Pruritus in Systemic Diseases

慢性瘙痒是许多全身疾病的重要临床负担，包括肝胆疾病、慢性肾脏疾病和骨髓增生性肿瘤。由于对潜在的分子机制的了解有限，治疗方案很少。在伴有瘙痒的胆汁淤积症患者的血清中，我们确定溶血磷脂酸(LPA)是小鼠背根神经节培养的激活剂。在第一个资助期间，我们研究了LPA在人类中的介导作用。皮内注射LPA会引起灼痛，而通过灭活的牛皮针应用LPA则会引起轻微的瘙痒。细胞外LPA主要来源于溶血磷脂酶自体趋化蛋白(ATX)。ATX活性与胆汁淤积症患者的瘙痒强度以及对不同但不是所有止痒治疗的反应密切相关。尽管这些数据表明ATX-LPA轴在肝胆疾病患者瘙痒中的主要作用，但仍有几个问题。在第二个资助期，我们将解决皮内注射和局部应用时的不同感觉。这种观察可以用空间对比理论来解释，或者也可以用表皮神经纤维密度降低或LPA受体表达改变来解释。除了ATX-LPA轴，胆汁酸也可能导致肝脏瘙痒。最近，其他人和我们自己的团队发现了与Mas相关的G蛋白偶联受体X4(MRPPRX4)，它是一种新的胆汁酸受体。MRGPRX4可能参与胆汁酸引起的人类瘙痒和神经纤维激活。在初步实验中，我们对肝胆疾病患者进行了电刺激。有趣的是，半正弦波和正弦波的电刺激只在那些患有慢性瘙痒的患者中引起明显的瘙痒感觉，而瘙痒患者和非瘙痒患者的痛感是相似的。除了这些分子机制外，我们的项目还着重于疾病患者的翻译，目的是提高对系统性疾病患者慢性瘙痒的病理生理机制的理解。因此，我们将纳入第二个与骨髓增生性肿瘤有关的系统性瘙痒患者。我们将通过躯体感觉功能的心理物理测试来描述肝脏和血液瘙痒的临床特征，并评估纵向变化。通过皮肤活检，我们将确定与慢性瘙痒相关的皮肤微生物种类、基因表达模式和结构上的表皮/真皮变化。我们将仔细研究不同强度的肝脏瘙痒患者与健康志愿者相比，与瘙痒直接相关的电生理瘙痒感受器/伤害感受器放电模式。最后，我们将在角质形成细胞、免疫细胞、感觉神经元和相应的共培养中验证ATX-LPA轴在瘙痒信号通路中的作用。

Chronic pruritus is a significant clinical burden in many systemic diseases including hepatobiliary disorders, chronic kidney disease and myeloproliferative neoplasms. Therapeutic options are scarce due to limited understanding of the underlying molecular mechanisms. In sera of cholestatic patients with pruritus, we identified lysophosphatidic acid (LPA) as activator of murine dorsal root ganglia cultures. During the first funding period, we investigated LPA-mediated action in humans. Intracutaneous LPA microinjections elicited burning pain, whereas LPA application via inactivated cowhage spicules evoked mild itch sensation. Extracellular LPA is largely derived from the lysophospholipase autotaxin (ATX). ATX activity closely correlated with the itch intensity in cholestatic patients and response to various but not all anti-pruritic treatments. Although these data indicate a major role of the ATX-LPA-axis in pruritus of patients suffering from hepatobiliary diseases, several questions remain.In the second funding period we will address the diverging sensation upon intradermal injection and focal application. This observation may be explained by the spatial contrast theory or alternatively a reduced nerve fiber density in the epidermis or an altered expression of LPA receptors. Aside the ATX-LPA-axis, bile acids may also contribute to hepatic itch. Recently, others and our own group identified the mas-related G protein-coupled receptor X4 (MRPPRX4) as novel receptor for bile acids. Possible involvement of MRGPRX4 in bile acid induced pruritus and nerve fiber activation in human will be addressed. In preliminary experiments, we performed electrical stimulation in patients with hepatobiliary diseases. Intriguingly, electrical stimulation by half sine and sine waves caused significant itch sensation only in those patients suffering from chronic pruritus, whereas pain sensation was comparable between pruritic and non-pruritic patients. Beside these molecular mechanisms our project has a strong translational focus on diseased patients with the aim to improve the understanding of pathophysiological mechanisms of chronic pruritus in patients with systemic diseases. We will therefore include a second patient cohort with systemic pruritus linked to myeloproliferative neoplasms. We will characterize the clinical profile of hepatic and hematological pruritus by psychophysical testing of somatosensory function and assess longitudinal changes. Using skin biopsies we will identify dermal microbial species, gene expression patterns, and structural epidermal/dermal changes associated with chronic pruritus. We will scrutinize electrophysiologically pruriceptor/nociceptor discharge patterns related to pruritus directly in patients with varying intensities of hepatic pruritus in comparison with healthy volunteers. Finally, we will validate the ATX-LPA-axis in itch signalling pathways in keratinocytes, immune cells, sensory neurons and corresponding co-cultures.