Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats

Background-Full recovery is always achieved after caerulein induced pancrea titis. Cyclosporin stimulates transforming growth factor beta (TGF-beta) an d may interfere with pancreatic regeneration. Aim-To investigate the effects of cyclosporin after caerulein induced pancr eatitis or after caerulein injury. Methods-Protocol A: rats received cyclosporin daily (20 mg/kg) and caerulei n pancreatitis was induced on days 2 and 8. Protocol B: six courses of caer ulein pancreatitis were induced at weekly intervals. Cyclosporin was admini stered on induction and the day before. Rats recovered for two weeks before being killed. Control groups received saline, cyclosporin, or caerulein al one. Results-Protocol A: plasma TGF-beta 1 and tissue collagenase rose after pan creatitis but decreased towards baseline values on day 15, matching a low c ollagen content. Morphology disclosed minimal inflammatory infiltration and some interstitial cells immunoreactive for smooth muscle alpha-actin (SMA) . TGF-beta 1 increased, and remained high in cyclosporin treated groups (cy closporin alone and cyclosporin plus caerulein). Rats treated with cyclospo rin and caerulein showed severe pancreatic weight reduction, abundant infla mmatory infiltrates, increased SMA immunoreactive interstitial cells, high collagen content, and delayed collagenase response. No SMA immunoreactive c ells were detected in normal rats. Cyclosporin alone also increased SMA imm unoreactive cells, despite the absence of inflammatory infiltration and fai rly conserved pancreatic structure. Protocol B: the combined pulse treatmen t induced appreciable collagen deposition and resulted in a smaller pancrea s than controls. Morphological examination showed atrophy, fibrosis, fibrob last proliferation, and mononuclear infiltrates. Conclusion-Cyclosporin greatly distorts pancreatic repair, transforming cae rulein induced pancreatitis into a fibrotic chronic-like disease. The mecha nism involves TGF-beta, myofibroblasts, and defective collagenase activatio n.