Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model

Yamazaki,Hiroto; Tajima,Hidehiro; Yamamoto,Yasuhiko; Munesue,Seiichi; Okazaki,Mitsuyoshi; Ohbatake,Yoshinao; Nakanuma,Shinichi; Makino,Isamu; Miyashita,Tomoharu; Takamura,Hiroyuki; Ohta,Tetsuo

doi:10.3892/mmr.2022.12717

Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model

Authors:
- Hiroto Yamazaki
- Hidehiro Tajima
- Yasuhiko Yamamoto
- Seiichi Munesue
- Mitsuyoshi Okazaki
- Yoshinao Ohbatake
- Shinichi Nakanuma
- Isamu Makino
- Tomoharu Miyashita
- Hiroyuki Takamura
- Tetsuo Ohta
View Affiliations

Affiliations: Department of Hepato‑Biliary‑Pancreatic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan, Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
Published online on: April 26, 2022 https://doi.org/10.3892/mmr.2022.12717
Article Number: 201

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Sinusoidal obstruction syndrome (SOS) is a type of fatal hepatic injury, which predominantly occurs following exposure to drugs, such as oxaliplatin, or bone marrow transplantation. Extravasated platelet aggregation (EPA) plays an important role in the development of SOS in rat and mouse models. Furthermore, platelets invading the space of Disse adhere to hepatocytes and are phagocytized in patients with SOS. Aging platelets and platelets in patients with sepsis are phagocytized by hepatocytes through Ashwell‑Morell receptors, and thrombopoietin (TPO) is produced by the JAK2‑STAT3 signaling pathway. The purpose of the present study was to examine the significance of TPO as a biomarker of SOS. SOS was induced in Crl:CD1(ICR) female mice by intraperitoneal administration of monocrotaline (MCT). TPO levels were measured in the serum and liver tissue. Pathological and immunohistochemical studies of the liver were performed to analyze the expression levels of TPO. TPO mRNA expression levels were measured using reverse transcription‑quantitative PCR. In the SOS model, the platelet counts in peripheral blood samples were significantly decreased at 24 and 48 h after MCT treatment as compared with that at 0 h. In addition, a pathological change in hepatic zone 3 was observed in the SOS model group. Furthermore, the protein levels of TPO in liver tissue were significantly increased in the SOS model group compared with those in the control group, which was confirmed by immunohistochemistry. By contrast, serum TPO protein levels were significantly decreased in the SOS model group compared with those in the control group. These results indicated that EPA may induce sinusoidal endothelial fenestration in a mouse model of SOS, preventing TPO from translocating into the blood. In conclusion, serum TPO levels may be reduced in a mouse model of SOS owing to the accumulation in hepatocytes, suggesting that TPO could be a useful biomarker of SOS.

View Figures

View References

1	Takamura H, Nakanuma S, Hayashi H, Tajima H, Kakinoki K, Kitahara M, Sakai S, Makino I, Nakagawara H, Miyashita T, et al: Severe veno-occlusive disease/sinusoidal obstruction syndrome after deceased-donor and living-donor liver transplantation. Transplant Proc. 46:3523–3535. 2014. View Article : Google Scholar : PubMed/NCBI
2	Nakanuma S, Miyashita T, Hayashi H, Tajima H, Takamura H, Tsukada T, Okamoto K, Sakai S, Makino I, Kinoshita J, et al: Extravasated platelet aggregation in liver zone 3 may correlate with the progression of sinusoidal obstruction syndrome following living donor liver transplantation: A case report. Exp Ther Med. 9:1119–1124. 2015. View Article : Google Scholar : PubMed/NCBI
3	Tajima H, Ohta T, Miyashita T, Nakanuma S, Matoba M, Miyata T, Sakai S, Okamoto K, Makino I, Kinoshita J, et al: Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver. Mol Clin Oncol. 3:555–558. 2015. View Article : Google Scholar : PubMed/NCBI
4	Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, Veys P and Potter MN; Haemato-oncology Task Force of British Committee for Standards in Haematology, ; British Society for Blood and Marrow Transplantation, : BCSH/BSBMT guideline: Diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol. 163:444–457. 2013. View Article : Google Scholar : PubMed/NCBI
5	Tamandl D, Klinger M, Eipeldauer S, Herberger B, Kaczirek K, Gruenberger B and Gruenberger T: Sinusoid obstruction syndrome impairs long-term outcome of colorectal liver metas- tases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol. 18:421–430. 2011. View Article : Google Scholar : PubMed/NCBI
6	Duret-Aupy N, Lagarce L, Blouet A, Kettani S, Conte C, Bourneau-Martin D, Drablier G, Umlil A and Briet M: Liver sinusoidal obstruction syndrome associated with trastuzumab emtansine treatment for breast cancer. Therapie. 74:675–677. 2019. View Article : Google Scholar : PubMed/NCBI
7	Bornhäuser M, Illmer T, Oelschlaegel U, Schetelig J, Ordemann R, Schaich M, Hänel M, Schuler U, Thiede C, Kiani A, et al: Gemtuzumab ozogamicin as part of reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in patients with relapsed acute myeloid leukemia. Clin Cancer Res. 14:5585–5593. 2008. View Article : Google Scholar : PubMed/NCBI
8	Efrati E, Zuckerman T, Ben-Ami E and Krivoy N: MTHFR C677T/A1298C genotype: A possible risk factor for liver sinusoidal obstruction syndrome. Bone Marrow Transplant. 49:726–727. 2014. View Article : Google Scholar : PubMed/NCBI
9	Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, Dousset B, Morel P, Soubrane O, Chaussade S, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 15:460–466. 2004. View Article : Google Scholar : PubMed/NCBI
10	Morine Y, Shimada M and Utsunomiya T: Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis. Hepatol Res. 44:59–69. 2014. View Article : Google Scholar : PubMed/NCBI
11	DeLeve LD and Wang X: Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology. 60:143–154. 2000. View Article : Google Scholar : PubMed/NCBI
12	Hirata M, Tajima H, Miyashita T, Miyata T, Nakanuma S, Makino I, Hayashi H, Oyama K, Takamura H, Ninomiya I, et al: Extravasated platelet aggregation in the livers of rats with drug induced hepatic sinusoidal obstruction syndrome. Mol Med Rep. 15:3147–3152. 2017. View Article : Google Scholar : PubMed/NCBI
13	Miyata T, Tajima H, Hirata M, Nakanuma SI, Makino I, Hayashi H, Oyama K, Miyashita T, Takamura H, Ninomiya I, et al: Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space. J Gastroenterol Hepatol. 33:950–957. 2018. View Article : Google Scholar : PubMed/NCBI
14	Takada S, Miyashita T, Yamamoto Y, Kanou S, Munesue S, Ohbatake Y, Nakanuma S, Okamoto K, Sakai S, Kinoshita J, et al: Soluble thrombomodulin attenuates endothelial cell damage in hepatic sinusoidal obstruction syndrome. In Vivo. 32:1409–1417. 2018. View Article : Google Scholar : PubMed/NCBI
15	Kanou S, Miyashita T, Yamamoto Y, Takada S, Nakura M, Okazaki M, Ohbatake Y, Nakanuma S, Makino I, Tajima H, et al: Prophylactic effect of recombinant human soluble thrombomodulin for hepatic sinusoidal obstruction syndrome model mice. In Vivo. 34:1037–1045. 2020. View Article : Google Scholar : PubMed/NCBI
16	Conotte R and Colet JM: A metabonomic evaluation of the monocrotaline-induced sinusoidal obstruction syndrome (SOS) in rats. Toxicol Appl Pharmacol. 276:147–156. 2014. View Article : Google Scholar : PubMed/NCBI
17	Grozovsky R, Giannini S, Falet H and Hoffmeister KM: Regulating billions of blood platelets: Glycans and beyond. Blood. 126:1877–1884. 2015. View Article : Google Scholar : PubMed/NCBI
18	Grozovsky R, Begonja AJ, Liu K, Visner G, Hartwig JH, Falet H and Hoffmeister KM: The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med. 21:47–54. 2015. View Article : Google Scholar : PubMed/NCBI
19	Hitchcock IS and Kaushansky K: Thrombopoietin from beginning to end. Br J Haematol. 165:259–268. 2014. View Article : Google Scholar : PubMed/NCBI
20	Kuter DJ: New thrombopoietic growth factors. Blood. 109:4607–4616. 2007. View Article : Google Scholar : PubMed/NCBI
21	Narita M, Hatano E, Ikai I, Miyagawa-Hayashino A, Yanagida A, Nagata H, Asechi H, Taura K and Uemoto S: A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction. Ann Surg. 249:806–813. 2009. View Article : Google Scholar : PubMed/NCBI
22	Nakura M, Miyashita T, Yamamoto Y, Takada S, Kanou S, Tajima H, Takamura H and Ohta T: Inhibitory effects of beraprost sodium in murine hepatic sinusoidal obstruction syndrome. Anticancer Res. 40:5171–5180. 2020. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Yakushijin K, Atsuta Y, Doki N, Yokota A, Kanamori H, Miyamoto T, Ohwada C, Miyamura K, Nawa Y, Kurokawa M, et al: Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes. Bone Marrow Transplant. 51:403–409. 2016. View Article : Google Scholar : PubMed/NCBI
25	Narita M, Oussoultzoglou E, Chenard MP, Fuchshuber P, Rather M, Rosso E, Addeo P, Jaeck D and Bachellier P: Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization. Ann Surg Oncol. 19:2230–2237. 2012. View Article : Google Scholar : PubMed/NCBI
26	Hickey PL, McLean AJ, Angus PW, Choo EF and Morgan DJ: Increased sensitivity of propranolol clearance to reduced oxygen delivery in the isolated perfused cirrhotic rat liver. Gastroenterology. 111:1039–1048. 1996. View Article : Google Scholar : PubMed/NCBI
27	Schaffner F and Poper H: Capillarization of hepatic sinusoids in man. Gastroenterology. 44:239–242. 1963. View Article : Google Scholar : PubMed/NCBI