Background: Transforming growth factors-β (TGF-β) are implicated in pancreatic tissue repair, but their role in acute pancreatitis (AP) is not known. To determine whether endogenous TGF-β modulate the course of caerulein-induced AP, caerulein was administered to wild type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant-negative type II TGF-β receptor (Tβ RII).
Methods: After 7 hourly supra-maximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.
Results: The normal mouse pancreas was devoid of inflammatory cells, whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross edema, and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.
Conclusion: Our findings indicate that a functional TGF-β signaling pathway may be required for caerulein to induce AP and for the CCK receptor to induce acinar cell damage at high ligand concentrations, and support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce AP.
- TGF-beta receptor
- TGF-beta signaling
- acute pancreatitis
- amylase release
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