Secretory Leukocyte Protease Inhibitor: A Pivotal Mediator of Anti-inflammatory Responses in Acetaminophen-Induced Acute Liver Failure
Secretory Leukocyte Protease Inhibitor: A Pivotal Mediator of Anti-inflammatory Responses in Acetaminophen-Induced Acute Liver Failure
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DOI：
10.1002/hep.26933
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发表时间：
2014-04-01
期刊：
影响因子：
13.5
通讯作者：
Thursz, Mark
中科院分区：
文献类型：
--
作者：
Antoniades, Charalambos Gustav;Khamri, Wafa;Thursz, Mark
对乙酰氨基酚诱导的急性肝衰竭（AALF）的特点是先天免疫反应激活和败血症易感性。循环单核细胞和肝巨噬细胞是人类 AALF 期间炎症反应和组织修复过程的中心介质。分泌性白细胞蛋白酶抑制剂 (SLPI) 通过抑制核因子 kappa B (NF-kappa B) 信号传导来调节单核细胞/巨噬细胞功能。本研究的目的是确定 SLPI 在 AALF 中的作用。测定 AALF、慢性肝病患者的 SLPI、单核细胞分化簇 163 (CD163)、人类白细胞抗原-DR (HLA-DR) 和脂多糖 (LPS) 刺激的 NF-κ Bp65、肿瘤坏死因子 α (TNF-α) 和白细胞介素 (IL)-6 的循环水平 疾病和健康控制。 AALF 外植体组织的免疫组织化学和多光谱成像确定了 SLPI 的细胞来源和肝巨噬细胞表型。在存在和不存在抗人 (α)SLPI 的情况下，用重组人 (rh)-SLPI、肝匀浆和来自 AALF 患者的血浆进行培养后，确定单核细胞和巨噬细胞的表型和功能。 AALF 中肝脏和循环中 SLPI 的浓度升高，免疫组织化学显示坏死区域的胆管上皮细胞和肝巨噬细胞 (h-m psi) 内有 SLPI 表达。 AALF 中的 H-m psi 和循环单核细胞表现出抗炎表型和功能特征； LPS 攻击后，NF-κBp65、TNF-α 和 IL-6 减少，IL-10 分泌保持不变。用 AALF 肝匀浆、血浆或 rhSLPI 培养健康单核细胞，诱导的单核细胞具有惊人相似的抗炎特性，而通过抑制 SLPI 的活性可以逆转这一特性。结论：SLPI 通过调节单核细胞/巨噬细胞功能是 AALF 抗炎反应的关键介质，这可能是 AALF 脓毒症易感性的原因。 （肝病学 2014；59：1564-1576）
Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-kappa B) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-kappa Bp65, tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (alpha)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-m psi) in areas of necrosis. H-m psi and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-kappa Bp65, TNF-alpha, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF. (Hepatology 2014;59:1564-1576)