Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes
Autor: | Tianhao Zhou, Lixian Chen, Paul Baker, Konstantina Kyritsi, Ying Wan, Amelia Sybenga, Shannon Glaser, Gianfranco Alpini, Nan Wu, Chaodong Wu, Fanyin Meng, Heather Francis, Pietro Invernizzi, Julie Venter, Francesca Bernuzzi, Qiaobing Huang, Ludovica Ceci |
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Přispěvatelé: | Wan, Y, Ceci, L, Wu, N, Zhou, T, Chen, L, Venter, J, Francis, H, Bernuzzi, F, Invernizzi, P, Kyritsi, K, Baker, P, Huang, Q, Wu, C, Sybenga, A, Alpini, G, Meng, F, Glaser, S |
Rok vydání: | 2019 |
Předmět: |
Liver Cirrhosis
Male 0301 basic medicine MAPK/ERK pathway Senescence MAP Kinase Signaling System Calcitonin Gene-Related Peptide cholestatic liver diseases Cholangitis Sclerosing Cholangiocyte proliferation Calcitonin gene-related peptide Article Cholangiocyte Pathology and Forensic Medicine 03 medical and health sciences biliary tract cellular senescence liver fibrosis primary sclerosing cholangitis 0302 clinical medicine MED/12 - GASTROENTEROLOGIA Fibrosis Hepatic Stellate Cells medicine Animals Humans Molecular Biology Mice Knockout Liver injury integumentary system Chemistry Cell Biology medicine.disease 3. Good health Cell biology Mice Inbred C57BL 030104 developmental biology nervous system Case-Control Studies 030220 oncology & carcinogenesis Hepatic stellate cell Female |
Zdroj: | Laboratory investigation; a journal of technical methods and pathology |
ISSN: | 0023-6837 |
Popis: | Background: α-Calcitonin gene-related peptide (α-CGRP) is a 37-amino acid neuropeptide involved in several pathophysiological processes. α-CGRP is involved in the regulation of cholangiocyte proliferation during cholestasis. In this study, we aimed to evaluate if α-CGRP regulates bile duct ligation (BDL)-induced liver fibrosis by using a α-CGRP knockout (α-CGRP−/−) mouse model. Methods: α-CGRP−/− and wild-type (WT) mice were subjected to sham surgery or BDL for 7 days. Then, liver fibrosis and cellular senescence as well as the expression of kinase such as p38 and C-Jun N-terminal protein kinase (JNK) in mitogen-activated protein kinases (MAPK) signaling pathway were evaluated in total liver, together with measurement of cellular senescence in cholangiocytes or hepatic stellate cells (HSCs). Results: There was enhanced hepatic expression of Calca (coding α-CGRP) and the CGRP-receptor components (CRLR, RAMP-1 and RCP) in BDL and in both WT α-CGRP−/− and BDL α-CGRP−/− mice, respectively. Moreover, there was increased CGRP serum levels and hepatic mRNA expression of CALCA and CGRP receptor components in late-stage PSC samples compared to healthy control samples. Depletion of α-CGRP reduced liver injury and fibrosis in BDL mice that was associated with enhanced cellular senescence of hepatic stellate cells and reduced senescence of cholangiocytes as well as decreased activation of p38 and JNK MAPK signaling pathway. Cholangiocyte supernatant from BDL α-CGRP−/− mice inhibited the activation and increased cellular senescence of cultured human HSCs (HHSCs) compared to HHSCs stimulated with BDL cholangiocyte supernatant. Taken together, endogenous α-CGRP promoted BDL-induced cholestatic liver fibrosis through differential changes in senescence of HSCs and cholangiocytes and activation of p38 and JNK signaling. Modulation of α-CGRP/CGRP receptor signaling may be key for the management of biliary senescence and liver fibrosis in cholangiopathies. |
Databáze: | OpenAIRE |
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