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Effect of sensory nerves and CGRP on the development of caerulein-induced pancreatitis and pancreatic recovery

100%

Warzecha Z., Dembinski A., Ceranowicz P., Stachura J., Tomaszewska R., Konturek S. J.

Journal of Physiology and Pharmacology

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2001

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tom 52

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nr 4,1

The function of primary sensory neurons is to receive and transmit information from external environment and these neurons are able to release neuromediators from the activated peripheral endings. The aim of this study was to determine the influence of sensory nerves and administration of their mediator — calcitonin gene related peptide (CGRP) on the course of acute pancreatitis (AP). Ablation of sensory nerves was performed by neurotoxic dose of capsaicin (100 mg/kg). Single or repeated episodes of AP were induced by caerulein infusion (10 µg/kg/h for 5 h). Five repeated AP were performed once a week. Capsaicin at the dose which stimulates sensory nerves (0.5 mg/kg/dose) or CGRP (10 µg/kg/dose) was administrated before and during or after single induction of AP, as well as, after each induction of repeated AP. Rats were killed at the time 0, 3 or 9 h after single induction of AP or two weeks after last induction of repeated AP. Ablation of sensory nerves aggravated pancreatic damage in caerulein-induced AP. Treatment with stimulatory doses of capsaicin or CGRP before and during single induction of AP attenuated the pancreatic damage in morphological examination. This effect was also manifested by partial reversion of AP evoked drop in DNA synthesis and pancreatic blood flow (PBF). Administration of CGRP after single AP induction aggravated histologically manifested pancreatic damage. The further decrease in PBF and DNA synthesis was also observed. Animals with five episodes of AP showed almost full pancreatic recovery two weeks after last induction of AP concerning all parameters tested. In stimulatory doses of capsaicin treated rats, we observed the decrease in pancreatic amylase and fecal chymotrypsin activity, as well as, the drop in DNA synthesis. Similar but less pronounced effects were observed after treatment with CGRP. We conclude that effect of sensory nerves and CGRP on AP is two-phase and time dependent. Stimulation of sensory nerves or the administration of CGRP during development of AP exhibits protective effects against pancreatic damage induced by caerulein overstimulation. After induction of AP, persistent activity of sensory nerves and presence of CGRP aggravate pancreatic damage and lead to functional insufficiency typical for chronic pancreatitis.

2

IGF-1 stimulates production of interleukin-10 and inhibits development of caerulein-induced pancreatitis

100%

Warzecha Z., Dembinski A., Ceranowicz P., Konturek S. J., Tomaszewska R., Stachura J., Konturek P. C.

Journal of Physiology and Pharmacology

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2003

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tom 54

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nr 4

Insulin-like growth factor-1 (IGF-1) and other growth factors overexpression was reported in acute pancreatitis. Previous studies have shown the protective effect of epidermal growth factor (EGF), Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor (FGF) in the course of experimental acute pancreatitis. The aim of our studies was to determine the effect of IGF-1 administration on the development of caerulein-induced pancreatitis. Methods: Acute pancreatitis was induced by infusion of caerulein (10 µg/kg/h) for 5 h. IGF-1 was administrated twice at the doses: 2, 10, 50, or 100 µg/kg s.c. Results: Administration of IGF-1 without induction of pancreatitis increased plasma interleukin-10 (IL-10). Infusion of caerulein led to development of acute edematous pancreatitis. Histological examination showed pancreatic edema, leukocyte infiltration and vacuolization of acinar cells. Also, acute pancreatitis led to an increase in plasma lipase and interleukin 1ß (IL-1ß) level, whereas pancreatic DNA synthesis and pancreatic blood flow were decreased. Treatment with IGF-1, during induction of pancreatitis, increased plasma IL-10 and attenuated the pancreatic damage, what was manifested by histological improvement of pancreatic integrity, the partial reversion of the drop in pancreatic DNA synthesis and pancreatic blood flow, and the reduction in pancreatitis-evoked increase in plasma amylase, lipase and IL-1ß level. Protective effect of IGF-1 administration was dose-dependent. Similar strong protective effect was observed after IGF-1 at the dose 2 x 50 and 2 x 100 µg/kg. Conclusions: (1) Administration of IGF-1 attenuates pancreatic damage in caerulein-induced pancreatitis; (2) This effect is related, at least in part, to the increase in IL-10 production, the reduction in liberation of IL-1ß and the improvement of pancreatic blood flow.

3

Missorting of cathepsin B into the secretory compartment of CI-MPR/IGFII-deficient mice does not induce spontaneous trypsinogen activation but leads to enhanced trypsin activity during experimental pancreatitis - without affecting disease severity

84%

Meister T., Niehues R., Hahn D., Domschke W., Sendler M., Lerch M. M., Schnekenburger J.

Journal of Physiology and Pharmacology

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2010

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tom 61

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nr 5

4

Ghrelin and melatonin in the regulation of pancreatic exocrine secretion and maintaining of integrity

84%

Jaworek J.

Journal of Physiology and Pharmacology. Supplement

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2006

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tom 57

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nr 5

83-96

Ghrelin and melatonin are produced in the central nervous system and in the gastrointestinal tissues; ghrelin in the stomach, and melatonin - in the liver and in the intestine. Both ghrelin and melatonin have been reported to protect the gastric mucosa against acute lesions and to influence gastrointestinal motility and secretions, however the physiological significance of these peptides in the gastrointestinal tissues remains unknown. In spite of the presence of ghrelin and melatonin receptors in the pancreatic tissue little is known about the role of these peptides in the pancreas. It is very likely that both ghrelin and melatonin, which are released from the gastrointestinal tract in relation to food ingestion, could be implicated in the postprandial stimulation of pancreatic enzyme secretion though the activation of cholinergic entero-pancreatic reflex and CCK release. Our experimental studies have shown that exogenous melatonin, as well as this produced endogenously from its precursor; L-tryptophan, strongly stimulates pancreatic amylase secretion when given intraperitoneally, or into the gut lumen. Intraduodenal administration of ghrelin also increases pancreatic enzyme secretion. This was accompanied by significant increases of CCK plasma levels. Above pancreatostimulatory effects of luminal administration of melatonin or ghrelin were completely reversed by bilateral vagotomy, capsaicin deactivation of sensory nerves or pretreatment of the rats with CCK1 receptor antagonist; tarazepide. Our previous findings have revealed that melatonin, as well as its precursor; L-tryptophan, effectively protects the pancreas against the damage induced by caerulein overstimulation. The beneficial effects of melatonin and L-tryptophan on the pancreas have been related to the ability of melatonin to scavenge the radical oxygen species (ROS), to activate antioxidative enzymes and to modulate the cytokine production. It has been previously shown that systemic application of ghrelin attenuated acute pancreatitis activating the immune defense mechanisms. Our recent data demonstrate that ghrelin is able to prevent pancreatic inflammatory damage though the activation of central nervous mechanisms leading to the improvement of antioxidative properties of pancreatic tissue. The results of experimental studies indicated that melatonin and ghrelin could take a part in the protection of pancreatic tissue against the damage under physiological conditions.

5

Role of endogenous melatonin and its MT2 receptor in the modulation of caerulein-induced pancreatitis in the rat

84%

Jaworek J., Konturek S. J., Leja-Szpak A., Nawrot K., Bonior J., Tomaszewska R., Stachura J., Pawlik W. W.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 4,2

The present study investigated the involvement of endogenous melatonin in the prevention of pancreatic damage provoked by caerulein-induced pancreatitis (CIP) by using the luzindole, the antagonist of melatonin MT2 receptors. CIP was produced by subcutaneous infusion of caerulein to conscious rats (25 µg/kg). Luzindole (1, 2 or 4 mg/kg) was given as an intraperitoneal bolus injection 30 min prior to the start of CIP. Lipid peroxidation products, malondialdehyde (MDA) and 4- hydroxynonenal (4-HNE) were measured in the pancreas by LPO-584 commercial kit. CIP was confirmed by histological examination and manifested by significant increases of plasma activities of amylase, lipase and tumor necrosis factor a (TNFalpha) (by 500%, 1000% and 600%, respectively) comparing to the control values. This was accompanied by a 40% limitation in pancreatic blood flow (PBF) and by 200% increase of MDA+4-HNE in the pancreas of CIP rats. Administration of luzindole to the CIP rats reduced PBF, aggravated the histological manifestations of pancreatitis, resulted in the significant augmentation of pancreatic MDA + 4-HNE content, and produced the marked increases of plasma levels of lipase, amylase and TNFalpha, comparing to the values observes in the rats with CIP alone. These results suggest that endogenous melatonin through its receptor MT2 plays an important role in the attenuation of pancreatic damage produced by overstimulation with caerulein.

6

Leptin is involved in the protective effect of lipopolysaccharide [LPS] in the caerulein-induced pancreatitis

84%

Bonior J., Jaworek J., Leja-Szpak A., Nawrot K., Kot M., Bielanski W., Sendur R., Pawlik W. W., Konturek S. J.

Journal of Physiology and Pharmacology. Supplement

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2001

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tom 52

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nr 2

7

Pretreatment with obestatin inhibits the development of cerulein-induced pancreatitis

67%

Ceranowicz P., Warzecha Z., Dembinski A., Cieszkowski J., Dembinski M., Sendur R., Kusnierz-Cabala B., Tomaszewska R., Kuwahara A., Kato I.

Journal of Physiology and Pharmacology

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2009

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tom 60

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nr 3

95-101

Obestatin is a peptide derived from the proghrelin, a common prohormone for ghrelin and obestatin. Obestatin, like the ghrelin has been originally extracted from rat stomach, and the stomach seems to be a major source of circulating obestatin. Previous studies have shown that administration of ghrelin exhibits protective effect in the pancreas, inhibiting the development of acute pancreatitis. Recent study has shown that obestatin promotes survival of ß-cells and pancreatic islets. Aim of the present study was to investigate the influence of obestatin administration on the development of cerulein-induced pancreatitis. Studies were performed on male Wistar rats. Acute pancreatitis was induced by cerulein given intraperitoneally 5 times at a dose of 50 µg/kg/dose with 1-h intervals. Obestatin was injected twice intraperitoneally at the dose of 4, 8 or 16 nmol/kg/dose. In control saline-treated rats, obestatin was without effect on pancreatic morphology, serum activity of pancreatic enzymes, serum level of pro-inflammatory interleukin-1b or pancreatic cells proliferation. In animals with induction of acute pancreatitis, morphological examination showed that administration of obestatin decreased pancreatic leukocyte infiltration and vacuolization of acinar cells. These effects were accompanied by reduction in the pancreatitis-evoked increase in serum level of pancreatic digestive enzymes, lipase amylase and poly-C ribonuclease. Obestatin administered at the highest dose of 16 nmo/kg/dose reduced serum activity of these enzymes by 33, 42 and 44%, respectively. Also serum concentration of pro-inflammatory interleukin-1ß was decreased by obestatin in rats with acute pancreatitis; whereas the pancreatitis-evoked decrease in pancreatic blood flow and pancreatic DNA synthesis was partially reversed. Administration of obestatin reduces the severity of cerulein-induced acute pancreatitis. This effect is related, at least in part, to the improvement of pancreatic blood flow and reduction in pro-inflammatory interleukin-1ß release.

8

Endotoxemia in the infant rats modulates HSP60 protein level in the pancreatic acinar cells

67%

Bonior J., Jaworek J., Kot M., Konturek S. J., Pawlik W. W.

Journal of Physiology and Pharmacology. Supplement

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2007

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tom 58

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nr 3

189-198

9

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The influence of polyamines synthesis inhibition on pancreas regeneration and phospholipase D activity after acute caerulein induced pancreatitis in rats. Biochemical and ultrastructural study

67%

Jurkowska G., Rydzewska G., Andrzejewska A.

Journal of Physiology and Pharmacology

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1997

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tom 48

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nr 4

10

Endotoxemia in newborn rats attenuates acute pancreatitis at adult age

67%

Jaworek J., Konturek S. J., Macko M., Kot M., Szklarczyk J., Leja-Szpak A., Nawrot-Porabka K., Stachura J., Tomaszewska R., Siwicki A., Pawlik W. W.

Journal of Physiology and Pharmacology

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2007

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tom 58

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nr 1

Bacterial endotoxin (lipopolysaccharide, LPS), at high concentration is responsible for sepsis, and neonatal mortality, however low concentration of LPS protected the pancreas against acute damage. The aim of this study was to investigate the effect of exposition of suckling rats to LPS on the course of acute pancreatitis at adult age. Suckling rat (30-40g) received intraperitoneal (i.p.) injection of saline (control) or LPS from Escherichia coli or Salmonella typhi (5, 10 or 15 mg/kg-day ) during 5 consecutive days. Two months later these rats have been subjected to i.p. caerulein infusion (25 µg/kg) to produce caerulein-induced pancreatitis (CIP). The following parameters were tested: pancreatic weight and morphology, plasma amylase and lipase activities, interleukin 1ß (IL-1 ß), interleukin 6 (IL-6), and interleukin 10 (IL-10) plasma concentrations. Pancreatic concentration of superoxide dysmutase (SOD) and lipid peroxidation products; malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) have been also measured. Caerulein infusion produced CIP in all animals tested, that was confirmed by histological examination. In the rats, which have been subjected in the neonatal period of life to LPS at doses 10 or 15 mg/kg-day x 5 days, all manifestations of CIP have been reduced. In these animals acute inflammatory infiltration of pancreatic tissue and pancreatic cell vacuolization have been significantly diminished. Also pancreatic weight, plasma lipase and a-amylase activities, as well as plasma concentrations of IL-1ß and IL-6 have been markedly decreased, whereas plasma anti-inflammatory IL-10 concentration was significantly increased in these animals as compared to the control rats, subjected in the infancy to saline injection instead of LPS. Caerulein-induced fall in pancreatic SOD concentration was reversed and accompanied by significant reduction of MDA + 4 HNE in the pancreatic tissue. The effects of LPS derived from E.coli or S.typhi were similar. Pretreatment of suckling rats with LPS at dose of 10 mg/kg-day x 5 days resulted in the most prominent attenuation of acute pancreatitis at adult age, whereas LPS at dose of 5 mg/kg-day x 5 days given to the neonatal rats failed to affect significantly acute pancreatitis induced in these animals 2 months later. We conclude that: 1/ Prolonged expositon of suckling rats to bacterial endotoxin attenuated acute pancreatitis induced in these animals at adult age. 2/ This effect could be related to the increased concentration of antioxidative enzyme SOD in the pancreatic tissue and to the modulation of cytokines production in these animals.

11

Protective effect of calcitonin gene-related peptide against caerulein-induced pancreatitis in rats

59%

Warzecha Z., Dembinski A., Ceranowicz P., Konturek P. C., Stachura J., Konturek S. J., Niemiec J.

Journal of Physiology and Pharmacology

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1997

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tom 48

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nr 4

Ograniczanie wyników

Effect of sensory nerves and CGRP on the development of caerulein-induced pancreatitis and pancreatic recovery

IGF-1 stimulates production of interleukin-10 and inhibits development of caerulein-induced pancreatitis

Missorting of cathepsin B into the secretory compartment of CI-MPR/IGFII-deficient mice does not induce spontaneous trypsinogen activation but leads to enhanced trypsin activity during experimental pancreatitis - without affecting disease severity

Ghrelin and melatonin in the regulation of pancreatic exocrine secretion and maintaining of integrity

Role of endogenous melatonin and its MT2 receptor in the modulation of caerulein-induced pancreatitis in the rat

Leptin is involved in the protective effect of lipopolysaccharide [LPS] in the caerulein-induced pancreatitis

Pretreatment with obestatin inhibits the development of cerulein-induced pancreatitis

Endotoxemia in the infant rats modulates HSP60 protein level in the pancreatic acinar cells

The influence of polyamines synthesis inhibition on pancreas regeneration and phospholipase D activity after acute caerulein induced pancreatitis in rats. Biochemical and ultrastructural study

Endotoxemia in newborn rats attenuates acute pancreatitis at adult age

Protective effect of calcitonin gene-related peptide against caerulein-induced pancreatitis in rats