The Portal Inflammatory Infiltrate and Ductular Reaction in Human Nonalcoholic Fatty Liver Disease
The Portal Inflammatory Infiltrate and Ductular Reaction in Human Nonalcoholic Fatty Liver Disease
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DOI：
10.1002/hep.26937
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发表时间：
2014-04-01
期刊：
影响因子：
13.5
通讯作者：
Clouston, Andrew D.
中科院分区：
文献类型：
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作者：
Gadd, Victoria L.;Skoien, Richard;Clouston, Andrew D.
虽然非酒精性脂肪肝（NAFLD）通常是通过组织学评估小叶炎症特征，但门静脉纤维化的发展似乎与疾病进展相关。我们研究了门静脉炎性浸润的成分及其与导管反应（DR）的关系，这是与纤维化有关的第二种门静脉现象。门静脉炎性浸润可能直接导致纤维化，并影响DR肝祖细胞（HPC）的命运，调节肝修复和纤维化之间的平衡。NAFLD中门静脉炎症的存在与疾病严重程度（纤维化阶段）和DR密切相关。门静脉浸润通过针对广泛的白细胞亚群标志物（CD 68、CD 3、CD 8、CD 4、CD 20和中性粒细胞弹性蛋白酶）和选定的炎症标志物（基质金属蛋白酶9和白细胞介素[IL]-17）对NAFLD肝活检切片（n = 33）进行免疫染色来表征。在整个肝小叶和汇管区中鉴定到表达所有检测的标记物的细胞，尽管汇管区更密集（P < 0.01），并且在疾病的所有阶段以CD 68（+）巨噬细胞和CD 8（+）淋巴细胞为主。在伴有脂肪变性的NAFLD患者中，门静脉巨噬细胞的增加（P < 0.01）是检测到的最早的变化，甚至在伴有早期NASH的患者中促炎细胞因子IL 1B和TNF的表达升高之前（P < 0.05）。在进展性NASH中，门静脉和导管周围的所有其他类型的细胞聚集均发生（均P < 0.05）。结论：了解NAFLD中门静脉炎性浸润和HPC/DR生态位的复杂细胞组成将有助于未来的功能研究，以阐明门静脉炎症对HPC分化和NAFLD发病机制的贡献。（肝病学2014;59：1393-1405）
Although nonalcoholic fatty liver disease (NAFLD) is conventionally assessed histologically for lobular features of inflammation, development of portal fibrosis appears to be associated with disease progression. We investigated the composition of the portal inflammatory infiltrate and its relationship to the ductular reaction (DR), a second portal phenomenon implicated in fibrogenesis. The portal inflammatory infiltrate may contribute directly to fibrogenesis as well as influence the fate of the DR hepatic progenitor cells (HPCs), regulating the balance between liver repair and fibrosis. The presence of portal inflammation in NAFLD was strongly correlated with disease severity (fibrosis stage) and the DR. The portal infiltrate was characterized by immunostaining NAFLD liver biopsy sections (n = 33) for broad leukocyte subset markers (CD68, CD3, CD8, CD4, CD20, and neutrophil elastase) and selected inflammatory markers (matrix metalloproteinase 9 and interleukin [IL]-17). Cells expressing all markers examined were identified throughout the liver lobules and in portal tracts, although portal tracts were more densely populated (P < 0.01), and dominated by CD68(+) macrophages and CD8(+) lymphocytes, at all stages of disease. An increase in portal macrophages in NAFLD patients with steatosis alone (P < 0.01) was the earliest change detected, even before elevated expression of the proinflammatory cytokines, IL1B and TNF, in patients with early NASH (P < 0.05). Portal and periductal accumulation of all other cell types examined occurred in progressed NASH (all P < 0.05). Conclusion: Knowledge of the complex cellular composition of the portal inflammatory infiltrate and HPC/DR niche in NAFLD will shape future functional studies to elucidate the contribution of portal inflammation to HPC differentiation and NAFLD pathogenesis. (Hepatology 2014;59:1393-1405)