Abstract
Sinusoidal obstruction syndrome (SOS) is a liver injury caused by clinical chemotherapy, of which pathogenesis is associated with the damage in liver sinusoidal endothelial cells (LSEC). The unavailability of appropriate specific biomarkers for the early diagnosis of SOS may potentially overlook SOS patients. In this study, we sought to find serum microRNAs (miRNAs) as non-invasive biomarkers for investigating SOS in rats. Male Sprague–Dawley rats were orally administered monocrotaline, and then, their livers and sera were collected after 0.25, 0.5, 1, 2, 4, and 7 days. The rats showed a typical SOS phenotype including LSEC damage as early as day 0.25, followed by severe hepatocyte damage on day 2, and developed hepatic fibrosis from days 4 to 7. The miRNA microarray showed that 65 serum miRNAs were increased in their levels on day 0.25, when LSEC damage was observed, while hepatocyte damage was absent. Among the increased serum miRNAs on days 0.25–1, miR-511-3p was enriched in normal LSECs and miR-21-5p was in both LSECs and hepatocytes, suggesting that they were released into blood from the damaged LSECs. The miR-122-5p, miR-192-5p, and miR-101b-3p, which were enriched in hepatocytes, reached the highest levels in serum on day 2, suggesting their utility as indicators for hepatocyte damage. No miRNA showing an increasing trend from days 4 to 7 was found as a biomarker for fibrosis. In conclusion, we found that LSEC-derived miR-21-5p and especially miR-511-3p in serum would serve as early phase biomarkers for SOS in response to LSEC damage.
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Abbreviations
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- Ath:
-
Arabidopsis thaliana
- AZAN:
-
Azocarmine and aniline blue
- H&E:
-
Hematoxylin and eosin
- LSEC:
-
Liver sinusoidal endothelial cell
- MCT:
-
Monocrotaline
- miRNA:
-
MicroRNA
- NPC:
-
Non-parenchymal cell
- SEM:
-
Standard error of the mean
- snRNA:
-
Small nuclear RNA
- SOS:
-
Sinusoidal obstruction syndrome
- T-Bil:
-
Total bilirubin
- TSI:
-
Tissue specificity index
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Acknowledgements
The authors wish to thank Kaori Ushida, Yuko Mizuno, Miwa Itoh, and Eri Yorifuji from the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine for their technical advice regarding the histological examinations.
Funding
This study was supported by a Grant from the Research Foundation for Pharmaceutical Sciences and by a Grants-in-Aid for Scientific Research (A) (16H02616) from the Japan Society for the Promotion of Science.
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All animal experiments were carried out in accordance with the guidelines established by the Institute for Laboratory Animal Research of the Medical School of Nagoya University, Japan.
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Takeuchi, M., Oda, S., Tsuneyama, K. et al. Comprehensive analysis of serum microRNAs in hepatic sinusoidal obstruction syndrome (SOS) in rats: implication as early phase biomarkers for SOS. Arch Toxicol 92, 2947–2962 (2018). https://doi.org/10.1007/s00204-018-2269-x
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DOI: https://doi.org/10.1007/s00204-018-2269-x