Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans
Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans
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DOI：
10.1002/hep.25657
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发表时间：
2012-08-01
期刊：
影响因子：
13.5
通讯作者：
Wendon, Julia
中科院分区：
文献类型：
--
作者：
Antoniades, Charalambos Gustav;Quaglia, Alberto;Wendon, Julia
对乙酰氨基酚诱导的急性肝衰竭（AALF）与先天免疫激活有关，这有助于肝损伤的严重程度和临床结果。在AALF的实验模型中观察到肝巨噬细胞（h-m?）的显著增加，但关于其作用存在争议，暗示h-m phi在肝损伤的加重和缓解中都有作用。h-m - phi在人类AALF中的作用几乎未被探索。我们试图研究趋化因子（C-C基序）配体2 （CCL2）在循环单核细胞向炎症肝脏募集中的作用，并确定h-m - phi浸润和肝脏微环境如何有助于AALF的组织修复对抗炎症。我们评估了AALF患者的循环单核细胞、它们的趋化因子（C-C基序）受体2 （CCR2）表达和血清CCL2水平。免疫组化法测定肝免疫浸润组织中循环源性（MAC387+）或常驻增殖（CD68/Ki67+） h-m phi的亚群和数量。采用蛋白质组阵列法测定全肝组织和激光显微解剖肝组织的炎性细胞因子水平。在AALF中，循环单核细胞被耗尽，在不良结局的患者中观察到最低水平。AALF血清和肝组织中CCL2水平高，循环单核细胞亚群表达CCR2，提示CCL2依赖性肝单核细胞募集。与表达增殖标志物Ki67的对照肝组织相比，AALF中MAC387+和CD68+ h-m phi均显著增加。与慢性肝病对照组相比，AALF肝组织中CCL2、CCL3、白细胞介素(IL)-6、IL-10和转化生长因子- β 1的水平显著升高。结论：在AALF中，h-m - phi群体在坏死区域扩大，通过驻留细胞的增殖和循环单核细胞的ccl2依赖性募集。h-m - phi在抗炎/再生微环境中的存在表明它们与AALF期间炎症/组织修复过程的解决有关。(肝脏病学2012)
Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-m?) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-m phi in both aggravation and resolution of liver injury. The role of h-m phi in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-m phi infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-m phi in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-m phi were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-beta 1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls. Conclusion: In AALF, the h-m phi population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-m phi within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF. (HEPATOLOGY 2012)