Muratore Christopher S, Harty Mark W, Papa Elaine F, Tracy Thomas F
Department of Surgery, Division of Pediatric Surgery and Surgical Research, Hasbro Children's Hospital and Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA.
J Surg Res. 2009 Oct;156(2):231-9. doi: 10.1016/j.jss.2009.04.016. Epub 2009 May 14.
Biliary atresia is characterized by extrahepatic bile duct obliteration along with persistent intrahepatic portal inflammation. Steroids are standard in the treatment of cholangitis following the Kasai portoenterostomy, and were advocated for continued suppression of the ongoing immunologic attack against intrahepatic ducts. Recent reports, however, have failed to demonstrate an improved patient outcome or difference in the need for liver transplant in postoperative patients treated with a variety of steroid regimes compared with historic controls. In the wake of progressive liver disease despite biliary decompression, steroids are hypothesized to suppress inflammation and promote bile flow without any supporting data regarding their effect on the emerging cellular and molecular mechanisms of liver repair. We have previously shown in a reversible model of cholestatic injury that repair is mediated by macrophages, neutrophils, and specific matrix metalloproteinase activity (MMP8); we questioned whether steroids would alter these intrinsic mechanisms.
Rats underwent biliary ductal suspension for 7 d, followed by decompression. Rats were treated with IV dexamethasone or saline at the time of decompression. Liver tissue obtained at the time of decompression or after 2 d of repair was processed for morphometric analysis, immunohistochemistry, and quantitative RT-PCR.
There was a dramatic effect of dexamethasone on the inflammatory component with the initiation of repair. Immunohistochemistry revealed a reduction of both ED1+ hepatic macrophages and ED2+Kupffer cells in repair compared with saline controls. Dexamethasone treatment also reduced infiltrating neutrophils by day 2. TNF-alpha expression, increased during injury in both saline and dexamethasone groups, was markedly reduced by dexamethasone during repair (day 2) whereas IL-6, IL-10, and CINC-1 remained unchanged compared with saline controls. Dexamethasone reduced both MMP8 and TIMP1 expression by day 2, whereas MMP9, 13, and 14 were unchanged compared with sham controls. Despite substantial cellular and molecular changes during repair, collagen resorption was the same in both groups
Dexamethasone has clear effects on both the hepatic macrophage populations and infiltrating neutrophils following biliary decompression. Altered MMP and TIMP gene expression might suggest that steroids have the potential to modify matrix metabolism during repair. Nevertheless, successful resorption of collagen fibrosis proceeded presumably through other MMP activating mechanisms. We conclude that steroids do not impede the rapid intrinsic repair mechanisms of matrix degradation required for successful repair.
胆道闭锁的特征是肝外胆管闭塞以及肝内门静脉持续炎症。类固醇是Kasai肝门空肠吻合术后胆管炎治疗的标准药物，并且被提倡用于持续抑制针对肝内胆管的免疫攻击。然而，最近的报告未能证明与历史对照相比，接受各种类固醇治疗方案的术后患者的预后有所改善或肝移植需求存在差异。尽管进行了胆道减压，但在进行性肝病的情况下，类固醇被假定为可抑制炎症并促进胆汁流动，但关于其对肝脏修复的新兴细胞和分子机制的影响尚无支持数据。我们之前在胆汁淤积性损伤的可逆模型中表明，修复是由巨噬细胞、中性粒细胞和特定的基质金属蛋白酶活性（MMP8）介导的；我们质疑类固醇是否会改变这些内在机制。
大鼠进行胆管悬吊7天，然后进行减压。在减压时，大鼠接受静脉注射地塞米松或生理盐水治疗。在减压时或修复2天后获取肝脏组织，进行形态计量分析、免疫组织化学和定量RT-PCR。
地塞米松对修复开始时的炎症成分有显著影响。免疫组织化学显示，与生理盐水对照组相比，修复过程中ED1+肝巨噬细胞和ED2+库普弗细胞均减少。地塞米松治疗在第2天时也减少了浸润的中性粒细胞。在生理盐水组和地塞米松组中，损伤期间均升高的TNF-α表达在修复（第2天）时被地塞米松显著降低，而与生理盐水对照组相比，IL-6、IL-10和CINC-1保持不变。地塞米松在第2天时降低了MMP8和TIMP1的表达，而与假手术对照组相比，MMP9、13和14没有变化。尽管修复过程中存在大量细胞和分子变化，但两组的胶原吸收情况相同。
地塞米松对胆道减压后的肝巨噬细胞群体和浸润的中性粒细胞均有明显影响。MMP和TIMP基因表达的改变可能表明类固醇有潜力在修复过程中改变基质代谢。然而，胶原纤维化的成功吸收可能是通过其他MMP激活机制进行的。我们得出结论，类固醇不会阻碍成功修复所需的基质降解的快速内在修复机制。
