Pancreatic growth: interaction of exogenous cholecystokinin, a protease inhibitor, and a cholecystokinin receptor antagonist in mice.

Abstract

SUMMARY The effects on pancreatic growth and plasma CCK concentration of chronic feeding of camostate (400 mg/kg day for 10 days), a potent inhibitor of serine proteases including trypsin, were assessed in the mouse. For comparison, the trophic effects of chronic exogenous administration of CCK octapeptide (sc injection of 1 jug/kg day every eight hours for 10 days) were also studied. In addition, the effects of a proglumide-analogue CCK-receptor antagonist (CR1409) on the stimulatory actions of camostate feeding and chronic administration of exogenous CCK were studied. The effects of the combination of chronic camostate feeding and sc injections of CCK, the effects of acute camostate feeding, and the effects of the CCK-receptor antagonist given without camostate or CCK were also studied. The results show that chronic camostate feeding markedly increased CCK plasma concentrations eight-fold over control values, and that acute camostate feeding increased plasma CCK concentration to four fold of control values. Correspondingly, chronic camostate feeding markedly increased pancreatic weight, protein and DNA content. Exogenous CCK-8 also had qualitatively similar, but quantitatively less potent stimulatory effects. The combination of camostate and CCK-8 resulted in an additive stimulatory effect. The trophic actions of exogenous and endogenous CCK grossly increased chymotrypsinogen content, but left amylase content unaffected. The CCK-receptor antagonist CR1409 completely abolished the trophic effects of exogenous CCK and greatly inhibited the effects of chronic camostate feeding. The CCK antagonist decreased pancreatic weight, DNA and protein content compared to control values when given without any CCK or camostate. We conclude that the protease inhibitor camostate is a very strong release effector of CCK and exerts a powerful trophic effect on mouse pancreas which is probably mediated by CCK. Furthermore, physiological increases of CCK during feeding of regular chow appear to exert trophic effects on the exocrine pancreas.It is well established that exogenous cholecystokinin and cholecystokinin analogues, like caerulein, stimulate pancreatic growth in the experimental animal.' 2 It is also well known that feeding of trypsin inhibitors markedly stimulates pancreatic growth.3-4 It has been shown recently, that pancreaticobiliary diversion also stimulates pancreatic growth.5 -6 Both feeding of trypsin inhibitors and pancreaticobiliary diversion may stimulate pancreatic growth by the same mechanism of decreasing intraduodenal activity of pro-

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

“…Therefore, we fed wild-type or acinar-Ras mice camostat for 4 weeks. Camostat feeding increased size ( Figure 3A) but caused no histological changes in the pancreata of control mice ( Figure 3B), confirming previous reports (24). In contrast, acinar-Ras animals fed camostat developed severe chronic pancreatitis and formed PanINs ( Figure 3C).…”

“…Camostat is a common trypsin inhibitor that has been widely used experimentally to increase circulating endogenous CCK. Increased levels of CCK generated by camostat feeding have trophic actions in rodents leading to increased pancreatic mass (24). However, no pathologies have been reported after camostat feeding.…”

“…For example, camostat feeding, which increases endogenous serum levels of CCK through a well-described trypsin feedback mechanism, leads to acinar cell hypertrophy and hyperplasia in normal animals (21,24,42). In contrast, camostat feeding amplified Ras activity sufficiently to generate chronic inflammation and PanIN formation in animals bearing oncogenic Ras.…”

Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2

“…However, our results are supported by observations that trypsin inhibitors stimulate growth. For example, feeding the trypsin inhibitor camostate stimulates pancreatic growth, possibly by inhibition of luminal trypsin and consequent release of cholecystokinin [29]. Pancreatic secretory trypsin inhibitor directly stimulates growth of the pancreasderived AR4-2J cell line [30].…”

Regulation of Normal and Adaptive Pancreatic Growth

“…Because of the short half-life of CCK in vivo, CCK or its analogue caerulein have been given as 2 or 3 subcutaneous injections per day or by continuous infusion. Studies in rats mice and hamsters all show an increase in pancreatic size of 30-50% (1,34,101,110,124,136). Secretin administration potentiates the increase in response to CCK in some but not all studies (51,97,98,136).…”