Pruritus in Systemic Diseases

慢性瘙痒是许多全身性疾病的重要临床负担，包括肝胆疾病、慢性肾病和骨髓增生性肿瘤。由于对潜在分子机制的了解有限，治疗方案很少。在患有瘙痒症的胆汁淤积症患者的血清中，我们发现溶血磷脂酸（LPA）是小鼠背根神经节培养的激活剂。在第一个资助期内，我们研究了lpa介导的人体作用。皮内注射LPA会引起灼痛，而通过灭活的牛皮针状体注射LPA会引起轻微的瘙痒感。细胞外LPA主要来源于溶血磷脂酶autotaxin （ATX）。ATX活性与胆汁淤积症患者的瘙痒强度和对各种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，但仍存在几个问题。在第二个资助期，我们将研究皮内注射和局部应用时的发散感觉。这种观察结果可能由空间对比理论或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痒。最近，其他人和我们自己的研究小组发现了质量相关的G蛋白偶联受体X4 （MRPPRX4）作为胆汁酸的新受体。MRGPRX4可能参与胆汁酸诱导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电刺激。有趣的是，半正弦波和半正弦波的电刺激只在那些患有慢性瘙痒症的患者中引起明显的痒感，而瘙痒症和非瘙痒症患者的痛感是相似的。除了这些分子机制外，我们的项目还专注于疾病患者的翻译，旨在提高对全身性疾病患者慢性瘙痒的病理生理机制的理解。因此，我们将纳入与骨髓增生性肿瘤相关的全身性瘙痒的第二组患者。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学瘙痒的临床特征，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表皮/真皮变化。与健康志愿者相比，我们将仔细检查不同强度肝瘙痒患者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，我们将验证atx - lpa轴在角质形成细胞、免疫细胞、感觉神经元和相应共培养物中的瘙痒信号通路。

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.