Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis - Implications for the pathogenesis of human nonalcoholic steatohepatitis
Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis - Implications for the pathogenesis of human nonalcoholic steatohepatitis
复制标题
DOI：
10.2353/ajpath.2007.060441
复制
发表时间：
2007-03-01
影响因子：
6
通讯作者：
Kawada, Norifumi
中科院分区：
文献类型：
--
作者：
Otogawa, Kohji;Kinoshita, Kohji;Kawada, Norifumi
非酒精性脂肪肝（NASH）是一种进行性纤维化疾病，其发病机制尚未完全阐明。在这里，我们报告了这种疾病的分子方面阐明了使用兔子喂养富含胆固醇的高脂肪饮食和表现出胰岛素抵抗。该模型中的肝脏显示脂肪性肝炎伴纤维化和某些细胞因子、血红素加氧酶-1、转化生长因子-β 1和胶原蛋白α 1（I）的高mRNA表达。从模型中分离的红细胞显示出明显的脆性和膜外叶上磷脂酰丝氨酸（PS）的外化，并且经常被肝窦中的枯否细胞/巨噬细胞吞噬。牛奶脂肪球表皮生长因子（EGF）因子8，PS结合蛋白的表达，在肝脏中增加。在培养中，RAW 264.7细胞吞噬了被叔丁基过氧化氢氧化的红细胞，这一过程被抗乳脂球-EGF-因子8抗体抑制。此外，在离体灌注实验中，PS阳性红细胞出现截留在模型肝脏中。最后，在NASH患者的标本中，红细胞在炎性肝窦中的聚集是显著的。这些结果表明，吞噬PS外化，凋亡信号阳性，红细胞的肝巨噬细胞可能会导致沉积的铁来源于血红蛋白在肝脏中，并参与脂肪性肝炎的发病机制。
Nonalcoholic steatobepatitis (NASH) is a progressive fibrotic disease, the pathogenesis of which has not been fully elucidated. Here, we report a molecular aspect of this disease elucidated using rabbits fed a cholesterol-rich high-fat diet and exhibiting insulin resistance. The liver in this model showed steatohepatitis with fibrosis and high mRNA expression for some cytokines, heme oxygenase-1, transforming growth factor-beta 1, and collagen alpha 1(I). Erythrocytes isolated from the model showed marked fragility and the externalization of phosphatidylserine (PS) on the outer leaflet of the membrane and were frequently engulfed by Kupffer cells/macrophages in the hepatic sinusoids. Expression of milk fat globule-epidermal growth factor (EGF)-factor 8, a PS-binding protein, was augmented in the liver. In culture, RAW 264.7 cells engulfed erythrocytes oxidized by tert-butyl hydroperoxide, a process that was inhibited by anti-milk fat globule-EGF-factor 8 antibody. In addition, PS-positive erythrocytes appeared entrapped in the model liver in ex vivo perfusion experiments. Finally, in specimens from NASH patients, the aggregation of erythrocytes in inflammatory hepatic sinusoids was notable. These results indicate that the engulfment of PS-externalized, apoptotic signal-positive, erythrocytes by hepatic macrophages may lead to the deposition of iron derived from hemoglobin in the liver and be involved in the pathogenesis of steatohepatitis.