TY - JOUR
T1 - Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus
AU - Kremer, Andreas E.
AU - Martens, Job J. W. W.
AU - Kulik, Wim
AU - Ruëff, Franziska
AU - Kuiper, Edith M. M.
AU - van Buuren, Henk R.
AU - van Erpecum, Karel J.
AU - Kondrackiene, Jurate
AU - Prieto, Jesus
AU - Rust, Christian
AU - Geenes, Victoria L.
AU - Williamson, Catherine
AU - Moolenaar, Wouter H.
AU - Beuers, Ulrich
AU - Elferink, Ronald P. J. Oude
PY - 2010
Y1 - 2010
N2 - 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)-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 [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 mu-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 therapeutic interventions
AB - 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)-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 [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 mu-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 therapeutic interventions
U2 - https://doi.org/10.1053/j.gastro.2010.05.009
DO - https://doi.org/10.1053/j.gastro.2010.05.009
M3 - Article
C2 - 20546739
SN - 0016-5085
VL - 139
SP - 1008-U399
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -