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Pruritus in systemic diseases

Barbara Namer, Steffen Koschmieder, Andreas Kremer

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.