CFTR delection ameliorates cerulein acute pancreatitis in mice

Abstract

PURPOSE: Idiopathic chronic pancreatitis is strongly associated with compound heterozygous CF gene mutations, or non-cla~acal CF, but subjects with classic CF, specifically' homozygous CF gene mutations and sufficiency, rarely (0.5%) develop acute pancreatitis (AP) (Pancreas 22:395, 2001). CFTR (-/-) mice have been shown to have a mild phenotype similar to early human CF but susceptibility to AP has been incompletely characterized. We investigated whether CFTR (-/-) mine exhibited an altered susceptibility to AP and how this correlated with in vivo secretion. METHODS: A colony of UNC CFTR (+/) exon 10 knockout mice was bred on a C57BL/6 background and oflspnng were fed Peptamen fulluwnig weaning. In vivo AP was induced by hourly ceralein rejections (50 ug/kg, lP). Mice were sacrificed 30 minutes after 1 injection or i hour after 12 injections. An in vivo CCK model of pancreatic secretion was performed in anesthetized mice in which the duct was cannulated and juice collected every 15 minutes. Proteni output (ug/min), expressed as % basal, was used as a marker of secretion, in response to 160 pmol/kg/h CCK. RESULTS: CFTR (4-) mice exhibited a blunted biochemical response to ceruleni AP. Basal trypsin activity and serum amylase and lipase values showed no difference between CFTR ( + / + ) and CFTR (-/-) groups. 30 minutes after ceralein treatment, trypsin activity (ng/mg protein) increased by 5 5 (+Al .3) in CFTR ( + / + ) mice and 2.6 (+ / -09 ) in CFTR (-/-) mice, and serum lipase (U/L) nicreased by 225 (+/-28) in CFTR ( + / + ) mice and 128 (+/-16) in CFTR (4-) mice. At 12 hours trypain activity (ng/mg protein) increased by 0.82 (+/'-0.19) in CFTR ( + / + ) mice and 0.42 (4-/0.15) in CFTR (-/-) mice, and serum amylase (KU/I_) increased by143 (+/-18) in CFTR ( + / + ) mice and only 52 (+ / 13) in CFTR (-A) mice. Further studies assessed alterations in pancreatm secretion in vivo. In normal C57BL/6 mice, CCK induced a dose dependent response, maximal at 160 pmol~g/h. No difference in basal protein output was observed between CFTR (4-) and ( + / + ) mice, however protein secretion was reduced 51% in CFTR (4-) mice compared to controls in ~vsponse to maximal CCK stimulation, CONCLUSION: CFTR (-A) mice exhibit a blunted biochemical response to in vivo cerulein AP and have z~duced in vivo secretion to CCK stimulation. These findnigs may lead to an explanatmn for why humans with classic CF and sufficiency rarely develop AP.