Abstract

Article commented Kremer AE, Martens JJ, Kulik W, Rueff F, Kui-per EM, van Buuren HR, van Erpecum KJ, Kon-drackiene J, Prieto J, Rust C, Geenes VL, Williamson C, Moolenaar WH, Beuers U, Oude El-ferink RP. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139:1008-18. Original Abstract 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 ([Ca(2+)] (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 [Ca(2+)] (i)-inducing 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 [Ca(2+)] (i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)] (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 vs. pregnant controls (P vs. without pruritus (P Conclusions. We suggest that LPA and autotaxin play a critical role in cholesta-tic pruritus and may serve as potential targets for future therapeutic interventions.

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