Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus
ANDREAS E. KREMER,* JOB J. W. W. MARTENS,* WIM KULIK,‡ FRANZISKA RUËFF,§ EDITH M. M. KUIPER,? HENK R. VAN BUUREN,? KAREL J. VAN ERPECUM,¶ JURATE KONDRACKIENE,# JESUS PRIETO,** CHRISTIAN RUST,‡‡ VICTORIA L. GEENES,§§ CATHERINE WILLIAMSON,§§ WOUTER H. MOOLENAAR,?? ULRICH BEUERS,* and RONALD P. J. OUDE ELFERINK* *Tytgat Institute for Liver and Intestinal Research and ‡Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; §Departments of Dermatology and Allergology, University of Munich, Munich, Germany; ‡‡Internal Medicine II – Grosshadern, University of Munich, Munich, Germany; ?Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; ¶Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands; #Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania; **Department of Medicine and Liver Unit, Clinica Universitaria, Medical School and Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; §§Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, England; and ?Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
BACKGROUND & AIMS: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons.
METHODS: Cytosolic free calcium ([Ca2?]i) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca2?]i-induc- ing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device.
RESULTS: Transient increases in neuronal [Ca2?]i induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca2?]i agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P ?<.0001) and cholestatic patients with versus without pruritus (P <? .0001). Autotaxin activity correlated with intensity of pruritus (P ?<.0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or ?-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal.
CONCLUSIONS: We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future thera- peutic interventions.
Keywords: Autotaxin; Bile Salts; Cholestasis; Itch.
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