Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats
Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats
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DOI：
10.1053/j.gastro.2004.10.005
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发表时间：
2005-01-01
期刊：
影响因子：
29.4
通讯作者：
Ueno, H
中科院分区：
文献类型：
--
作者：
Imamura, M;Ogawa, T;Ueno, H
背景与目的：单核细胞/巨噬细胞浸润损伤肝脏。我们试图通过单核细胞趋化蛋白1的突变形式（7ND； n端缺失了7个氨基酸）抑制它们的浸润来阐明它们在炎症和随后的纤维形成中的作用，这可能是一个显性阴性突变体。方法：大鼠通过尾静脉注射表达人7ND （Ad7ND）、截断型转化生长因子β受体（adtβ - tr）的腺病毒、细菌β -半乳糖苷酶（AdLacZ）或生理盐水。7 d后给予二甲基硝基胺1 ~ 21 d。结果：单次注射二甲基硝基胺后24小时内，肝脏中可见巨噬细胞。二甲基亚硝胺治疗3天后，AdLacZ-、adtβ - tr -和盐水注射大鼠肝脏中检测到活化的肝星状细胞。相比之下，ad7nd处理大鼠的巨噬细胞浸润明显减少，未检测到活化的肝星状细胞。二甲基硝基胺治疗3周后，Ad7ND-和adtβ -tr -治疗的大鼠肝脏中几乎看不到活化的肝星状细胞，纤维化发生几乎完全被抑制。结论：阻断巨噬细胞浸润可抑制肝星状细胞活化，抑制肝纤维化发生。在adtβ - tr处理的肝脏中，损伤后初始阶段存在活化的肝星状细胞，而后期则不存在，这表明转化生长因子β不是肝星状细胞的激活因子，这表明转化生长因子β是激活的肝星状细胞存活所必需的。我们的研究表明，浸润的巨噬细胞本身可能产生一种激活肝星状细胞的因子。
Background& Aims: Monocytes/ macro phages infiltrate into injured livers. We tried to clarify their roles in inflammation and subsequent fibrogenesis by inhibiting their infiltration with a mutated form (7ND; 7 amino acids at the N-terminal were deleted) of monocyte chemoattractant protein :1, which may function as a dominant-negative mutant. Methods: Rats were injected via the tail vein with an adenovirus expressing either human 7ND (Ad7ND), a truncated type II transforming growt factor beta receptor (AdTbeta-TR), which works as a dominant-negative receptor, bacterial beta-galactosidase (AdLacZ), or saline. Seven days later, the rats were treated with dimethyinitrosamine for 1-21 days. Results: Within 24 hours after a single dimethyinitrosamine injection, macrophages were observed in livers. With a 3-day dimethylnitrosamine treatment, activated hepatic stellate cells were detectable in livers in AdLacZ-, AdTbeta-TR-, and saline-injected rats. In contrast, in the Ad7ND-treated rats, infiltration of macrophages was markedly reduced, and activated hepatic stellate cells were not detectable. After a 3-week dimethyinitrosamine treatment, fibrogenesis was almost completely inhibited, and activated hepatic stellate cells were hardly seen in livers in both Ad7ND- and AdTbeta-TR-treated rats. Conclusions: Our results show that blockade of macrophage infiltration inhibits activation of hepatic stellate cells and leads to suppression of liver fibrogenesis. The presence of activated hepatic stellate cells in the initial phase after injury and its absence at a later phase in the AdTbeta-TRtreated livers indicate that transforming growth factor beta is not an activating factor for hepatic stellate cells, and this suggests that transforming growth factor beta is required for the survival of activated hepatic stellate cells. Our study suggests that infiltrated macrophages may themselves produce an activating factor for hepatic stellate cells.