Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets?
Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets?
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作者：
Gao B;Xu M
酒精性肝炎（AH）是一种严重的酒精性肝病，与高死亡率相关。尽管在过去几十年中对AH进行了广泛的研究，但AH的发病机制在很大程度上仍然未知，并且没有批准的靶向治疗。炎症（中性粒细胞浸润）通常被认为在AH的发病机制中起重要作用;然而，AH中中性粒细胞浸润的潜在机制以及中性粒细胞在AH中的功能尚不完全清楚。1尽管其作用模糊，但炎症已被积极研究作为治疗AH的治疗靶点。例如，皮质类固醇，广泛的免疫抑制药物，已被广泛用于AH治疗超过五十年。然而，结果一直存在争议。人们普遍认为，皮质类固醇治疗可以改善重度AH患者的短期生存率，但不能改善其长期生存率。2最近，我们已经证明，泼尼松龙，一种合成的类固醇药物，通过抑制嗜中性粒细胞介导的吞噬作用和肝再生，减少肝毒素（如乙醇和四氯化碳）诱导的小鼠肝损伤，表明类固醇治疗肝毒素诱导的肝炎的有害影响。3此外，已知类固醇治疗对于嗜中性粒细胞介导的疾病的治疗是无效的，并且偶尔甚至是有害的，因为类固醇治疗刺激骨髓嗜中性粒细胞释放并增加嗜中性粒细胞存活。4基于这一现象，我们有理由推测，类固醇治疗AH可能对受损肝脏本身没有有益作用，但可能在减轻全身炎症反应方面保留某些有益作用，从而提高短期生存率。因此，迫切需要确定可以抑制肝脏炎症（中性粒细胞浸润）的特异性靶点，用于治疗AH。在过去的三十年中，使用慢性酒精喂养的啮齿动物模型的研究确定了许多在慢性酒精性肝损伤的发病机制中起重要作用的炎症介质。1然而，大多数这些慢性乙醇喂养模型没有表现出或表现出低水平的肝脏中性粒细胞浸润。因此，许多确定的炎症介质可能不会导致急性AH中观察到的中性粒细胞浸润。最近，我们开发了一种慢性酒精摄入模型，表现出显著的中性粒细胞浸润。5使用该模型的研究可能有助于确定AH中中性粒细胞浸润的几种炎症介质。然而，这种慢性酗酒乙醇喂养模型只代表了中度AH的一些特征，目前还没有动物模型再现人类AH的全部谱。为了克服动物模型的缺点，Bataller小组通过实时PCR和微阵列分析了人类AH活检样本。他们使用实时PCR分析的早期研究显示，与正常健康对照肝脏相比，AH肝脏中几种CXC亚家族成员（包括IL-8、Gro-α、CXCL 5、CXCL 6、CXCL 10和血小板因子4）的水平显著升高，并且与中性粒细胞浸润和门静脉高压症的严重程度相关。6还发现CC趋化因子CCL 2而不是CCL 5被上调。IL-8、CXCL 5、Gro-γ和CXCL 6的高表达水平与预后差相关。最近，Bataller小组对人类AH样本进行了微阵列分析，并进一步证明与健康对照肝脏样本相比，AH活检样本中许多CXC和CC家族成员的水平显着升高。7 …
Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease that is associated with high mortality. Despite extensive research on AH over the last several decades, the pathogenesis of AH remains largely unknown, and there are no approved targeted therapies. Inflammation (neutrophil infiltration) is generally believed to play an important role in the pathogenesis of AH; however, the mechanisms underlying neutrophil infiltration in AH and the functions of neutrophils in AH are not fully understood. 1 Despite its obscure role, inflammation has been actively investigated as a therapeutic target for the treatment of AH. For example, corticosteroids, which are broadly immunosuppressive drugs, have been widely used for AH therapy for more than five decades. However, the results have been controversial. It is generally accepted that corticosteroid therapy improves short-term, but not long-term, survival rates in patients with severe AH. 2 Recently, we have demonstrated that treatment with prednisolone, a synthetic steroid drug, reduced hepatotoxin (eg, ethanol and CCl4)-induced liver injury in mice by inhibiting neutrophil-mediated phagocytosis and liver regeneration, suggesting a detrimental effect of steroid therapy in hepatotoxin-induced hepatitis. 3 Additionally, it is known that steroid therapy is ineffective and, occasionally, even detrimental for the treatment of neutrophil-mediated diseases because steroid treatment stimulates bone marrow neutrophil release and increases neutrophil survival. 4 Based on this phenomenon, it is plausible to speculate that steroid therapy for AH may have no beneficial effects on the injured liver itself but may retain certain beneficial effects in attenuating systemic inflammatory responses and, thus, improving the short-term survival rate. Therefore, there is an urgent need to identify specific targets that can inhibit liver inflammation (neutrophil infiltration) for the treatment of AH. Over the last three decades, studies using rodent models of chronic alcohol feeding identified many inflammatory mediators that play important roles in the pathogenesis of chronic alcoholic liver injury. 1 However, most of these chronic ethanol-feeding models exhibit no or low levels of hepatic neutrophil infiltration. Therefore, many of the identified inflammatory mediators may not contribute to the neutrophil infiltration observed in acute AH. Recently, we developed a chronic-binge ethanol-feeding model that presents significant neutrophil infiltration. 5 Studies using this model will likely aid in identifying several inflammatory mediators of neutrophil infiltration in AH. However, this chronic-binge ethanolfeeding model only represents some features of moderate AH, and currently there are no animal models that reproduce the full spectrum of human AH. To overcome the shortcomings of animal models, the Bataller group analysed human AH biopsy samples by real-time PCR and microarray. Their early studies using real-time PCR analyses revealed that the levels of several CXC subfamily members, including IL-8, Gro-α, CXCL5, CXCL6, CXCL10 and platelet factor 4, are significantly elevated in AH livers compared with normal healthy control livers, and are correlated with neutrophil infiltration and the severity of portal hypertension. 6 The CC chemokine CCL2, but not CCL5, was also found to be upregulated. Higher expression levels of IL-8, CXCL5, Gro-γ, and CXCL6 were associated with a worse prognosis. Recently, the Bataller group performed microarray analyses of human AH samples, and further demonstrated that the levels of many CXC and CC family members are markedly elevated in AH biopsy samples compared with healthy control liver samples. 7 …