在搜索的妙法：可肝脏炎症和纤维化的药物被逆转？

StephenW

Editorials
In search of the magic bullet: can liver inflammation and fibrosis be reversed with medications?

September 2015, Vol. 9, No. 9 , Pages 1139-1141 (doi:10.1586/17474124.2015.1063417)

   
Henning W Zimmermann, and Frank Tacke
Department of Medicine III, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen,
Germany
*Author for correspondence: +49 241 80 35848 +49 241 80 82455 [email protected]
ABSTRACT
Recent clinical studies comprising patients successfully treated for viral hepatitis have shown that liver fibrogenesis may be reverted, even at later stages including during bridging fibrosis and cirrhosis. Intensive research has identified numerous potential novel targets in liver disease. Multiple innovative compounds have now entered clinical trials, mostly in non-alcoholic steatohepatitis (NASH) and NASH-associated cirrhosis due to their outstanding epidemiological relevance. In general, regression from liver fibrosis follows four major mechanistic principles: termination of chronic damage, shifting the cellular bias from inflammation to resolution, deactivation of myofibroblasts and direct matrix degradation. Obeying these principles, several promising approaches are currently evaluated, for example, targeting inflammatory macrophages via inhibition of chemokine CCL2, its receptor CCR2 or galectin-3, bone marrow-derived cell transfer, or antibodies against matrix-stabilizing lysyl oxidase-like-2. The ongoing trials will reveal which of the many potential targets prove to have clinical efficacy, bearing in mind that fibrosis reversibility is less likely to be achieved in humans than in animal models.
Keywords: chemokine, hepatic stellate cell, liver fibrosis, macrophages, matrix, regression

Perpetuating liver damage that does not subside eventually leads to fibrosis and cirrhosis. Clinical hepatologists earlier apprehended cirrhosis as an irreversible sequela to chronic liver injury, which may result in decompensation and development of hepatocellular carcinoma. However, recent clinical observations and trials have fueled the hope that liver fibrogenesis by far is not a unidirectional process but may be reverted even at later stages including bridging fibrosis (i.e., cirrhosis), provided that the underlying cause can be removed [1]. Most compelling evidence that successful medical treatment of a liver disease helps in amelioration of architectural disturbances originates from chronic hepatitis B virus infection. In hepatitis B virus-infected patients with cirrhosis at baseline, administration of the nucleotide analog tenofovir led to reversal of cirrhosis in almost 75% of cases [2]. However, there is still an unmet need to combat established cirrhosis due to the lack of specific therapeutic tools in many conditions. Non-alcoholic fatty liver disease, for instance, encompasses non-alcoholic steatohepatitis (NASH) as its most severe form, which in turn can result in end-stage liver disease. Despite a growing prevalence of this disease, no specific pharmacological therapies are currently at hand. Similarly, cirrhosis in the course of alcoholic liver disease, which still represents one of the major causes for liver transplantation in western countries, cannot be reverted in most cases in spite of cessation of alcohol consumption [1]. In addition, autoimmune liver diseases such as autoimmune hepatitis or primary biliary cirrhosis are often only diagnosed at very late stages, in which immunosuppressive drugs or ursodeoxycholic acid fail to re-establish the integrity of liver histology, respectively [1]. Thus, whenever the goal of curing the primary disease cannot be achieved, we need approaches that interfere with generic mechanisms of liver scar formation. Intensive research in recent years has identified a multitude of potential novel targets in liver disease and a considerable number of innovative compounds have now entered clinical trials [3]. The outstanding epidemiological relevance of NASH and NASH-associated cirrhosis entails that the vast majority of clinical trials involving antifibrotic drugs in liver disease are conducted in this patient cohort.

In general, regression may follow four major mechanistic principles: termination of chronic damage, shifting the cellular bias from inflammation to resolution, deactivation of myofibroblasts and direct matrix degradation [4,5]. Macrophages are key players in the fibrotic intercellular network and exert dual functions orchestrating either fibrosis progression or regression depending on their phenotype, origin and functional state [6,7]. Monocyte-derived macrophages, expressing Ly6C in mice, are massively recruited from blood stream to the injured liver, drive inflammation as vigorous secretors of inflammatory cytokines including TNF-α, activate hepatic stellate cells and, hence, trigger a cascade of events leading to fibrosis [7]. Furthermore, inflammatory macrophages foster angiogenesis, a process that is closely linked to fibrosis progression and hepatocellular carcinoma formation [8]. However, angiogenesis driven by myeloid-derived vascular endothelial growth factor is also critical for fibrosis resolution, as vascular endothelial growth factor-stimulated sinusoidal endothelium secretes matrix degrading metalloproteinases [9].

During the further course, Ly6Chi macrophages can transdifferentiate into restorative Ly6Clo macrophages that promote scar resolution through phagocytosing cellular debris and secreting metalloproteinases [10]. This phenomenon could be recapitulated by transplantation of bone marrow–derived macrophages that deliver collagen-degrading proteinases into the scar and imprint a rather anti-inflammatory environment in experimental liver fibrosis [11]. Similar to the latter study, transfer of autologous mixed bone marrow–derived cells corroborated fibrosis resolution mediated by matrix degrading metalloproteinase 9 and matrix degrading metalloproteinase 13 in mice [12]. Delivering immune cells to the fibrotic nodules seems to be a rational approach considering the fact that acellular scars are those that lack the potential to resolve [13]. Of note, there is already evidence that infusion of bone marrow–derived cells might be beneficial in end-stage liver disease, and a large controlled trial (REALISTIC trial) investigating the effect of G-CSF–mobilized stem cells on cirrhosis outcome is under way (EuDRACT number 2009-010335-41). Given the postphagocytic nature of restorative macrophages, either in vivo or ex vivo modification of macrophages using, for example, liposomes could even enhance their beneficial capacities [14].

Hampering macrophage influx into the inflamed liver can be achieved by aiming at the chemokine axis CCL2/CCR2. We could previously demonstrate that an RNA-aptamer–based inhibitor of CCL2, termed mNOX-E36, reduces the constant infiltration of Ly6Chi macrophage subsets in fibrotic mouse models, thereby favoring the net accumulation of their restorative Ly6Clo counterparts. This resulted in accelerated fibrosis regression [15]. Apart from fibrogenesis, this compound also proved effective in amelioration of liver steatosis [16]. A clinical trial (CENTAUR) investigating the efficacy and safety of the oral combined CCR2/CCR5 inhibitor cenicriviroc in NASH patients has recently been initiated (NCT02217475). Another chemokine-based approach that seems feasible in combating liver fibrosis is the compound Met-RANTES that counteracts CCL5. It interferes with stellate cell activation and migration, and thereby directly limits excessive matrix synthesis [17].

Galectin-3 is an interesting molecule emerging as a possible target to revert liver fibrosis. It acts as a pleiotropic lectin that is released by macrophages and other immune cells and supports fibrogenesis in a multifaceted fashion [18]. In a rodent toxic model of cirrhosis, the Galectin-3 inhibitors GR-MD-02 and GM-CT-01 both led to sustained amelioration of liver scarring and inflammation [19]. Given the putative distinguished role of Galectin-3 in cirrhosis and fibrotic diseases of other organs, a company was founded that launched a Phase-I trial to explore the therapeutic use of GR-MD-02 in NASH patients (NCT01899859). The trial is now completed and reports of preliminary results heralded excellent tolerability and improved surrogate markers of cell death, inflammation and fibrosis.

Besides macrophage recruitment, differentiation or functionality, the complex inflammatory micro-milieu in chronic liver disease provides a substantial number of additional potential targets [3]. The cytokine osteopontin is highly upregulated in fibrotic tissues and functionally linked to progenitor cell responses as well as wound healing [20]. In mouse models, neutralization of osteopontin effectively abrogates fibrogenesis [20]. Other fibrosis-restricting mechanisms are the gamma–delta T cell–mediated and NK cell–mediated apoptosis of hepatic stellate cells [21], as well as the IL-22 driven senescence of stellate cells [22]. Recent data from patients with chronic liver infections suggest that IL-22 protects against liver fibrosis and its competitor IL-22 binding protein aggravates liver fibrosis, suggesting that pharmacological modulation of IL-22 binding protein may be a promising strategy to limit cirrhosis [23].

The endocannabinoid system is profoundly involved in modulating the inflammatory and fibrotic response upon liver damage. Interestingly, the endocannabinoid receptors CB1 and CB2 display opposing functions. Whereas CB1 downstream signaling is detrimental by promoting matrix deposition and its steatogenic properties, CB2 mediates hepatoprotection [24]. Counteracting CB1 signaling is potentially harmful, as observed with the CB1 antagonist rimonabant that was previously licensed for treating morbid obesity and had to be withdrawn from the market owing to severe mood disorders. Albeit currently available CB1 antagonists preclude application in man, non blood–brain barrier penetrating second-generation CB1 antagonist drugs might be a future option given the encouraging findings in small animal models [25]. In contrast, stimulating CB2 by the drug JWH-133 efficiently reduced fibrosis directly through promoting stellate cell apoptosis/quiescence and indirectly via containing immune cell infiltration and various other beneficial impacts on parenchymal and non-parencyhmal cells [24]. Though these findings render CB2 agonists as interesting novel compounds for liver fibrosis, no testing in humans has been performed so far.

Another budding approach is the cell-independent targeting of scar formation. Polymerization of collagen is a prerequisite during organ fibrosis and is catalyzed by the matrix enzymes, lysyl oxidases. In a seminal work, lysyl oxidase-like-2 was identified as critical for liver fibrosis [26]. A humanized monoclonal antibody against lysyl oxidase-like-2, Simtuzumab (GS-6624), is currently being investigated in diverse ongoing Phase II trials involving HCV (NCT01707472), primary sclerosing cholangitis (NCT01672853) and NASH-related fibrosis (NCT01672866)/cirrhosis (NCT01672879).

Taken together, there is a substantial body of evidence that liver inflammation and fibrosis can be reverted with medications. However, many hurdles have to be overcome in search of the ‘magic bullet’, including appropriate patient selection and timing of drug application. Whenever possible, therapeutic efforts should aim at the primary disease. Successful exertion of pharmacological means to treat inflammation and fibrosis has to accommodate a myriad of individual parameters such as stage of fibrosis and etiology of the underlying liver disease. Results of the ongoing trials have to be awaited to clearly dissect which of the many potential targets prove clinical efficacy, bearing in mind that fibrosis reversibility is less likely achieved in humans than in animal models.
Financial & competing interests disclosure

The authors were supported by grants from the German Research Foundation (grant numbers: DFG; SFB/TRR57, TA434/3-1). The work in the laboratory of F Tacke is supported by funding from Noxxon Inc. and Tobira Therapeutics Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



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StephenW

社论
在搜索的妙法：可肝脏炎症和纤维化的药物被逆转？

2015年九月，卷。 9,9号，页1139至1141年（DOI：10.1586 / 17474124.2015.1063417）

   
亨宁W¯¯齐默尔曼和弗兰克·塔克
医药三，大学附属医院亚琛，Pauwelsstrasse 30，52074亚琛系，
德国
*作者的书信：+49 241 80 35848 +49 241 80 82455 [email protected]
摘要
包含成功治疗病毒性肝炎患者最近的临床研究表明，肝纤维化可被还原，即使在稍后的阶段，包括桥接纤维化和肝硬化中。强化研究确定肝病许多潜在的新靶点。现在多的创新化合物已进入临床试验，主要是在非酒精性脂肪性肝炎（NASH）和NASH相关的肝硬化，由于其出色的流行病学关联性。在一般情况下，从肝纤维化回归如下四个主要机械原则：终止慢性损伤，蜂窝偏压从炎症转向分辨率，肌纤维母细胞和直接矩阵降解的失活。服从这些原则，若干有希望的方法是当前评估的，例如，通过对抑制趋化因子CCL2，其受体CCR2或半乳凝素3，骨髓来源的细胞转移，或抗体的靶向炎性巨噬细胞基质稳定化赖氨酰氧化酶样-2- 。正在进行的试验将揭示其中的许多潜在目标证明具有临床疗效，铭记纤维化可逆性不太可能被在人类中实现比在动物模型。
关键词：趋化因子，肝星状细胞，肝纤维化，巨噬细胞，基质，回归

延续肝损伤不消退，最终导致纤维化和肝硬化。临床肝病较早被捕肝硬化作为一种​​不可逆的后遗症对慢性肝损伤，其可导致代偿失调和肝细胞癌的发展。然而，最近的临床观察和试验已经推动了希望肝纤维化远远不是单向的过程，但即使在稍后的阶段，包括桥接纤维化（即，肝硬化）可以还原，条件是根本原因可以被删除[1]。最有说服力的证据表明，肝脏疾病的成功的医疗帮助建筑骚乱改善源于慢性乙肝病毒感染。在B型肝炎在基线病毒感染患者的肝硬化，核苷酸类似物替诺福韦的施用导致逆转肝硬化的病例几乎75％的[2]。然而，仍然有未满足的需要，以打击既定肝硬化由于在许多条件下，缺乏具体的治疗工具。非酒精性脂肪肝疾病，例如，包括非酒精性脂肪性肝炎（NASH），作为其最严重的形式，而这又可能导致终末期肝病。尽管这种疾病的发病率不断增加，没有具体的药物治疗，目前在手。同样，肝硬化酒精性肝病，这仍然是主要的原因，在西方国家肝移植的一个过程，不能被还原在大多数情况下，尽管停止饮酒[1]的。此外，自身免疫性肝病如自身免疫性肝炎或原发性胆汁性肝硬化往往只能诊断在很晚的阶段，其中，免疫抑制药或熊去氧胆酸未能肝脏组织学的，分别重新建立完整性[1]。因此，无论何时固化原发病的目标无法实现，我们需要与肝脏疤痕形成的通用机制干扰的方法。深入研究在近几年已经确定了许多潜在的新目标，在肝脏疾病和相当数量的创新化合物，目前已进入临床试验[3]。 NASH和NASH相关肝硬化的突出流行病学相关性引起该涉及抗纤维化药物在肝脏疾病临床试验中，绝大多数在该患者人群进行的。

在一般情况下，回归可能会遵循四个主要原则机械：终止的慢性损伤，细胞偏置发炎转向分辨率，肌纤维母细胞和直接基质降解[4,5]失活。巨噬细胞是主要参与者纤维化细胞间网络，并发挥双重作用要么策划纤维化进展或消退取决于它们的表型，起源和功能状态[6,7]。单核细胞衍生的巨噬细胞，在小鼠中表达的Ly6C，被大量从血液流招募到损伤肝脏，驱动炎症炎性细胞因子，包括TNF-α的蓬勃分泌者，激活的肝星状细胞，并因此触发导致纤维化事件的级联[7]。此外，炎症的巨噬细胞培养血管生成，这是密切相关的纤维化进程和肝细胞癌的形成过程[8]。然而，血管发生由骨髓来源的血管内皮生长因子从动也是纤维化分辨率重要的，因为血管内皮生长因子刺激肝窦内皮细胞分泌基质降解金属蛋白酶[9]。

在进一步的过程中，Ly6Chi巨噬细胞可以分化为恢复Ly6Clo巨噬细胞，通过吞噬细胞碎片和分泌金属蛋白酶[10]促进疤痕的分辨率。这种现象可以通过骨髓衍生的巨噬细胞能够提供胶原降解蛋白酶到疤痕和压印一个相当抗炎环境实验肝纤维化[11]的移植来概括。类似于后者的研究中，证实了纤维化分辨率自身混合骨髓来源的细胞通过基质金属蛋白酶降解9和基质降解金属蛋白酶13在小鼠中[12]介导的转移。递送的免疫细胞的纤维化结节似乎是一种合理的方法是在考虑到非细胞疤痕那些缺乏解决[13]的电位。值得注意的是，这里已经有证据表明，输液骨的骨髓来源的细胞可能是有益的终末期肝病，和一个大对照试验（写实试验）调查的G-CSF动员干细胞的效果上肝硬化结果是下方法（EuDRACT数2009-010335-41）。给定的恢复性巨噬细胞的postphagocytic性质，无论是在体内或离体使用，例如，脂质体甚至可以增强其有利的能力[14]的巨噬细胞的修饰。

阻碍巨噬细胞流入发炎的肝脏可以通过针对趋化因子CCL2轴/ CCR2来实现。我们可以预先证明CCL2的RNA适体为基础的抑制剂，称为的MnOx-E36，减少Ly6Chi巨噬细胞亚群的不断渗透纤维化小鼠模型，从而有利于他们的恢复性Ly6Clo同行的净积累。这导致加速纤维化回归[15]。除了纤维形成，这种化合物也被证明是有效的肝脏脂肪变性[16]的改善。临床试验（CENTAUR）调查NASH患者口腔组合CCR2 / CCR5抑制剂cenicriviroc的有效性和安全性，最近已经开始（NCT02217475）。另一种趋化因子为基础的方法，似乎在打击肝纤维化可行的是，抵消CCL5遇见-RANTES的化合物。它干扰星状细胞活化和迁移，从而直接限制过多基质的合成[17]。

半乳糖凝集素-3是一个有趣的分子正在成为恢复肝纤维化的一个可能的目标。它可以作为该被释放由巨噬细胞和其他免疫细胞和支持纤维形成在多方面的方式[18]一种多效性的凝集素。肝硬化的啮齿动物毒性模型中，半乳凝素3抑制剂GR-MD-02和GM-CT-01都导致肝瘢痕形成和炎症[19]的持续改善。鉴于半乳凝素3的肝硬化和其他器官的纤维化疾病的公认卓越的角色，该公司成立了推出了相I试验探索治疗用途GR-MD-02在NASH患者（NCT01899859）中。该试验已经完成，初步结果的报告预示着良好的耐受性和细胞死亡，炎症和纤维化改善的替代指标。

除了巨噬细胞募集，分化或功能性，复杂的炎性微环境中的慢性肝病提供的附加的潜在目标[3]为数不少。细胞因子骨桥蛋白被高度上调在纤维化组织和功能性连接到祖细胞应答以及伤口愈合[20]。在小鼠模型中，骨桥蛋白中和有效地废除纤维化[20]。其他纤维化限制机构是伽玛-ΔT细胞介导和肝星状细胞[21] NK细胞介导的​​细胞凋亡，以及星状细胞的IL-22驱动的衰老[22]。从慢性肝病患者的感染最近的数据表明，IL-22的防止肝纤维化和其竞争者的IL-22结合蛋白加重肝纤维化，提示IL-22结合蛋白的药理学调制可以是一种很有前途的策略来限制肝硬化[23] 。

内源性大麻素系统是深刻参与调节后肝损害的炎症和纤维化反应。有趣的是，内源性大麻素受体CB1和CB2显示相对的功能。而CB1下游信号是不利的，促进基质沉积和其steatogenic属性，CB 2介导保肝[24]。抵消CB1信令是潜在有害的，因为与先前许可用于治疗病态肥胖和必须从由于严重的情绪障碍退出市场的CB1拮抗剂利莫那班观察。尽管目前可用的CB1拮抗剂排除在人申请，非血脑屏障穿透第二代CB1拮抗剂的药物可能是在小动物模型[25]给出的令人鼓舞的结果的未来的选项。与此相反，刺激CB2由药物JWH-133直接通过促星状细胞凋亡/静止和经由含有免疫细胞浸润和实质和非parencyhmal细胞[24]各种其它有利影响间接有效地减少纤维化。虽然这些发现使CB2受体激动剂有趣的新化合物的肝纤维化，在人类没有测试已经完成为止。

另一种萌芽的方法是瘢痕形成的细胞无关的目标。胶原聚合是器官纤维化过程的先决条件，由矩阵酶，赖氨酰氧化酶催化。在一开创性工作，赖氨酰氧化状-2被确定为肝纤维化[26]为严重。对人源化单克隆抗体，赖氨酰氧化酶样2，Simtuzumab（GS-6624），目前正在研究在不同正在进行II期临床试验，涉及丙型肝炎病毒（NCT01707472），原发性硬化性胆管炎（NCT01672853）和NASH相关的肝纤维化（NCT01672866）/肝硬化（NCT01672879）。

总之，有大量证据机构，肝脏炎症和纤维化可以用药物来恢复。然而，许多障碍都在寻找的“灵丹妙药”，包括选择合适的病人和药物的应用时间来克服。只要有可能，治疗努力的目标应该是原发疾病。药理成功消耗装置来治疗炎症和纤维化必须适应个人参数的无数如纤维化分期和底层肝病的病因。正在进行的临床试验结果必须等待清楚地剖析其中的许多潜在目标，证明临床疗效，同时铭记纤维化的可逆性​​是人类不太可能取得比动物模型。
金融与相互竞争的利益披露

作者由来自德国研究基金会资助（：; SFB / TRR57，TA434 / 3-1 DFG资助号）的支持。在F中塔克的实验室的工作是支持由Noxxon公司和TOBIRA Therapeutics公司资助的作者有没有其他相关的关系或资金参与任何组织或实体有经济利益或金融冲突的题材或材料在手稿除了那些公开的讨论。



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