlani, M,
Conte B,
Lopez G,
Majmone S,
Maggi CA,
Furio M,
and
Giachetti A.
The contractile effect of tachykinins on human prostatic urethra: involvement of NK-2 receptors.
Pharmacol Res
1:
21-22,
1990.
31.
Pierre, KJ,
Tung KK,
and
Nadj H.
A new enzymatic kinetic method for the determination of serum and urine amylase (Abstract).
Clin Chem
22:
1219,
1976[ISI].
32.
Pothoulakis, C,
Castagliuolo I,
Leeman SE,
Wang CC,
Li H,
Hoffman BJ,
and
Mezey E.
Substance P receptor expression in intestinal epithelium in Clostridium difficile toxin A enteritis in rats.
Am J Physiol Gastrointest Liver Physiol
275:
G68-G75,
1998
32a.
Quinlan, KL,
Song IS,
Bunnett NW,
Letran E,
Steinhoff M,
Harten B,
Olerud JE,
Armstrong CA,
Caughman SW,
and
Ansel JC.
Neuropeptide regulation of human dermal microvascular endothelial cell ICAM-1 expression and function.
Am J Physiol Cell Physiol
275:
C1580-C1590,
1998
33.
Regoli, D,
Boudon A,
and
Fauchere JL.
Receptors and antagonists for substance P and related peptides.
Pharmacol Rev
46:
551-599,
1994[ISI][Medline].
34.
Roch-Arveiller, M,
Regoli D,
Chanaud B,
Lenoir M,
Muntaner O,
Stralzko S,
and
Giroud JP.
Tachykinins: effects on motility and metabolism of rat polymorphonuclear leucocytes.
Pharmacology
33:
266-273,
1986[ISI][Medline].
35.
Schmidlin, F,
Dery O,
Bunnett NW,
and
Grady EF.
Heterologous regulation of trafficking and signaling of G protein-coupled receptors: -arrestin-dependent interactions between neurokinin receptors.
Proc Natl Acad Sci USA
99:
3324-3329,
2002
36.
Serra, MC,
Calzetti F,
Ceska M,
and
Cassatella MA.
Effect of substance P on superoxide anion and IL-8 production by human PMNL.
Immunology
82:
63-69,
1994[ISI][Medline].
37.
Sjodin, L,
Dahlen HG,
and
Gylfe E.
Calcium oscillations in guinea-pig pancreatic acinar cells exposed to carbachol, cholecystokinin and substance P.
J Physiol
444:
763-776,
1991[Abstract].
38.
Sjodin, L,
Viitanen E,
and
Gylfe E.
Rapid down-regulation of substance P binding to guinea-pig pancreatic acinar cells during homologous desensitization.
J Physiol
476:
69-77,
1994[Abstract].
39.
Song, SY,
Iwashita S,
Noguchi K,
and
Konishi S.
Inositol trisphosphate-linked calcium mobilization couples substance P receptors to conductance increase in a rat pancreatic acinar cell line.
Neurosci Lett
95:
143-148,
1988[ISI][Medline].
40.
Walsh, DA,
Mapp PI,
Wharton J,
Rutherford RA,
Kidd BL,
Revell PA,
Blake DR,
and
Polak JM.
Localisation and characterisation of substance P binding to human synovial tissue in rheumatoid arthritis.
Ann Rheum Dis
51:
313-317,
1992[Abstract].
41.
Yamamoto, H,
Morise K,
Kusugami K,
Furusawa A,
Konagaya T,
Nishio Y,
Kaneko H,
Uchida K,
Nagai H,
Mitsuma T,
and
Nagura H.
Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease.
J Gastroenterol
31:
525-532,
1996[ISI][Medline].
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