Anti-inflammatory actions of perfluorooctanoic acid and peroxisome proliferator-activated receptors (PPAR) alpha and gamma in experimental acute pancreatitis.

Perfluorooctanoic acid (PFOA) and agonists of peroxisome proliferator-activated receptors (PPAR) alpha and gamma were investigated for potential anti-inflammatory effects in cerulein-induced acute pancreatitis in rats. PFOA significantly reduced both leukocyte accumulation and prostanoid synthesis. The PPAR-alpha agonist clofibrate had no effect on leukocyte activation but significantly inhibited prostanoid synthesis whereas the PPAR-gamma agonist rosiglitazone significantly reduced leukocyte activation but did not affect synthesis of prostaglandins in the pancreas. Neither PFOA, nor clofibrate or rosiglitazone had an effect on the formation of the inflammatory edema or elevated levels of lipase activity in the blood serum. In summary, PFOA attenuates the accumulation of activated leukocytes and reduces the synthesis of prostanoids in the pancreas during cerulein-induced acute pancreatitis. An activation of PPAR-alpha causes inhibition of prostanoid synthesis while activation of PPAR-gamma inhibits leukocyte activation.

Haemodynamic and exocrine effects of caerulein at submaximal and supramaximal levels on the rat pancreas: role of cholecystokinin receptor subtypes.

BACKGROUND: We have investigated the involvement of cholecystokinin (CCK) receptor subtypes in haemodynamic changes in the pancreas of anaesthetized rats during submaximal and supramaximal stimulation with the CCK analogue, caerulein. METHODS: For submaximal stimulation, caerulein (0.4 nmol/kg/h) was infused intravenously, while acute pancreatitis was induced by intraperitoneal injections of high doses of caerulein (3 x 25 nmol/kg). Pancreatic blood flow was measured by hydrogen clearance. RESULTS: Low caerulein doses increased pancreatic blood flow by 26 +/- 8% and vascular conductance by 24 +/- 4%. This effect was mimicked by the CCK2 agonist gastrin-17. All effects were abolished by a CCK2 antagonist while a CCK1 antagonist remained inactive. Conversely, amylase output by caerulein was abolished by CCK1 receptor blockade, but not by inhibition of CCK2 receptors. During caerulein-induced pancreatitis, vascular conductance increased by 109 +/- 26% and remained elevated throughout the experiment; vascular flow initially increased by 62 +/- 27% and then returned to baseline. The vascular effects were prevented by a CCK2 receptor antagonist, while the induction of pancreatitis was due to CCK1 receptor stimulation. CONCLUSIONS: Caerulein increases pancreatic vascular flow via activation of CCK2 receptors. This effect occurs both at submaximal and at supramaximal levels of exocrine stimulation.

Mechanism of kinin release during experimental acute pancreatitis in rats: evidence for pro- as well as anti-inflammatory roles of oedema formation.

1 Kinin B(2) receptor antagonists or tissue kallikrein (t-KK) inhibitors prevent oedema formation and associated sequelae in caerulein-induced pancreatitis in the rat. We have now further investigated the mechanism of kinin generation in the pancreas. 2 Kinins were elevated in the pancreatic tissue already before oedema formation became manifest. Peak values (421+/-59 pmol g(-1) dry wt) were reached at 45 min and remained elevated for at least 2 h; a second increase was observed at 24 h. Pretreatment with the B(2) receptor antagonist icatibant abolished kinin formation, while post-treatment was ineffective. 3 Total kininogen levels were very low in the pancreas of controls, but increased 75-fold during acute pancreatitis. This increase was absent in rats that were pretreated with icatibant. 4 During pancreatitis, t-KK-like and plasma kallikrein (p-KK)-like activity in the pancreas, as well as trypsinogen activation peptide (TAP) increased significantly. Icatibant pretreatment further augmented t-KK about 100-fold, while p-KK was significantly attenuated; TAP levels remained unaffected. 5 Endogenous protease inhibitors (alpha(1)-antitrypsin, alpha(2)-macroglobulin) were low in normal tissues, but increased 45- and four-fold, respectively, during pancreatitis. This increase was abolished when oedema formation was prevented by icatibant. 6 In summary, oedema formation is initiated by t-KK; the ensuing plasma protein extravasation supplies further kininogen and active p-KK to the tissue. Concomitantly, endogenous protease inhibitors in the oedema fluid inhibit up to 99% of active t-KK. Our data thus suggest a complex interaction between kinin action and kinin generation involving positive and negative feedback actions of the inflammatory oedema.

Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats.

In order to investigate the mechanism of kinin release leading to vascular symptoms in acute interstitial-oedematous pancreatitis, the novel, selective inhibitors of tissue kallikrein, (2S,2'R)-2-(2'-amino-3'-(4'-chlorophenyl)propanoylamino)-N-(3-guanidinopropyl)-3-(1-naphthyl)propanoamide (FE999024, CH-2856), and of plasma kallikrein, (2'S,2"R)-4-(2'-(2"(carboxymethylamino)-3"-cyclohexyl-propanoylamino)-3'-phenyl-propanoylamino)piperidine-1-carboxamidin (FE999026, CH-4215), were used in experimental caerulein-induced pancreatitis in rats. Oedema formation and plasma protein extravasation during the 2 h infusion of caerulein were inhibited in a dose-dependent manner by i.p. pretreatment with FE999024 (7-60 micromol kg(-1)) while FE999026 had no effect at the same doses. Haemoconcentration and hypovolaemia associated with the pancreatic oedema formation during pancreatitis were significantly attenuated by FE999024 at a dose of 20 micro mol kg(-1). The reduction in circulating plasma volume was not affected by FE999026. Accumulation of amylase and lipase in the pancreas was dose-dependently reduced by FE999024 while enzyme activities in the blood serum were increased by FE999024 at 60 micromol kg(-1) indicating improved enzyme removal from the tissue. Enzyme activities in the tissue and in the blood remained unaffected by FE999026. FE999024 (20 micromol kg(-1)) largely inhibited increased tissue kallikrein-like activity in the pancreas during acute pancreatitis and also strongly attenuated influx of plasma kallikrein into the tissue. FE999026 (20 micromol kg(-1)) significantly inhibited plasma kallikrein-like activity in the pancreas but had no effect on tissue kallikrein-like activity. In conclusion, vascular kinin-mediated symptoms observed during oedematous pancreatitis in the rat are caused by the action of tissue kallikrein in the pancreas whereas an involvement of plasma kallikrein seems to be unlikely.

Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats.

The cutaneous neurosensory system is suggested to be involved in the pathophysiology of pruritus and skin diseases such as psoriasis. We investigated if repeated subinflammatory doses of ultraviolet B (UVB) irradiation similar to those used to treat pruritus or psoriasis would affect the cutaneous neurosensory system. Sprague-Dawley rats were irradiated thrice weekly for 2-4 weeks with subinflammatory doses of UVB. Three days after the last UVB exposure: (i), the skin contents of substance P (SP), calcitonin gene-related peptide (CGRP), and nerve growth factor (NGF) were quantified; (ii), the skin nerve fiber density was observed; and (iii), the effect of UVB on mustard oil-induced neurogenic inflammation was determined. UV exposure significantly increased SP and CGRP content and mustard oil-induced neurogenic inflammation in UV-irradiated but not non-irradiated skin; however, it did not affect cutaneous NGF content or overall nerve fiber density. These data suggest that repeated subinflammatory UVB irradiation locally increases the content of cutaneous SP and CGRP by an increase of neuropeptide content of nerve fibers rather than by an increase of overall nerve fiber density.