Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis

摘要 尽管临床结果很差，但针对肝炎性疾病的治疗反应非常有限。 应对措施，特别是营养不良患者。骨质疏松症或骨骼肌丢失是 急性胰腺炎患者营养不良，并对这些患者的临床结局产生不利影响。潜在的机制 骨质疏松症可加重AH，包括骨骼肌酒精代谢降低和氨受损 处理因减少肝脏尿失禁，促进氨所致肝毒性。即使 靶向骨质疏松症是一种创新的方法，具有改善患者预后的机械原理 啊，这不是NIAAA资助的AlcHep网络正在进行的治疗策略的一部分。我们出版的和 初步数据显示，酒精引起的骨骼肌蛋白质稳态或蛋白质稳态失调 在肌管、小鼠模型和包括AH在内的人类酒精性肝病患者中。我们还观察到 酒精暴露增加了骨骼肌对脂多糖(LPS)的敏感性，从而导致 蛋白质合成受损，自噬增加，随之而来的是肉质减少。有趣的是，表达 典型的内毒素受体TLR4在酒精和酒精暴露的小鼠的肌管和肌肉中增加 酒精性肝病患者。始终如一地，TLR4的下游靶P65NFkB被激活 增加了。已知的P65NFkB转录靶点转化生长因子β超家族成员Myostatin的表达 同时，内毒素和乙醇也增加了骨骼肌蛋白质合成的负调控因子。有趣的是， 据报道，低分子量透明质酸，特别是35kD及以下片段(HA35)可抑制 或通过特定的受体以上下文特定的方式调节TLR4信号。我们做了一个新奇的观察 HA35逆转乙醇和脂多糖诱导的肌管内径减小、蛋白稳定和信号转导受损 乙醇对肌管和小鼠的影响。我们最初将在暴露在肌管中的HA35 乙醇和长期酗酒的小鼠(GAO模型)，有明显的石棺减少和肝脏损伤 与人类AH相似。在这些临床前研究中，我们将确定 HA35可逆转急性胰腺炎患者的骨质疏松症。我们将研究酒精喂养的小鼠对HA35的组织反应，包括 骨骼肌蛋白质合成、分解和信号反应。我们将把我们的初步和 HA35作为一种食品补充剂，在急性发作后应用于临床前数据的临床应用 酒精暴露。我们还将测试HA35是否对中度AH患者有益，一组患者 尽管有严重的肌肉损失，但目前还没有可用的治疗方法，也没有正在进行的临床 在Alchep网络中进行中度急性呼吸暂停试验。数据协调中心将协助这些人体研究。 这些研究将允许使用HA35作为一种新的、基于机制的治疗方法来快速翻译我们的研究 治疗急性胰腺炎的石棺减少症，目前这一患者群体的主要需求尚未得到满足。

Abstract Despite poor clinical outcomes there has been very limited response to therapies targeting hepatic inflammatory response especially in patients with malnutrition. Sarcopenia or skeletal muscle loss is a major component of malnutrition in AH and adversely affects clinical outcomes in these patients. Potential mechanisms by which sarcopenia can aggravate AH include reduced skeletal muscle metabolism of ethanol and impaired ammonia disposal due to decreased hepatic ureagenesis promoting ammonia induced hepatotoxicity. Even though targeting sarcopenia is an innovative approach with a mechanistic rationale to improve outcomes in patients with AH, this is not part of the therapeutic strategy in the ongoing NIAAA funded AlcHep network. Our published and preliminary data show dysregulated skeletal muscle protein homeostasis or proteostasis in response to ethanol in myotubes, mouse models, and human patients with alcoholic liver disease including AH. We also observed that ethanol exposure increases the skeletal muscle sensitivity to lipopolysaccharide (LPS) that results in impaired protein synthesis and increased autophagy and consequent sarcopenia. Interestingly, expression of canonical LPS receptor, TLR4, is increased in myotubes and in muscles from mice exposed to ethanol and patients with alcoholic liver disease. Consistently, P65NFkB, a downstream target of TLR4, is activated with increased. Expression of myostatin, a TGFβ superfamily member, a known transcriptional target of P65NFkB and negative regulator of skeletal muscle protein synthesis is also increased with LPS and ethanol. Interestingly, low molecular weight hyaluronic acid, especially fragments 35Kd and lower (HA35) have been reported to inhibit or modulate TLR4 signaling via specific receptors in a context specific manner. We made a novel observation that HA35 reversed ethanol and LPS induced reduction in myotube diameter, impaired proteostasis and signaling perturbations in both myotubes and mice exposed to ethanol. We will use HA35 initially in myotubes exposed to ethanol and mice chronically fed ethanol with binge (Gao model) that has significant sarcopenia and liver injury similar to that in human AH. In these preclinical studies, we will determine the molecular mechanisms by which HA35 reverses sarcopenia in AH. We will study the tissue responses to HA35 in ethanol-fed mice including skeletal muscle protein synthesis and breakdown and signaling responses. We will translate our preliminary and preclinical data into clinical application by treating human subjects with HA35, a food supplement, following acute ethanol exposure. We will also test if HA35 is beneficial in patients with moderate AH, a group of patients for whom there are currently no therapies available despite significant muscle loss and there are no ongoing clinical trials in moderate AH in the Alchep network. A data coordinating center will assist with these human studies. These studies will permit rapid therapeutic translation of our studies using HA35 as a novel, mechanism-based therapy for sarcopenia in AH, currently a major unmet need in this patient population.