环孢素诱导大鼠肌成纤维细胞增殖、纤维化及胰腺修复缺陷
Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats.
作者信息
Vaquero E, Molero X, Tian X, Salas A, Malagelada J R
机构信息
Digestive System Research Unit, Hospital General Universitari Vall d'Hebron, Barcelona, Spain.
出版信息
Gut. 1999 Aug;45(2):269-77. doi: 10.1136/gut.45.2.269.
BACKGROUND
Full recovery is always achieved after caerulein induced pancreatitis. Cyclosporin stimulates transforming growth factor beta (TGF-beta) and may interfere with pancreatic regeneration.
AIM
To investigate the effects of cyclosporin after caerulein induced pancreatitis or after caerulein injury.
METHODS
Protocol A: rats received cyclosporin daily (20 mg/kg) and caerulein pancreatitis was induced on days 2 and 8. Protocol B: six courses of caerulein pancreatitis were induced at weekly intervals. Cyclosporin was administered on induction and the day before. Rats recovered for two weeks before being killed. Control groups received saline, cyclosporin, or caerulein alone.
RESULTS
Protocol A: plasma TGF-beta1 and tissue collagenase rose after pancreatitis but decreased towards baseline values on day 15, matching a low collagen content. Morphology disclosed minimal inflammatory infiltration and some interstitial cells immunoreactive for smooth muscle alpha-actin (SMA). TGF-beta1 increased, and remained high in cyclosporin treated groups (cyclosporin alone and cyclosporin plus caerulein). Rats treated with cyclosporin and caerulein showed severe pancreatic weight reduction, abundant inflammatory infiltrates, increased SMA immunoreactive interstitial cells, high collagen content, and delayed collagenase response. No SMA immunoreactive cells were detected in normal rats. Cyclosporin alone also increased SMA immunoreactive cells, despite the absence of inflammatory infiltration and fairly conserved pancreatic structure. Protocol B: the combined pulse treatment induced appreciable collagen deposition and resulted in a smaller pancreas than controls. Morphological examination showed atrophy, fibrosis, fibroblast proliferation, and mononuclear infiltrates.
CONCLUSION
Cyclosporin greatly distorts pancreatic repair, transforming caerulein induced pancreatitis into a fibrotic chronic-like disease. The mechanism involves TGF-beta, myofibroblasts, and defective collagenase activation.
背景
蛙皮素诱导的胰腺炎后总能实现完全恢复。环孢素刺激转化生长因子β（TGF-β），可能会干扰胰腺再生。
目的
研究环孢素在蛙皮素诱导的胰腺炎后或蛙皮素损伤后的作用。
方法
方案A：大鼠每天接受环孢素（20mg/kg），在第2天和第8天诱导蛙皮素性胰腺炎。方案B：每周诱导6个疗程的蛙皮素性胰腺炎。在诱导时和前一天给予环孢素。大鼠恢复两周后处死。对照组分别单独接受生理盐水、环孢素或蛙皮素。
结果
方案A：胰腺炎后血浆TGF-β1和组织胶原酶升高，但在第15天降至基线值，与低胶原含量相符。形态学显示炎症浸润极少，一些间质细胞对平滑肌α-肌动蛋白（SMA）呈免疫反应。TGF-β1升高，在环孢素治疗组（单独环孢素和环孢素加蛙皮素）中保持高水平。接受环孢素和蛙皮素治疗的大鼠胰腺重量严重减轻，炎症浸润丰富，SMA免疫反应性间质细胞增加，胶原含量高，胶原酶反应延迟。正常大鼠未检测到SMA免疫反应性细胞。单独使用环孢素也增加了SMA免疫反应性细胞，尽管没有炎症浸润且胰腺结构相当保留。方案B：联合脉冲治疗导致明显的胶原沉积，胰腺比对照组小。形态学检查显示萎缩、纤维化、成纤维细胞增殖和单核浸润。
结论
环孢素极大地扭曲了胰腺修复，将蛙皮素诱导的胰腺炎转变为纤维化的慢性样疾病。其机制涉及TGF-β、肌成纤维细胞和有缺陷的胶原酶激活。
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