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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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2
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Gairola A, Wetten A, Dyson J. Sodium/bile acid co-transporter inhibitors currently in preclinical or early clinical development for the treatment of primary biliary cholangitis. Expert Opin Investig Drugs 2024; 33:485-495. [PMID: 38613839 DOI: 10.1080/13543784.2024.2343789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/12/2024] [Indexed: 04/15/2024]
Abstract
INTRODUCTION Pruritus is common and often undertreated in patients with primary biliary cholangitis (PBC). Existing treatments largely have an aging and low-quality evidence base, and studies included only small numbers of patients. More recent data that has added to our understanding of pruritus treatments has often come from clinical trials where itching was a secondary outcome measure in a trial designed primarily to assess disease-modifying agents. This area represents an unmet clinical need in the management of PBC. AREAS COVERED In this manuscript, we first summarize the proposed mechanisms for PBC-related pruritus and the current treatment paradigm. We then present an appraisal of the existing pre-clinical and clinical evidence for the use of ileal bile acid transporter inhibitors (IBATis) for this indication in PBC patients. EXPERT OPINION Evidence for the efficacy of IBATis is promising but limited by the currently available volume of data. Furthermore, larger clinical trials with long-term data on efficacy, safety and tolerability are needed to confirm the role of using IBATis in clinical practice and their place on the itch treatment ladder. Additional focus should also be given to exploring the disease-modifying potential of IBATis in PBC.
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Affiliation(s)
- Abhishek Gairola
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Aaron Wetten
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | - Jessica Dyson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
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3
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Kupari J, Ernfors P. Molecular taxonomy of nociceptors and pruriceptors. Pain 2023; 164:1245-1257. [PMID: 36718807 PMCID: PMC10184562 DOI: 10.1097/j.pain.0000000000002831] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/10/2022] [Accepted: 11/21/2022] [Indexed: 02/01/2023]
Affiliation(s)
- Jussi Kupari
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Patrik Ernfors
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Dacheux MA, Norman DD, Tigyi GJ, Lee SC. Emerging roles of lysophosphatidic acid receptor subtype 5 (LPAR5) in inflammatory diseases and cancer. Pharmacol Ther 2023; 245:108414. [PMID: 37061203 DOI: 10.1016/j.pharmthera.2023.108414] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/17/2023]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that regulates a variety of cellular functions such as cell proliferation, migration, survival, calcium mobilization, cytoskeletal rearrangements, and neurite retraction. The biological actions of LPA are mediated by at least six G protein-coupled receptors known as LPAR1-6. Given that LPAR1-3 were among the first LPARs identified, the majority of research efforts have focused on understanding their biology. This review provides an in-depth discussion of LPAR5, which has recently emerged as a key player in regulating normal intestinal homeostasis and modulating pathological conditions such as pain, itch, inflammatory diseases, and cancer. We also present a chronological overview of the efforts made to develop compounds that target LPAR5 for use as tool compounds to probe or validate LPAR5 biology and therapeutic agents for the treatment of inflammatory diseases and cancer.
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Affiliation(s)
- Mélanie A Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Gábor J Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America.
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Ciotu CI, Kistner K, Kaindl U, Millesi F, Weiss T, Radtke C, Kremer A, Schmidt K, Fischer MJM. Schwann cell stimulation induces functional and structural changes in peripheral nerves. Glia 2023; 71:945-956. [PMID: 36495059 DOI: 10.1002/glia.24316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 11/19/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022]
Abstract
Signal propagation is the essential function of nerves. Lysophosphatidic acid 18:1 (LPA) allows the selective stimulation of calcium signaling in Schwann cells but not neurons. Here, the time course of slowing and amplitude reduction on compound action potentials due to LPA exposure was observed in myelinated and unmyelinated fibers of the mouse, indicating a clear change of axonal function. Teased nerve fiber imaging showed that Schwann cell activation is also present in axon-attached Schwann cells in freshly isolated peripheral rat nerves. The LPA receptor 1 was primarily localized at the cell extensions in isolated rat Schwann cells, suggesting a role in cell migration. Structural investigation of rat C-fibers demonstrated that LPA leads to an evagination of the axons from their Schwann cells. In A-fibers, the nodes of Ranvier appeared unchanged, but the Schmidt-Lanterman incisures were shortened and myelination reduced. The latter might increase leak current, reducing the potential spread to the next node of Ranvier and explain the changes in conduction velocity. The observed structural changes provide a plausible explanation for the functional changes in myelinated and unmyelinated axons of peripheral nerves and the reported sensory sensations such as itch and pain.
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Affiliation(s)
- Cosmin I Ciotu
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Katrin Kistner
- Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Ulrich Kaindl
- Department of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Flavia Millesi
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Tamara Weiss
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Andreas Kremer
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Katy Schmidt
- Department of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Michael J M Fischer
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol 2023; 20:26-36. [PMID: 36307649 DOI: 10.1038/s41575-022-00687-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 02/01/2023]
Abstract
Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.
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Zhang Y, Richter N, König C, Kremer AE, Zimmermann K. Generalized resistance to pruritogen-induced scratching in the C3H/HeJ strain. Front Mol Neurosci 2022; 15:934564. [PMID: 36277491 PMCID: PMC9581333 DOI: 10.3389/fnmol.2022.934564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Previously the effect of the pruritogens, such as histamine and chloroquine, was tested in 11 inbred mouse strains, and this study aimed to identify resistant and sensitive strains, consistent with the observation that underlies the large variability in human populations. In the present study, we used the low responder C3H/HeJ (C3H) and the more sensitive C57BL/6J (C57) strain to find out if resistance and sensitivity to develop pruritus is restricted to only histamine and chloroquine or extends to other known pruritogens as well. We tested five additional commonly known pruritogens. We established dose-response relationships by injecting four concentrations of the pruritogens in the range of 0.3, 1, 3, and ten-fold in the nuchal fold. Then we assessed the scratching behavior for 30 min after injection with an automated custom-designed device based on the bilateral implantation of mini-magnets in the hind paws and on single cages placed within a magnetic coil. We found that the resistance to pruritogens is a general phenotype of the C3H strain and extends to all pruritogens tested, including not only histamine and chloroquine, but also endothelin, trypsin, 5-HT (serotonin), the short peptide SLIGRL, and Lysophosphatidic acid (LPA). C57 was more sensitive to all pruritogens and, in contrast to C3H, dose-response relationships were evident for some of the pruritogens. In general, comparable peak scratch responses were observed for the 0.3-fold concentrations of the pruritogens in C57 whereas C3H required at least the ten-fold concentration and still displayed only between 5 and 33% of the scratch responses observed in C57 for the respective pruritogen. The general resistance to pruritogens and the low level of scratching behavior found in the C3H strain is an interesting trait and represents a model for the study of the heritability of itch. It is accompanied in C3H with a higher sensitivity in assays of nociception.
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Affiliation(s)
- Yanbin Zhang
- Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Nicole Richter
- Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Christine König
- Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas E. Kremer
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zurich, Switzerland
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Katharina Zimmermann
- Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Katharina Zimmermann
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Süzen Çaypınar S, Oğlak SC, Behram M, Gedik Özköse Z, Sezer S, Karakaş S. Serum autotaxin levels correlate with the severity of pruritus in intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res 2022; 48:3093-3102. [PMID: 36164271 DOI: 10.1111/jog.15444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/25/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE This study aimed to examine autotaxin (ATX) concentrations in the serum of pregnant women complicated with intrahepatic cholestasis of pregnancy (ICP) and compare them with individuals with uncomplicated healthy pregnancies. METHODS This prospective case-control study took place with 83 pregnant women. The study group included 43 pregnant women presenting with a singleton pregnancy diagnosed with ICP in their third trimester of pregnancy. The diagnostic power of the ATX variable was examined by receiver operating characteristic analysis, and the cut-off value calculated according to the Youden index was summarized with the related sensitivity and specificity points. RESULTS The mean serum concentration of maternal ATX was significantly higher in the ICP cases (8.91 ± 2.69 pg/mL) compared to the pregnant women in the control group (3.59 ± 1.39 ng/mL, p < 0.001). According to the Youden index, a 5.80 ng/mL cut-off value of serum ATX concentrations can be used to diagnose ICP with 97.7% sensitivity and 97.5% specificity. A significant highly positive correlation was found between maternal serum ATX levels and maternal serum total bile acid levels (r = 0.633 and p < 0.001) and itch intensity, which was objectified by the visual analog scale score (r = 0.951 and p < 0.001). CONCLUSION Maternal serum ATX levels were significantly increased in ICP patients as compared with healthy pregnant women. Also, serum ATX activity was highly correlated with the itch intensity. We consider that ATX might represent a robust, accurate, and reliable circulating biomarker to diagnose ICP.
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Affiliation(s)
- Sema Süzen Çaypınar
- Department of Perinatology, Başakşehir Çam ve Sakura City Hospital, Istanbul, Turkey
| | - Süleyman Cemil Oğlak
- Department of Obstetrics and Gynecology, Health Sciences University, Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey
| | - Mustafa Behram
- Department of Perinatology, Health Sciences University, Antalya Training and Research Hospital, Istanbul, Turkey
| | - Zeynep Gedik Özköse
- Department of Perinatology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| | - Salim Sezer
- Department of Perinatology, Esenyurt University Hospital, Istanbul, Turkey
| | - Sema Karakaş
- Department of Gynecologic Oncology, Health Sciences University, Bakırköy Dr Sadi Konuk Training and Research Hospital, Istanbul, Turkey
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Langedijk J, Araya EI, Barroso AR, Tolenaars D, Nazaré M, Belabed H, Schoene J, Chichorro JG, Oude Elferink R. An LPAR5-antagonist that reduces nociception and increases pruriception. FRONTIERS IN PAIN RESEARCH 2022; 3:963174. [PMID: 35959236 PMCID: PMC9360597 DOI: 10.3389/fpain.2022.963174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The G-protein coupled receptor LPAR5 plays a prominent role in LPA-mediated pain and itch signaling. In this study we focus on the LPAR5-antagonist compound 3 (cpd3) and its ability to affect pain and itch signaling, both in vitro and in vivo. Methods Nociceptive behavior in wild type mice was induced by formalin, carrageenan or prostaglandin E2 (PGE2) injection in the hind paw, and the effect of oral cpd3 administration was measured. Scratch activity was measured after oral administration of cpd3, in mice overexpressing phospholipase A2 (sPLA2tg), in wild type mice (WT) and in TRPA1-deficient mice (Trpa1 KO). In vitro effects of cpd3 were assessed by measuring intracellular calcium release in HMC-1 and HEK-TRPA1 cells. Results As expected, nociceptive behavior (induced by formalin, carrageenan or PGE2) was reduced after treatment with cpd3. Unexpectedly, cpd3 induced scratch activity in mice. In vitro addition of cpd3 to HEK-TRPA1 cells induced an intracellular calcium wave that could be inhibited by the TRPA1-antagonist A-967079. In Trpa1 KO mice, however, the increase in scratch activity after cpd3 administration was not reduced. Conclusions Cpd3 has in vivo antinociceptive effects but induces scratch activity in mice, probably by activation of multiple pruriceptors, including TRPA1. These results urge screening of antinociceptive candidate drugs for activity with pruriceptors.
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Affiliation(s)
- Jacqueline Langedijk
- Amsterdam University Medical Centers (UMC), Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AG&M), Amsterdam, Netherlands
| | - Erika Ivanna Araya
- Department of Pharmacology, Biological Sciences Sector, Federal University of Parana, Curitiba, Brazil
| | - Amanda Ribeiro Barroso
- Department of Pharmacology, Biological Sciences Sector, Federal University of Parana, Curitiba, Brazil
| | - Dagmar Tolenaars
- Amsterdam University Medical Centers (UMC), Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AG&M), Amsterdam, Netherlands
| | - Marc Nazaré
- Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Hassane Belabed
- Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Jens Schoene
- Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | | | - Ronald Oude Elferink
- Amsterdam University Medical Centers (UMC), Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AG&M), Amsterdam, Netherlands
- *Correspondence: Ronald Oude Elferink
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10
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Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin. Pain 2021; 163:445-460. [PMID: 34166323 DOI: 10.1097/j.pain.0000000000002363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 04/13/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors e.g. from the Mrgpr family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules.In this study, we scrutinized the effects of LPA in humans by two different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application via inactivated cowhage spicules evoked a moderate itch sensation. LPA microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of TRPA1 or TRPV1 reduced heat hyperalgesia but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechano-sensitive (CM) and mechano-insensitive (CMi) C-fibers. LPA microinjections activated a greater proportion of CMi and more strongly than CM fibers; spicule-application of LPA activated CM and CMi fibers to a similar extent but excited CM more and CMi fibers less intensely than microinjections.In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C-fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents, and a specific combination of activated fiber subclasses might contribute.
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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12
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Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165958. [PMID: 32896605 DOI: 10.1016/j.bbadis.2020.165958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/21/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
Cholestasis, a condition characterized by an abnormal decrease in bile flow, is accompanied by various symptoms such as pruritus. Although cholestatic pruritus is a prominent condition, its precise mechanisms have largely been elusive. Recently, advancements have been made for understanding the etiology and pathogenesis of cholestatic pruritus. The current review therefore focuses on summarizing the overall progress made in the elucidation of its molecular mechanisms. We have reviewed the available animal models on cholestasis to compare the differences between them, characterized potential pruritogens involved in cholestatic pruritus, and have summarized the receptor and ion channels implicated in the condition. Finally, we have discussed the available treatment options for alleviation of cholestatic pruritus. As our understanding of the mechanisms of cholestatic pruritus deepens, novel strategies to cure this condition are awaited.
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Affiliation(s)
- Babina Sanjel
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
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13
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Abstract
Itch is a unique sensation that helps organisms scratch away external threats; scratching itself induces an immune response that can contribute to more itchiness. Itch is induced chemically in the peripheral nervous system via a wide array of receptors. Given the superficial localization of itch neuron terminals, cells that dwell close to the skin contribute significantly to itch. Certain mechanical stimuli mediated by recently discovered circuits also contribute to the itch sensation. Ultimately, in the spinal cord, and likely in the brain, circuits that mediate touch, pain, and itch engage in cross modulation. Much of itch perception is still a mystery, but we present in this review the known ligands and receptors associated with itch. We also describe experiments and findings from investigations into the spinal and supraspinal circuitry responsible for the sensation of itch.
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Affiliation(s)
- Mark Lay
- The Solomon H. Snyder Department of Neuroscience and the Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;,
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience and the Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;,
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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14
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Yanagida K, Valentine WJ. Druggable Lysophospholipid Signaling Pathways. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1274:137-176. [DOI: 10.1007/978-3-030-50621-6_7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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15
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Hussain AB, Samuel R, Hegade VS, Jones DE, Reynolds NJ. Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy. Br J Dermatol 2019; 181:1138-1145. [PMID: 30920648 DOI: 10.1111/bjd.17933] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood. OBJECTIVES To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch. METHODS A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area. RESULTS Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor. CONCLUSIONS Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC. What's already known about this topic? Primary biliary cholangitis (PBC) is frequently associated with intractable pruritus for which current treatment options are often unsuccessful. Phototherapy is used as an experimental treatment for PBC-associated pruritus when alternative better-studied treatments fail. What does this study add? This study reviews the current literature on the pathophysiology and management of cholestatic pruritus, an area which remains poorly understood. We propose testable hypotheses of the mechanisms behind the attenuation of cholestatic pruritus with phototherapy.
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Affiliation(s)
- A B Hussain
- Newcastle Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - R Samuel
- Newcastle Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
| | - V S Hegade
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
- Liver Unit, Freeman Hospital, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - D E Jones
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
- Liver Unit, Freeman Hospital, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - N J Reynolds
- Newcastle Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, NHS Foundation Trust, Newcastle upon Tyne, U.K
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
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16
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Patel SP, Vasavda C, Ho B, Meixiong J, Dong X, Kwatra SG. Cholestatic pruritus: Emerging mechanisms and therapeutics. J Am Acad Dermatol 2019; 81:1371-1378. [PMID: 31009666 DOI: 10.1016/j.jaad.2019.04.035] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/08/2019] [Accepted: 04/13/2019] [Indexed: 01/01/2023]
Abstract
Patients suffering from cholestasis often report experiencing a debilitating, unrelenting itch. In contrast to conditions, such as urticaria, in which histamine primarily drives itch (pruritus), cholestatic pruritus is multifactorial and more difficult to treat. Existing therapies are not always effective and have undesirable adverse effect profiles. Here, we conducted a systematic literature review to evaluate conventional treatment strategy, current pathophysiologic understanding, and the role of new therapies in the context of cholestatic pruritus. We discuss novel findings implicating bile acids, lysophosphatidic acid, and bilirubin as potential important mediators of cholestatic itch. New therapies that aim to remove or modulate pruritogens have been supported in observational cohort studies and randomized controlled trials. Although these new therapies show promise, further research is needed to confirm the pathophysiology of cholestatic pruritus so that targeted therapy can be developed.
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Affiliation(s)
- Sagar P Patel
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Chirag Vasavda
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Byron Ho
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - James Meixiong
- The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Xinzhong Dong
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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17
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Robering JW, Gebhardt L, Wolf K, Kühn H, Kremer AE, Fischer MJM. Lysophosphatidic acid activates satellite glia cells and Schwann cells. Glia 2019; 67:999-1012. [PMID: 30637823 DOI: 10.1002/glia.23585] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 12/14/2018] [Accepted: 12/20/2018] [Indexed: 12/16/2022]
Abstract
Pruritus is a common and disabling symptom in patients with hepatobiliary disorders, particularly in those with cholestatic features. Serum levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in patients suffering from hepatic pruritus, correlated with itch severity and response to treatment. Here we show that in a culture of dorsal root ganglia LPA 18:1 surprisingly activated a large fraction of satellite glia cells, and responses to LPA 18:1 correlated inversely with responses to neuronal expressed transient receptor potential channels. LPA 18:1 caused only a marginal activation of heterologously expressed TRPV1, and responses in dorsal root ganglion cultures from TRPV1-deficient mice were similar to controls. LPA 18:1 desensitized subsequent responsiveness to chloroquine and TGR5 agonist INT-777. The LPA 18:1-induced increase in cytoplasmatic calcium stems from the endoplasmatic reticulum. LPA receptor expression in dorsal root ganglia and Schwann cells, LPAR1 immunohistochemistry, and pharmacological results indicate a signaling pathway through LPA receptor 1. Peripheral rat Schwann cells, which are of glial lineage as the satellite glia cells, were also responsive to LPA 18:1. Summarizing, LPA 18:1 primarily activates rather glial cells than neurons, which may subsequently modulate neuronal responsiveness and sensory sensations such as itch and pain.
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Affiliation(s)
- Jan W Robering
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Gebhardt
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.,Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Katharina Wolf
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Helen Kühn
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas E Kremer
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Michael J M Fischer
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.,Center for Physiology and Pharmacology, University of Vienna, Vienna, Austria
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18
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Lei L, Su J, Chen J, Chen W, Chen X, Peng C. The role of lysophosphatidic acid in the physiology and pathology of the skin. Life Sci 2018; 220:194-200. [PMID: 30584899 DOI: 10.1016/j.lfs.2018.12.040] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/25/2018] [Accepted: 12/21/2018] [Indexed: 12/13/2022]
Abstract
Lysophosphatidic acid (LPA) is the simplest phospholipid found in nature. LPA is mainly biosynthesized in tissues and cells by autotoxin and PA-PLA1α/PA-PLA1β and is degraded by lipid phosphate phosphatases (LPPs). It is an important component of biofilm, an extracellular signal transmitter and intracellular second messenger. After targeting to endothelial differentiation gene (Edg) family LPA receptors (LPA1, LPA2, LPA3) and non-Edg family LPA receptors (LPA4, LPA5, LPA6), LPA mediates physiological and pathological processes such as embryonic development, angiogenesis, tumor progression, fibrogenesis, wound healing, ischemia/reperfusion injury, and inflammatory reactions. These processes are induced through signaling pathways including mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)/Akt, protein kinase C (PKC)-GSK3β-β-catenin, Rho, Stat, and hypoxia-inducible factor 1-alpha (HIF-1α). LPA is involved in multiple physiological and pathological processes in the skin. It not only regulates skin function but also plays an important role in hair follicle development, skin wound healing, pruritus, skin tumors, and scleroderma. Pharmacological inhibition of LPA synthesis or antagonization of LPA receptors is a new strategy for the treatment of various skin disorders. This review focuses on the current understanding of the pathophysiologic role of LPA in the skin.
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Affiliation(s)
- Li Lei
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Junchen Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Wangqing Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China.
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19
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TRP Channels as Drug Targets to Relieve Itch. Pharmaceuticals (Basel) 2018; 11:ph11040100. [PMID: 30301231 PMCID: PMC6316386 DOI: 10.3390/ph11040100] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/26/2018] [Accepted: 10/03/2018] [Indexed: 12/14/2022] Open
Abstract
Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch at the molecular, cellular, and circuit levels. There is growing evidence that transient receptor potential (TRP) channels play important roles in itch signaling. The purpose of this review is to summarize our current knowledge about the role of TRP channels in the generation of itch under both physiological and pathological conditions, thereby identifying them as potential drug targets for effective anti-itch therapies.
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20
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Jafferany M, Davari ME. Itch and psyche: psychiatric aspects of pruritus. Int J Dermatol 2018; 58:3-23. [PMID: 29917231 DOI: 10.1111/ijd.14081] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 04/07/2018] [Accepted: 05/16/2018] [Indexed: 01/02/2023]
Abstract
Itch, also referred to as pruritus, is an unpleasant cutaneous sensation provoking the desire to scratch. It is often an uncomfortable, subjective sensation responsible for decreased quality of life in a variety of psychodermatological conditions. Comorbid psychiatric conditions, including depression and anxiety, are frequently associated with itch and scratch cycle. The reciprocal and intricate relationship between the psyche and itch has been widely studied. The neurobiology of itch involves the complexity of specific mediators, itch-related neuronal pathways, and central processing of itch. The connection between itch and the psyche can be grouped under three headings: pruritic diseases with psychosocial sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Itch and pain modulation go together in most circumstances and involve various substances including histamine, interleukins, protease-activated receptors, transient receptor potential receptors, opioids, and cannabinoids. The close interaction between keratinocytes and nerve endings modulating pain and itch also play a major role. Management of itch associated with its psychosomatic components is directed at an underlying cause and adopting a holistic approach to address not only dermatologic and somatosensory aspects, but also the cognitive, emotional, and psychosocial components. An integrated multidisciplinary team consisting of a dermatologist, psychiatrist, psychologist, and social worker is vital in addressing the multifaceted aspects of pruritus.
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21
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Thébaut A, Debray D, Gonzales E. An update on the physiopathology and therapeutic management of cholestatic pruritus in children. Clin Res Hepatol Gastroenterol 2018; 42:103-109. [PMID: 29031874 DOI: 10.1016/j.clinre.2017.08.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 08/18/2017] [Accepted: 08/25/2017] [Indexed: 02/06/2023]
Abstract
Pruritus is a disabling symptom accompanying chronic cholestasis. In extreme cases, the refractory nature of pruritus can result in a need for invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway (similar to that associated with pain) regulated by several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adults, there is no consensus in children, in light of the difficulty of conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of specific therapies that should be associated with skin hydration and with non-specific treatment of cholestasis including ursodeoxycholic acid. Pruritus should be assessed as objectively as possible between each line of therapy. Rifampicin, a potent CYP3A4 inducer, is the first-line treatment of cholestatic pruritus. Second-line therapies require evaluation of the child in an expert center and are discussed on a case-by-case basis depending on the underlying disease and the experience of the center. These include inhibitors of serotonin reuptake (sertraline), opioid antagonists (naloxone), or ASBT inhibitors. Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases. The aim of the current update is to review the physiopathologic mechanisms implicated in cholestatic pruritus and to propose potential therapeutic strategies in children.
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Affiliation(s)
- A Thébaut
- Hépatologie et transplantation hépatique pédiatrique, hôpital Bicêtre, université Paris-Sud-11, Assistance Publique-Hôpitaux de Paris, 78, rue du Général-Leclerc, 94270 Le-Kremlin-Bicêtre, France; Inserm UMR-S-1174, Université-Paris-Sud-11, Orsay, France
| | - D Debray
- Hépatologie pédiatrique, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Inserm UMR-S-938, centre de recherche Saint-Antoine, Paris cedex 12, France
| | - E Gonzales
- Hépatologie et transplantation hépatique pédiatrique, hôpital Bicêtre, université Paris-Sud-11, Assistance Publique-Hôpitaux de Paris, 78, rue du Général-Leclerc, 94270 Le-Kremlin-Bicêtre, France; Inserm UMR-S-1174, Université-Paris-Sud-11, Orsay, France.
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22
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Thébaut A, Debray D, Gonzales E. Physiopathologie et prise en charge thérapeutique du prurit cholestatique de l’enfant. Arch Pediatr 2017; 24:682-688. [DOI: 10.1016/j.arcped.2017.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 02/10/2017] [Accepted: 04/24/2017] [Indexed: 01/12/2023]
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Kittaka H, Uchida K, Fukuta N, Tominaga M. Lysophosphatidic acid-induced itch is mediated by signalling of LPA 5 receptor, phospholipase D and TRPA1/TRPV1. J Physiol 2017; 595:2681-2698. [PMID: 28176353 DOI: 10.1113/jp273961] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/31/2017] [Indexed: 01/28/2023] Open
Abstract
KEY POINTS Lysophosphatidic acid (LPA) is an itch mediator, but not a pain mediator by a cheek injection model. Dorsal root ganglion neurons directly respond to LPA depending on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1). LPA-induced itch-related behaviours are decreased in TRPA1-knockout (KO), TRPV1KO or TRPA1TRPV1 double KO mice. TRPA1 and TRPV1 channels are activated by intracellular LPA, but not by extracellular LPA following LPA5 receptor activation with an activity of Ca2+ -independent phospholipase A2 and phospholipase D. Intracellular LPA interaction sites of TRPA1 are KK672-673 and KR977-978 (K: lysine, R: arginine). ABSTRACT Intractable and continuous itch sensations often accompany diseases such as atopic dermatitis, neurogenic lesions, uremia and cholestasis. Lysophosphatidic acid (LPA) is an itch mediator found in cholestatic itch patients and it induces acute itch and pain in experimental rodent models. However, the molecular mechanism by which LPA activates peripheral sensory neurons remains unknown. In this study, we used a cheek injection method in mice to reveal that LPA induced itch-related behaviours but not pain-related behaviours. The LPA-induced itch behaviour and cellular effects were dependent on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which are important for itch signal transduction. We also found that, among the six LPA receptors, the LPA5 receptor had the greatest involvement in itching. Furthermore, we demonstrated that phospholipase D (PLD) plays a critical role downstream of LPA5 and that LPA directly and intracellularly activates TRPA1 and TRPV1. These results suggest a unique mechanism by which cytoplasmic LPA produced de novo could activate TRPA1 and TRPV1. We conclude that LPA-induced itch is mediated by LPA5 , PLD, TRPA1 and TRPV1 signalling, and thus targeting TRPA1, TRPV1 or PLD could be effective for cholestatic itch interventions.
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Affiliation(s)
- Hiroki Kittaka
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan
| | - Kunitoshi Uchida
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.,Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, 814-0193, Japan
| | - Naomi Fukuta
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.,Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8787, Japan.,Institute for Environmental and Gender-Specific Medicine, Juntendo University, Urayasu, 279-0021, Japan
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Alhmada Y, Selimovic D, Murad F, Hassan SL, Haikel Y, Megahed M, Hannig M, Hassan M. Hepatitis C virus-associated pruritus: Etiopathogenesis and therapeutic strategies. World J Gastroenterol 2017; 23:743-750. [PMID: 28223719 PMCID: PMC5296191 DOI: 10.3748/wjg.v23.i5.743] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 11/17/2016] [Accepted: 12/08/2016] [Indexed: 02/06/2023] Open
Abstract
In addition to its contributing role in the development of chronic liver diseases, chronic hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, particularly, cutaneous-based disorders including those with pruritus as a symptom. Pruritus is frequently associated with the development of chronic liver diseases such as cholestasis and chronic viral infection, and the accumulation of bile acids in patients’ sera and tissues as a consequence of liver damage is considered the main cause of pruritus. In addition to their role in dietary lipid absorption, bile acids can trigger the activation of specific receptors, such as the G protein-coupled bile acid receptor (GPBA/ TGR5). These types of receptors are known to play a crucial role in the modulation of the systemic actions of bile acids. TGR5 expression in primary sensory neurons triggers the activation of the transient receptor potential vanilloid 1 (TRPV1) leading to the induction of pruritus by an unknown mechanism. Although the pathologic phenomenon of pruritus is common, there is no uniformly effective therapy available. Understanding the mechanisms regulating the occurrence of pruritus together with the conduction of large-scale clinical and evidence-based studies, may help to create a standard treatment protocol. This review focuses on the etiopathogenesis and treatment strategies of pruritus associated with chronic HCV infection.
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25
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Hegade VS, Bolier R, Oude Elferink RPJ, Beuers U, Kendrick S, Jones DEJ. A systematic approach to the management of cholestatic pruritus in primary biliary cirrhosis. Frontline Gastroenterol 2016; 7:158-166. [PMID: 28839853 PMCID: PMC5369477 DOI: 10.1136/flgastro-2015-100618] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/04/2023] Open
Abstract
Pruritus (itch) is an important symptom of primary biliary cirrhosis (PBC), an archetypal cholestatic liver disease. Cholestatic pruritus can be a debilitating symptom causing significant deterioration in patients' quality of life. Effective management of pruritus in PBC involves awareness among clinicians to adequately assess its severity, and treatment with specific drug therapies in line with current practice guidelines. In PBC, antipruritic drugs are not universally effective and/or have significant side effects, and despite best efforts with various combinations of drugs, some patients remain significantly symptomatic, eventually opting for invasive or experimental treatments. Therefore, there is a clear unmet need for better alternative treatments for patients with refractory or intractable cholestatic pruritus. Recent advances in the understanding of pathogenesis of cholestatic pruritus and bile acid physiology have raised hopes for novel therapies, some of which are currently under trial. In this review, we aim to provide a practical guide to the management of this important and complex problem, discussing current knowledge and recent advances in the pathogenesis, summarise the evidence base for available therapeutic approaches and update potential novel future therapies for the management of pruritus in PBC.
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Affiliation(s)
- Vinod S Hegade
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Ruth Bolier
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald PJ Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stuart Kendrick
- GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, Hertfordshire, UK
| | - David EJ Jones
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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26
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27
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Abstract
Itch is a unique sensation associated with the scratch reflex. Although the scratch reflex plays a protective role in daily life by removing irritants, chronic itch remains a clinical challenge. Despite urgent clinical need, itch has received relatively little research attention and its mechanisms have remained poorly understood until recently. The goal of the present review is to summarize our current understanding of the mechanisms of acute as well as chronic itch and classifications of the primary itch populations in relationship to transient receptor potential (Trp) channels, which play pivotal roles in multiple somatosensations. The convergent involvement of Trp channels in diverse itch signaling pathways suggests that Trp channels may serve as promising targets for chronic itch treatments.
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Affiliation(s)
- Shuohao Sun
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
- Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
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28
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Bolier R, Tolenaars D, Kremer AE, Saris J, Parés A, Verheij J, Bosma PJ, Beuers U, Oude Elferink RP. Enteroendocrine cells are a potential source of serum autotaxin in men. Biochim Biophys Acta Mol Basis Dis 2016; 1862:696-704. [DOI: 10.1016/j.bbadis.2016.01.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/22/2015] [Accepted: 01/12/2016] [Indexed: 12/26/2022]
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Abstract
OBJECTIVE Pruritus is a common symptom of cholestatic liver disorders. The present study aimed at evaluating autotaxin (ATX), a lysophospholipase recently identified as potential cause for cholestatic pruritus, in pediatric cholestatic diseases presenting with or without itching. METHODS A cohort of 45 children consisting of 14 patients experiencing itching (Alagille syndrome [n = 10], complete extrahepatic biliary atresia [n = 2], neonatal sclerosing cholangitis (n = 1), progressive familial intrahepatic cholestasis type 2 [n = 1]), 9 patients with bile acid synthesis defects (3β-hydroxy-C27-steroid-oxidoreductase [n = 7] and Δ-3-oxosteroid-5β-reductase deficiency [n = 2]), and 22 healthy children were studied. Serum ATX activity and total serum bile salt were determined enzymatically, ATX protein content was semiquantified by Western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor agonists or vehicle. RESULTS Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean ± standard deviation: 16.1 ± 4.3 nmol · mL · min) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 ± 4.7 nmol · mL · min; P < 0.01) and healthy controls (7.6 ± 2.3 nmol · mL · min; P < 0.001). ATX protein levels closely correlated with serum ATX activity. Serum ATX activity and total serum bile salt showed a linear correlation with itch intensity (r = 0.66, P < 0.001 and r = 0.80, P < 0.001, respectively). No correlation was observed between ATX activity and bilirubin. ATX mRNA expression in HepG2 cells was not induced by farnesoid-X-receptor ligands. CONCLUSIONS Serum ATX activity correlated with itch intensity in children with cholestatic diseases. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in pediatric cholestatic disorders.
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Bassari R, Koea JB. Jaundice associated pruritis: A review of pathophysiology and treatment. World J Gastroenterol 2015; 21:1404-1413. [PMID: 25663760 PMCID: PMC4316083 DOI: 10.3748/wjg.v21.i5.1404] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/19/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective.
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Festa C, Renga B, D’Amore C, Sepe V, Finamore C, De Marino S, Carino A, Cipriani S, Monti MC, Zampella A, Fiorucci S. Exploitation of Cholane Scaffold for the Discovery of Potent and Selective Farnesoid X Receptor (FXR) and G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1) Ligands. J Med Chem 2014; 57:8477-95. [DOI: 10.1021/jm501273r] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Carmen Festa
- Department
of Pharmacy, University of Naples “Federico II”, Via D. Montesano
49, I-80131 Naples, Italy
| | - Barbara Renga
- Department
of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
| | - Claudio D’Amore
- Department
of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
| | - Valentina Sepe
- Department
of Pharmacy, University of Naples “Federico II”, Via D. Montesano
49, I-80131 Naples, Italy
| | - Claudia Finamore
- Department
of Pharmacy, University of Naples “Federico II”, Via D. Montesano
49, I-80131 Naples, Italy
| | - Simona De Marino
- Department
of Pharmacy, University of Naples “Federico II”, Via D. Montesano
49, I-80131 Naples, Italy
| | - Adriana Carino
- Department
of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
| | - Sabrina Cipriani
- Department
of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
| | - Maria Chiara Monti
- Department
of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084, Fisciano, Salerno, Italy
| | - Angela Zampella
- Department
of Pharmacy, University of Naples “Federico II”, Via D. Montesano
49, I-80131 Naples, Italy
| | - Stefano Fiorucci
- Department
of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
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Lysophosphatidic acid and signaling in sensory neurons. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1851:61-5. [PMID: 25218302 DOI: 10.1016/j.bbalip.2014.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 08/22/2014] [Accepted: 09/05/2014] [Indexed: 12/23/2022]
Abstract
Lysophosphatidic acid is a potent signaling lipid molecule that has initially been characterized as a growth factor. However, later studies have revealed many more functions such as modulation of cell shape, cell migration, prevention of apoptosis, platelet aggregation, wound healing, osteoclast differentiation, vasopressor activity, embryo implantation, angiogenesis, lung fibrosis, hair growth and more. The molecule mainly acts through the activation of a set of at least 6 G-protein-coupled receptors (LPA1-6), but intracellular LPA was also shown to signal through the activation of the nuclear receptor PPARγ. In this short review we discuss the recent observations which suggest that in pathological conditions LPA also modulates signaling in sensory neurons. Thus, LPA has been shown to play a role in the initiation of neuropathic pain and, more recently, a relation was observed between increased LPA levels in the circulation and cholestatic itch. The mechanism by which this occurs remains to be elucidated. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics.
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Song M, Lee D, Kim S, Bae JS, Lee J, Gong YD, Lee T, Lee S. Identification of metabolites of N-(5-benzoyl-2-(4-(2-methoxyphenyl)piperazin-1-yl)thiazol-4-yl)pivalamide including CYP3A4-mediated C-demethylation in human liver microsomes with high-resolution/high-accuracy tandem mass. Drug Metab Dispos 2014; 42:1252-60. [PMID: 24829290 DOI: 10.1124/dmd.114.057570] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
KRO-105714 [N-(5-benzoyl-2-(4-(2-methoxyphenyl)piperazin-1-yl)thiazol-4-yl)pivalamide] is a 2,4,5-trisubstituted 1,3-thiazole derivative that exerts anti-atopic dermatitis activity via robust suppression of the sphingosylphosphorylcholine receptor. This study used high-resolution/high-accuracy tandem mass spectroscopy (HRMS) and recombinant cDNA-expressed cytochrome P450 (P450) isoforms to identify the metabolic pathway and metabolites of KRO-105714 in human liver microsomes (HLMs) as therapeutic agents for inflammation. The incubation of KRO-105714 with pooled HLMs in the presence of NADPH generated four metabolites (M1-M4). The metabolites were identified using HRMS and confirmed using synthetic standards for M2 and M4. M1 and M2 were identified as monohydroxylated metabolites, and M3 and M4 were identified as O-demethyl KRO-105714 and C-demethyl KRO-105714, respectively. In the inhibition study with selective CYP3A4 inhibitors and incubation in recombinant cDNA-expressed P450 enzymes, all the metabolites of KRO-105714 were formed by CYP3A4 in HLMs. The CYP3A4-mediated formation of M4 from M2 was confirmed via incubation of M2 in HLMs. These results showed that the unusual C-demethylated metabolite M4 was generated from monohydroxyl metabolite M2 via a CYP3A4-mediated enzymatic reaction in HLMs.
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Affiliation(s)
- Min Song
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Doohyun Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Sun Kim
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Jong-Sup Bae
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Jaeick Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Young-Dae Gong
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Taeho Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
| | - Sangkyu Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea (M.S., D.L., S.K., J.-S.B., T.L., S.L.); Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul, Republic of Korea (J.L.); and Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University, Seoul, Republic of Korea (Y.-D.G.)
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Kremer AE, Bolier R, van Dijk R, Oude Elferink RPJ, Beuers U. Advances in pathogenesis and management of pruritus in cholestasis. Dig Dis 2014; 32:637-45. [PMID: 25034299 DOI: 10.1159/000360518] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, μ-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the μ-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis.
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Affiliation(s)
- Andreas E Kremer
- Department of Medicine 1, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany
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Beuers U, Kremer AE, Bolier R, Elferink RPJO. Pruritus in cholestasis: facts and fiction. Hepatology 2014; 60:399-407. [PMID: 24807046 DOI: 10.1002/hep.26909] [Citation(s) in RCA: 152] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 10/21/2013] [Indexed: 12/13/2022]
Abstract
Pruritus is a common symptom in patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, or hereditary pediatric cholestatic disorders and may accompany, although less frequently, many other liver diseases. Recent findings indicate that lysophosphatidic acid (LPA), a potent neuronal activator, and autotaxin (ATX; ectonucleotide pyrophosphatase/phosphodiesterase 2), the enzyme which forms LPA, may form a key element of the long-sought pruritogenic signaling cascade in cholestatic patients suffering from itch. Serum ATX, but no other pruritogen candidate studied so far, correlates with pruritus intensity and responds to therapeutic interventions. In this comprehensive review, we provide a short update on actual insights in signal transmission related to pruritus and discuss pruritogen candidates in cholestasis. We also summarize evidence-based and guideline-approved as well as experimental therapeutic approaches for patients suffering from pruritus in cholestasis.
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Affiliation(s)
- Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, The Netherlands
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36
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Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta Mol Basis Dis 2014; 1842:869-92. [DOI: 10.1016/j.bbadis.2014.02.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 02/16/2014] [Accepted: 02/18/2014] [Indexed: 12/12/2022]
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Potentials of the Circulating Pruritogenic Mediator Lysophosphatidic Acid in Development of Allergic Skin Inflammation in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:1593-603. [DOI: 10.1016/j.ajpath.2014.01.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 01/05/2014] [Accepted: 01/16/2014] [Indexed: 01/03/2023]
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Abstract
While considerable effort has been made to investigate the neural mechanisms of pain, much less effort has been devoted to itch, at least until recently. However, itch is now gaining increasing recognition as a widespread and costly medical and socioeconomic issue. This is accompanied by increasing interest in the underlying neural mechanisms of itch, which has become a vibrant and rapidly-advancing field of research. The goal of the present forefront review is to describe the recent progress that has been made in our understanding of itch mechanisms.
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Affiliation(s)
- Tasuku Akiyama
- University of California, Davis, Department of Neurobiology, Physiology & Behavior, 1 Shields Avenue, Davis, CA 95616, United States
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Rancoule C, Attané C, Grès S, Fournel A, Dusaulcy R, Bertrand C, Vinel C, Tréguer K, Prentki M, Valet P, Saulnier-Blache JS. Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice. Diabetologia 2013; 56:1394-402. [PMID: 23508306 DOI: 10.1007/s00125-013-2891-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 03/04/2013] [Indexed: 12/12/2022]
Abstract
AIMS/HYPOTHESIS Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. METHODS First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mg kg(-1) day(-1), i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. RESULTS In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucose-induced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. CONCLUSIONS/INTERPRETATION Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice.
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Affiliation(s)
- C Rancoule
- Institut des Maladies Métaboliques et Cardiovasculaires, Université Paul Sabaties, Inserm U1048, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France
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Liu T, Ji RR. New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch 2013; 465:1671-85. [PMID: 23636773 DOI: 10.1007/s00424-013-1284-2] [Citation(s) in RCA: 135] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Revised: 04/13/2013] [Accepted: 04/14/2013] [Indexed: 12/30/2022]
Abstract
Itch and pain are closely related but distinct sensations. They share largely overlapping mediators and receptors, and itch-responding neurons are also sensitive to pain stimuli. Itch-mediating primary sensory neurons are equipped with distinct receptors and ion channels for itch transduction, including Mas-related G protein-coupled receptors (Mrgprs), protease-activated receptors, histamine receptors, bile acid receptor, toll-like receptors, and transient receptor potential subfamily V1/A1 (TRPV1/A1). Recent progress has indicated the existence of an itch-specific neuronal circuitry. The MrgprA3-expressing primary sensory neurons exclusively innervate the epidermis of skin, and their central axons connect with gastrin-releasing peptide receptor (GRPR)-expressing neurons in the superficial spinal cord. Notably, ablation of MrgprA3-expressing primary sensory neurons or GRPR-expressing spinal cord neurons results in selective reduction in itch but not pain. Chronic itch results from dysfunction of the immune and nervous system and can manifest as neural plasticity despite the fact that chronic itch is often treated by dermatologists. While differences between acute pain and acute itch are striking, chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitization (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and neuro-glial interactions. Notably, painful stimuli can elicit itch in some chronic conditions (e.g., atopic dermatitis), and some drugs for treating chronic pain are also effective in chronic itch. Thus, itch and pain have more similarities in pathological and chronic conditions.
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Affiliation(s)
- Tong Liu
- Pain Signaling and Plasticity Laboratory, Department of Anesthesiology and Neurobiology, Duke University Medical Center, 595 LaSalle Street, GSRB-I, Room 1027A, DUMC 3094, Durham, NC, 27710, USA,
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Bolier R, Oude Elferink RPJ, Beuers U. Advances in pathogenesis and treatment of pruritus. Clin Liver Dis 2013; 17:319-29. [PMID: 23540505 DOI: 10.1016/j.cld.2012.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The pathogenesis of itch during cholestasis is largely unknown and treatment options are limited. Lysophosphatidate, female steroid hormones, and endogenous opioids are among the agents discussed as potential pruritogens in cholestasis. The itch-alleviating action of guideline-based therapeutic interventions with anion exchanger resins, rifampicin, opioid antagonists, and serotonin reuptake inhibitors are studied to unravel the molecular pathogenesis of itch. Still, a considerable part of the patients is in need of alternative experimental therapeutic approaches (eg, UV-B phototherapy, extracorporeal albumin dialysis, nasobiliary drainage), providing additional information about the enigmatic pathophysiology of cholestatic pruritus.
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Affiliation(s)
- Ruth Bolier
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, G4-216, PO Box 22600, Amsterdam NL-1100 DD, The Netherlands
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Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F, Cevikbas F, Steinhoff M, Nassini R, Materazzi S, Guerrero-Alba R, Valdez-Morales E, Cottrell GS, Schoonjans K, Geppetti P, Vanner SJ, Bunnett NW, Corvera CU. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123:1513-30. [PMID: 23524965 DOI: 10.1172/jci64551] [Citation(s) in RCA: 282] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 01/17/2013] [Indexed: 12/23/2022] Open
Abstract
Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.
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Affiliation(s)
- Farzad Alemi
- Department of Surgery, UCSF, San Francisco, California 94121, USA
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Affiliation(s)
- Yasushi Kuraishi
- Laboratory of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study. J Hepatol 2012; 57:637-41. [PMID: 22613002 DOI: 10.1016/j.jhep.2012.04.023] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Revised: 04/04/2012] [Accepted: 04/04/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Pruritus is a disabling complication of cholestatic liver disorders. Its management remains challenging. Ultraviolet B (UVB) phototherapy has been successfully used to treat pruritus in other indications. METHODS This is an observational case series. The study population consists of 13 patients (10 females, mean age 52 years) with pruritus due to different cholestatic liver disorders: PBC (n=4), PSC (n=2), drug-induced (n=3) and persistent cholestasis after liver transplantation (LT) (n=4). Serum alkaline phosphatase levels were: 686 ± 363 μ/L and serum bile acids levels: 147 ± 15 μmol/L. In all patients, conventional medical treatment had failed to control pruritus. Perception of pruritus was recorded by the visual analogue scale (VAS). RESULTS The mean follow-up was 3 years. Ten patients (77%) had more than 60% reduction in perceived pruritus of which 4 had more than an 80% reduction. Median [25-75% percentiles] VAS score before and after treatment decreased from 8.0 [8.0-10] to 2.0 [1.5-2.1] (p<0.001). The mean number of irradiations required to obtain this effect was 26 ± 17 (average duration of phototherapy: 8 weeks). No significant changes in cholestatic serum markers were observed. Four patients (30%) needed an additional phototherapy course because of recurrent pruritus and in all of them again a marked improvement of pruritus was observed. The therapy was well tolerated, except in two patients who developed, during retreatment, pronounced erythema in one case and paresthesia in the other case. CONCLUSIONS UVB phototherapy appears to be a promising and well tolerated treatment also for cholestasis-associated pruritus.
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Current progress in non-Edg family LPA receptor research. Biochim Biophys Acta Mol Cell Biol Lipids 2012; 1831:33-41. [PMID: 22902318 DOI: 10.1016/j.bbalip.2012.08.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 08/01/2012] [Accepted: 08/02/2012] [Indexed: 01/08/2023]
Abstract
Lysophosphatidic acid (LPA) is the simplest phospholipid yet possesses myriad biological functions. Until 2003, the functions of LPA were thought to be elicited exclusively by three subtypes of the endothelial differentiation gene (Edg) family of G protein-coupled receptors - LPA(1), LPA(2), and LPA(3). However, several biological functions of LPA could not be assigned to any of these receptors indicating the existence of one or more additional LPA receptor(s). More recently, the discovery of a second cluster of LPA receptors which includes LPA(4), LPA(5), and LPA(6) has paved the way for new avenues of LPA research. Analyses of these non-Edg family LPA receptors have begun to fill in gaps to understand biological functions of LPA such as platelet aggregation and vascular development that could not be ascribed to classical Edg family LPA receptors and are also unveiling new biological functions. Here we review recent progress in the non-Edg family LPA receptor research, with special emphasis on the pharmacology, signaling, and physiological roles of this family of receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
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Imam MH, Gossard AA, Sinakos E, Lindor KD. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012; 27:1150-1158. [PMID: 22413872 DOI: 10.1111/j.1440-1746.2012.07109.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.
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Affiliation(s)
- Mohamad H Imam
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN 55905, USA
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Abstract
Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, USA
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Kuraishi Y. [Mechanisms of itch and the pharmacology of anti-pruritic agents]. Nihon Yakurigaku Zasshi 2012; 139:160-164. [PMID: 22498680 DOI: 10.1254/fpj.139.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
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Chen SC, Liu CC, Huang SY, Chiou SJ. Vascular hyperpermeability in response to inflammatory mustard oil is mediated by Rho kinase in mice systemically exposed to arsenic. Microvasc Res 2011; 82:182-9. [PMID: 21703283 DOI: 10.1016/j.mvr.2011.06.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2010] [Revised: 06/07/2011] [Accepted: 06/08/2011] [Indexed: 10/18/2022]
Abstract
The mechanisms underlying vascular dysfunction and cardiovascular disease induced by chronic arsenic exposure are not completely understood. We have previously shown that mice chronically fed sodium arsenite are hypersensitive to the permeability-increasing effects of inflammatory mustard oil. The aim of this study was to investigate whether RhoA/Rho kinase (ROCK)-mediated vascular leakage (hyperpermeability) is induced by mustard oil in mice systemically exposed to arsenic. Animals were orally fed water (control group) or sodium arsenite for 8weeks. We compared the blood pressure and microvessel density of the ears between these two groups. Both control and arsenic groups exhibited a similar mean arterial pressure and microvessel density. Microvessel permeability changes that occurred following mustard oil treatment in the presence of Y-27632, a ROCK inhibitor, were quantified using the Evans blue (EB) technique and vascular labeling with carbon particles. Both the excessive leakiness of EB and the high density of carbon-labeled microvessels upon stimulation with mustard oil in the arsenic-fed mice were reduced by Y-27632 treatment. However, RhoA and ROCK2 expression levels were similar between control and arsenic-fed mice. We further investigated ROCK2 levels and ROCK activity in the ears following mustard oil challenge. ROCK2 levels in mouse ears treated with mustard oil were higher in the arsenic group as compared with the control group. Following mustard oil application, ROCK activity was significantly higher in the arsenic-fed mice compared with the control mice. These findings indicate that increased ROCK2 levels and enhanced ROCK activity are responsible for mustard oil-induced vascular hyperpermeability in arsenic-fed mice.
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Affiliation(s)
- Shih-Chieh Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Abstract
Chronic itch represents a burdensome clinical problem that can originate from a variety of aetiologies. Pruriceptive itch originates following the activation of peripheral sensory nerve endings following damage or exposure to inflammatory mediators and ascends to the brain through the spinal thalamic tract. Much insight has been gained into the understanding of the mechanisms underlying pruriceptive itch through studies using humans and experimental animals. More than one sensory nerve subtype is thought to subserve pruriceptive itch which includes both unmyelinated C-fibres and thinly myelinated Aδ nerve fibres. There are a myriad of mediators capable of stimulating these afferent nerves leading to itch, including biogenic amines, proteases, cytokines, and peptides. Some of these mediators can also evoke sensations of pain and the sensory processing underlying both sensations overlaps in complex ways. Studies have demonstrated that both peripheral and central sensitization to pruritogenic stimuli occur during chronic itch.
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Affiliation(s)
- C Potenzieri
- Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, MD, USA
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