Recombinant human erythropoietin attenuates hepatic dysfunction by suppressing hepatocellular apoptosis in lipopolysaccharide‑induced disseminated intravascular coagulation in rats

Suga,Yukio; Akita,Fumio; Yamada,Shinya; Morishita,Eriko; Asakura,Hidesaku

doi:10.3892/br.2021.1488

Recombinant human erythropoietin attenuates hepatic dysfunction by suppressing hepatocellular apoptosis in lipopolysaccharide‑induced disseminated intravascular coagulation in rats

Authors:
- Yukio Suga
- Fumio Akita
- Shinya Yamada
- Eriko Morishita
- Hidesaku Asakura
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Affiliations: Department of Clinical Pharmacy and Healthcare Science, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, Takaramachi, Kanazawa, Ishikawa 920‑8641, Japan, Department of Hematology, Kanazawa University Hospital, Takaramachi, Kanazawa, Ishikawa 920‑8641, Japan
Published online on: November 22, 2021 https://doi.org/10.3892/br.2021.1488
Article Number: 5
Copyright: © Suga et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to clarify the effect of recombinant human erythropoietin (EPO) and low molecular weight heparin (LMWH) on a rat model of lipopolysaccharide (LPS)‑induced disseminated intravascular coagulation (DIC). Experimental DIC was induced by sustained infusion of 5 mg/kg LPS for 4 h. EPO or LMWH was then administered to the LPS‑induced DIC model. LPS‑induced consumption coagulopathy, hemostatic activation and plasma TNF elevation remained unaltered in the LPS+EPO group, except for the D‑dimer levels, and these abnormalities were significantly improved in the LPS+LMWH group. Plasma alanine aminotransferase (ALT) levels were markedly reduced in the LPS+EPO group, accompanied by a significant suppression of hepatocellular apoptosis. In the LPS+LMWH group, plasma creatinine levels and glomerular fibrin deposition were significantly attenuated, along with plasma ALT levels and hepatocellular apoptosis. Thus, a single administration of EPO may improve hepatic dysfunction by primarily exerting an anti‑apoptotic, not anticoagulant, effect in the LPS‑induced DIC model.

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1	Levi M and Ten Cate H: Disseminated intravascular coagulation. N Engl J Med. 341:586–592. 1999.PubMed/NCBI View Article : Google Scholar
2	Adelborg K, Larsen JB and Hvas AM: Disseminated intravascular coagulation: Epidemiology, biomarkers, and management. Br J Haematol. 192:803–818. 2021.PubMed/NCBI View Article : Google Scholar
3	Asakura H: Classifying types of disseminated intravascular coagulation: Clinical and animal models. J Intensive Care. 2(20)2014.PubMed/NCBI View Article : Google Scholar
4	Angus DC and van der Poll T: Severe sepsis and septic shock. N Engl J Med. 369:840–851. 2013.PubMed/NCBI View Article : Google Scholar
5	Brooks MB, Turk JR, Guerrero A, Narayanan PK, Nolan JP, Besteman EG, Wilson DW, Thomas RA, Fishman CE, Thompson KL, et al: Non-lethal endotoxin injection: A rat model of hypercoagulability. PLoS One. 12(e0169976)2017.PubMed/NCBI View Article : Google Scholar
6	Schöchl H, Solomon C, Schulz A, Voelcke W, Hanke A, Van Griensven M, Redl H and Bahrami S: Thromboelastometry (TEM) findings in disseminated intravascular coagulation in a pig model of endotoxinemia. Mol Med. 17:266–272. 2011.PubMed/NCBI View Article : Google Scholar
7	Schoergenhofer C, Schwameis M, Gelbenegger G, Buchtele N, Thaler B, Mussbacher M, Schabbauer G, Wojta J, Jilma-Stohlawetz P and Jilma B: Inhibition of Protease-activated receptor (PAR1) reduces activation of the endothelium, coagulation, fibrinolysis and inflammation during human endotoxemia. Thromb Haemost. 118:1176–1184. 2018.PubMed/NCBI View Article : Google Scholar
8	Levi M and van der Poll T: Coagulation and sepsis. Thromb Res. 149:38–44. 2017.PubMed/NCBI View Article : Google Scholar
9	Suresh S, Rajvanshi PK and Noguchi CT: The Many Facets of erythropoietin physiologic and metabolic response. Front Physiol. 10(1534)2019.PubMed/NCBI View Article : Google Scholar
10	Bonomini M, Del Vecchio L, Sirolli V and Locatelli F: New Treatment approaches for the anemia of CKD. Am J Kidney Dis. 67:133–142. 2016.PubMed/NCBI View Article : Google Scholar
11	Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M and Reddan D: CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 355:2085–2098. 2006.PubMed/NCBI View Article : Google Scholar
12	Yang J, Zhou J, Wang X, Wang X, Ji L, Wang S, Chen X and Yang L: Erythropoietin attenuates experimental contrast-induced nephrology: A role for the janus Kinase 2/Signal transducer and activator of transcription 3 signaling pathway. Front Med (Lausanne). 8(634882)2021.PubMed/NCBI View Article : Google Scholar
13	Golmohammadi MG, Banaei S, Nejati K and Chinifroush-Asl MM: Vitamin D3 and erythropoietin protect against renal ischemia-reperfusion injury via heat shock protein 70 and microRNA-21 expression. Sci Rep. 10(20906)2020.PubMed/NCBI View Article : Google Scholar
14	Thiemermann C: Beneficial effects of erythropoietin in preclinical models of shock and organ failure. Crit Care. 11(132)2007.PubMed/NCBI View Article : Google Scholar
15	Silva I, Alipio C, Pinto R and Mateus V: Potential anti-inflammatory effect of erythropoietin in non-clinical studies in vivo: A systematic review. Biomed Pharmacother. 139(111558)2021.PubMed/NCBI View Article : Google Scholar
16	Li K, Liu TX, Li JF, Ma YR, Liu ML, Wang YQ, Wu R, Li B, Shi LZ and Chen C: rhEPO inhibited cell apoptosis to alleviate acute kidney injury in sepsis by AMPK/SIRT1 activated autophagy. Biochem Biophys Res Commun. 517:557–565. 2019.PubMed/NCBI View Article : Google Scholar
17	Tu Q, Zhu Y, Yuan Y, Guo L, Liu L, Yao L, Zou Y, Li J and Chen F: Gypenosides inhibit inflammatory response and apoptosis of endothelial and epithelial cells in LPS-Induced ALI: A study based on bioinformatic analysis and in vivo/vitro experiments. Drug Des Devel Ther. 15:289–303. 2021.PubMed/NCBI View Article : Google Scholar
18	Duan H, Zhang Q, Liu J, Li R, Wang D, Peng W and Wu C: Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis. Pharmacol Res. 168(105599)2021.PubMed/NCBI View Article : Google Scholar
19	Bombeli T, Karsan A, Tait JF and Harlan JM: Apoptotic vascular endothelial cells become procoagulant. Blood. 89:2429–2442. 1997.PubMed/NCBI
20	Toltl LJ, Swystun LL, Pepler L and Liaw PC: Protective effects of activated protein C in sepsis. Thromb Haemost. 100:582–592. 2008.PubMed/NCBI
21	Woo S, Krzyzanski W and Jusko WJ: Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous administration in rats. J Pharmacol Exp Ther. 319:1297–1306. 2006.PubMed/NCBI View Article : Google Scholar
22	Asakura H, Sano Y, Yoshida T, Omote M, Ontachi Y, Mizutani T, Yamazaki M, Morishita E, Takami A, Miyamoto K and Nakao S: Beneficial effect of low-molecular-weight heparin against lipopolysaccharide-induced disseminated intravascular coagulation in rats is abolished by coadministration of tranexamic acid. Intensive Care Med. 30:1950–1955. 2004.PubMed/NCBI View Article : Google Scholar
23	Asakura H, Sano Y, Omote M, Yoshida T, Ontachi Y, Mizutani T, Kaneda M, Yamazaki M, Morishita E, Takami A, et al: Significance of decreased plasma D-dimer levels following lipopolysaccharide-induced disseminated intravascular coagulation in rats. Int J Hematol. 79:394–399. 2004.PubMed/NCBI View Article : Google Scholar
24	Koroglu TF, Yilmaz O, Ozer E, Baskin H, Gokmen N, Kumral A, Duman M and Ozkan H: Erythropoietin attenuates lipopolysaccharide-induced splenic and thymic apoptosis in rats. Physiol Res. 55:309–316. 2006.PubMed/NCBI
25	Zhou HB, Chen JM, Cai JT, Du Q and Wu CN: Anticancer activity of genistein on implanted tumor of human SG7901 cells in nude mice. World J Gastroenterol. 14:627–631. 2008.PubMed/NCBI View Article : Google Scholar
26	Colantuoni A, Martini R, Caprari P, Ballestri M, Capecchi PL, Gnasso A, Lo Presti R, Marcoccia A, Rossi M and Caimi G: COVID-19 Sepsis and microcirculation dysfunction. Front Physiol. 11(747)2020.PubMed/NCBI View Article : Google Scholar
27	Okajima K: Regulation of inflammatory responses by natural anticoagulants. Immunol Rev. 184:258–274. 2001.PubMed/NCBI View Article : Google Scholar
28	Suga Y, Kubo A, Katsura H, Staub Y, Tashiro K, Yamada S, Morishita E and Asakura H: Detailed exploration of pathophysiology involving inflammatory status and bleeding symptoms between lipopolysaccharide- and tissue factor-induced disseminated intravascular coagulation in rats. Int J Hematol. 114:172–178. 2021.PubMed/NCBI View Article : Google Scholar
29	Stoyanoff TR, Todaro JS, Aguirre MV, Zimmermann MC and Brandan NC: Amelioration of lipopolysaccharide-induced acute kidney injury by erythropoietin: Involvement of mitochondria-regulated apoptosis. Toxicology. 318:13–21. 2014.PubMed/NCBI View Article : Google Scholar
30	Le Minh K, Klemm K, Abshagen K, Eipel C, Menger MD and Vollmar B: Attenuation of inflammation and apoptosis by pre- and posttreatment of darbepoetin-alpha in acute liver failure of mice. Am J Pathol. 170:1954–1963. 2007.PubMed/NCBI View Article : Google Scholar
31	Deepa PR and Varalakshmi P: Influence of a low-molecular-weight heparin derivative on the nitric oxide levels and apoptotic DNA damage in adriamycin-induced cardiac and renal toxicity. Toxicology. 217:176–183. 2006.PubMed/NCBI View Article : Google Scholar
32	Zhang W, Tian Y, Gao Q, Li X, Li Y, Zhang J, Yao C, Wang Y, Wang H, Zhao Y, et al: Inhibition of apoptosis reduces diploidization of haploid mouse embryonic stem cells during differentiation. Stem Cell Reports. 15:185–197. 2020.PubMed/NCBI View Article : Google Scholar
33	Wang H, Zhang W, Gao Q, Cao X, Li Y, Li X, Min Z, Yu Y, Guo Y and Shuai L: Extractive from Hypericum ascyron L promotes serotonergic neuronal differentiation in vitro. Stem Cell Res. 31:42–50. 2018.PubMed/NCBI View Article : Google Scholar