Characterization of liver injury induced by a pyrrolizidine alkaloid in rats

TY - JOUR

T1 - Characterization of liver injury induced by a pyrrolizidine alkaloid in rats

AU - Chen, Xinmeng

AU - Ma, Jiang

AU - He, Yisheng

AU - Xue, Junyi

AU - Song, Zijing

AU - Xu, Qihe

AU - Lin, Ge

N1 - Funding Information: This work was supported by GRF grant from Research Grants Council of HKSAR (GRF Project No.: 14111816) and Direct Grant from CUHK (Project No. 4054302). Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/8

Y1 - 2021/8

N2 - BACKGROUND: Pyrrolizidine alkaloids (PAs) are common phytotoxins. PA intoxication is reported to cause severe acute liver damage, typically known as hepatic sinusoidal obstruction syndrome (HSOS), but it remains obscure whether the acute liver damage may progress into chronic liver disease characterized by hepatic fibrosis.PURPOSE: This study aims to characterize the biochemical markers of liver injury and histological features of regressive and progressive liver fibrosis, and to examine changes in hepatic gene expression that may underpin mechanisms of fibrogenesis in rats induced by retrorsine (RTS), a representative toxic PA.STUDY DESIGN/METHODS: Rats were gavaged with RTS via two dosing regimens, i.e. a single dose of 40 mg/kg (Group 1) and two doses of 40 mg/kg and 20 mg/kg on day 0 and day 7 (Group 2), respectively. Rats receiving one (Group 3) or two (Group 4) doses of vehicle served as negative controls. The animals were followed for up to 16 weeks by serum biochemical analyses and histological examination, and gene expression assays of liver tissues.RESULTS: Acute liver injury on day 2 manifested as HSOS, characterized by sinusoidal dilation, endothelial cell damage, and elevated serum alanine aminotransferase activity and bilirubin levels. In Group 1, mild liver fibrosis developed at sinusoids and perisinusoidal space surrounding the central veins at week 1 and 2, and thereafter, all liver injury resolved gradually. In Group 2, liver fibrosis progressed within the 16-week observation period. No apparent liver injury was observed in Groups 3 and 4. Compared with negative control groups, RTS induced myofibroblastic activation, TGF-β1 signaling, and changes in expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). These dynamic changes differed in Groups 1 and 2, corresponding with the regression and progression of liver fibrosis, respectively, in these groups.CONCLUSION: This study has provided in-vivo proof of concept that "one hit" and "two hits" of RTS lead to acute resolving liver injury and chronic progressive liver fibrosis, respectively. These animal models may serve as powerful tools for studying RTS toxicology and related preventive and therapeutic strategies and as positive controls for studying other PA- and non-PA-induced liver injury.

AB - BACKGROUND: Pyrrolizidine alkaloids (PAs) are common phytotoxins. PA intoxication is reported to cause severe acute liver damage, typically known as hepatic sinusoidal obstruction syndrome (HSOS), but it remains obscure whether the acute liver damage may progress into chronic liver disease characterized by hepatic fibrosis.PURPOSE: This study aims to characterize the biochemical markers of liver injury and histological features of regressive and progressive liver fibrosis, and to examine changes in hepatic gene expression that may underpin mechanisms of fibrogenesis in rats induced by retrorsine (RTS), a representative toxic PA.STUDY DESIGN/METHODS: Rats were gavaged with RTS via two dosing regimens, i.e. a single dose of 40 mg/kg (Group 1) and two doses of 40 mg/kg and 20 mg/kg on day 0 and day 7 (Group 2), respectively. Rats receiving one (Group 3) or two (Group 4) doses of vehicle served as negative controls. The animals were followed for up to 16 weeks by serum biochemical analyses and histological examination, and gene expression assays of liver tissues.RESULTS: Acute liver injury on day 2 manifested as HSOS, characterized by sinusoidal dilation, endothelial cell damage, and elevated serum alanine aminotransferase activity and bilirubin levels. In Group 1, mild liver fibrosis developed at sinusoids and perisinusoidal space surrounding the central veins at week 1 and 2, and thereafter, all liver injury resolved gradually. In Group 2, liver fibrosis progressed within the 16-week observation period. No apparent liver injury was observed in Groups 3 and 4. Compared with negative control groups, RTS induced myofibroblastic activation, TGF-β1 signaling, and changes in expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). These dynamic changes differed in Groups 1 and 2, corresponding with the regression and progression of liver fibrosis, respectively, in these groups.CONCLUSION: This study has provided in-vivo proof of concept that "one hit" and "two hits" of RTS lead to acute resolving liver injury and chronic progressive liver fibrosis, respectively. These animal models may serve as powerful tools for studying RTS toxicology and related preventive and therapeutic strategies and as positive controls for studying other PA- and non-PA-induced liver injury.

KW - pyrrolizidine alkaloids

KW - retrorsine

KW - hepatotoxicity

KW - hepatic sinusoidal obstruction syndrome

KW - fibrosis

UR - http://www.scopus.com/inward/record.url?scp=85109003214&partnerID=8YFLogxK

U2 - 10.1016/j.phymed.2021.153595

DO - 10.1016/j.phymed.2021.153595

M3 - Article

C2 - 34153877

SN - 0944-7113

VL - 89

SP - 153595

JO - PHYTOMEDICINE

JF - PHYTOMEDICINE

M1 - 153595

ER -