Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, Pernambuco, Brazil.
Cytotherapy. 2012 Mar;14(3):339-49. doi: 10.3109/14653249.2011.637668. Epub 2011 Dec 13.
Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury, associated with persistent inflammation. Galectin-3 is an important regulator of fibrosis that links chronic inflammation to fibrogenesis. We investigated the role of bone marrow cell (BMC) transplantation in chronic inflammation and hepatic fibrosis.
Liver cirrhosis was induced by administration of carbon tetrachloride and ethanol to wild-type C57BL/6 or bone marrow chimeric mice. Bone marrow chimeras were generated by lethal irradiation and transplantation with BMC obtained from green fluorescent protein (GFP(+) )donors. Wild-type cirrhotic mice were transplanted with BMC without irradiation. Livers from chimeras and cirrhotic transplanted mice were obtained for evaluation of inflammation, fibrosis and regulatory factors [galectin-3, matrix metallopeptidase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β].
The development of cirrhosis was associated with increased expression of galectin-3 by F4/80(+) cells and intense migration of BMC to the liver. Furthermore, when transplanted after the establishment of cirrhosis, BMC also migrated to the liver and localized within the fibrous septa. Two months after BMC therapy, cirrhotic mice had a significant reduction in liver fibrosis and expression of type I collagen. We did not find any difference in levels of TGF-β, TIMP-1 and MMP-9 between saline and BMC groups. However, the numbers of inflammatory cells, phagocytes and galectin-3(+) cells were markedly lower in the livers of cirrhotic mice treated with BMC.
Our results demonstrate an important role for BMC in the regulation of liver fibrosis and that transplantation of BMC can accelerate fibrosis regression through modulatory mechanisms.
肝硬化是由不同的损伤机制引起的终末期肝病，与持续的炎症有关。半乳糖凝集素-3是纤维化的重要调节因子，它将慢性炎症与纤维生成联系起来。我们研究了骨髓细胞（BMC）移植在慢性炎症和肝纤维化中的作用。
通过给予四氯化碳和乙醇诱导野生型 C57BL/6 或骨髓嵌合小鼠发生肝硬化。通过致死性照射和移植来自绿色荧光蛋白（GFP(+)）供体的 BMC 来生成骨髓嵌合体。未照射的野生型肝硬化小鼠接受 BMC 移植。对嵌合体和肝硬化移植小鼠的肝脏进行炎症、纤维化和调节因子[半乳糖凝集素-3、基质金属蛋白酶（MMP）-9、金属蛋白酶组织抑制剂（TIMP）-1 和转化生长因子（TGF）-β]的评估。
肝硬化的发展与 F4/80(+)细胞中半乳糖凝集素-3的表达增加以及 BMC 向肝脏的强烈迁移有关。此外，在肝硬化建立后进行移植时，BMC 也迁移到肝脏并定位于纤维性间隔内。BMC 治疗两个月后，肝硬化小鼠的肝纤维化和 I 型胶原表达显著减少。我们在盐水和 BMC 组之间没有发现 TGF-β、TIMP-1 和 MMP-9 的水平有任何差异。然而，在接受 BMC 治疗的肝硬化小鼠的肝脏中，炎症细胞、吞噬细胞和半乳糖凝集素-3(+)细胞的数量明显减少。
我们的结果表明 BMC 在调节肝纤维化中起着重要作用，并且 BMC 的移植可以通过调节机制加速纤维化的消退。
