Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Surgery Today
Published in: Surgery Today 11/2019

01-11-2019 | Cytokines | Original Article

Recombinant human soluble thrombomodulin reduces the severity and incidence of necrotizing enterocolitis in a newborn rat model

Authors: Bo Li, Ryuta Saka, Yuichi Takama, Takehisa Ueno, Yuko Tazuke, Hiroomi Okuyama

Published in: Surgery Today | Issue 11/2019

Login to get access

Abstract

Purpose

Necrotizing enterocolitis (NEC) remains the leading cause of death in preterm infants. Recombinant human soluble thrombomodulin (rTM) has been reported to have anti-inflammatory effects as well as antithrombogenic effects. The aim of this study was to evaluate the effect of rTM in a rat NEC model.

Methods

NEC was induced by enteral feeding with hyperosmolar formula, gavage administration of lipopolysaccharide and asphyxia stress. Controls were fed by their mother ad libitum. In the treatment group, rTM was administered subcutaneously twice (once each on the first and second day). All animals surviving beyond 96 h or that developed signs of distress were euthanized. The ileum was harvested for a histological evaluation and the measurement of the mRNA and protein expression.

Results

The rate of NEC-like intestinal injury in the treatment group (9/25, 36%) was significantly lower than in the NEC group (25/34, 73.5%). Tissue levels of TNF-α, IL-6 and HMGB1 were significantly elevated in the NEC group, whereas those in the treatment group were decreased to similar values as in the control group.

Conclusions

Our experimental study showed that rTM is able to reduce the severity and incidence of NEC. It may be an alternative option for the treatment of NEC.
Appendix
Available only for authorised users
Literature
1.
2.
Ganapathy V, Hay JW, Kim JH, Lee ML, Rechtman DJ. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatr. 2013;13:127.CrossRefPubMedPubMedCentral
3.
Lu P, Sodhi CP, Jia H, Shaffiey S, Good M, Branca MF, et al. Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol. 2014;306:G917–928.CrossRefPubMedPubMedCentral
4.
Tanner SM, Berryhill TF, Ellenburg JL, Jilling T, Cleveland DS, Lorenz RG, et al. Pathogenesis of necrotizing enterocolitis: modeling the innate immune response. Am J Pathol. 2015;185:4–16.CrossRefPubMedPubMedCentral
5.
Morser J. Thrombomodulin links coagulation to inflammation and immunity. Curr Drug Targets. 2012;13:421–31.CrossRefPubMed
6.
Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation. Thromb Haemost. 1999;82:718–21.CrossRefPubMed
7.
Nagato M, Okamoto K, Abe Y, Higure A, Yamaguchi K. Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia. Crit Care Med. 2009;37:2181–6.CrossRefPubMed
8.
Kadono K, Uchida Y, Hirao H, Miyauchi T, Watanabe T, Iida T, et al. Thrombomodulin attenuates inflammatory damage due to liver ischemia and reperfusion injury in mice in toll-like receptor 4-dependent manner. Am J Transplant. 2017;17:69–80.CrossRefPubMed
9.
Hunter CJ, De Plaen IG. Inflammatory signaling in NEC: role of NF-κB, cytokines and other inflammatory mediators. Pathophysiology. 2014;21:55–65.CrossRefPubMed
10.
Osumi W, Jin D, Imai Y, Tashiro K, Li ZL, Otsuki Y, et al. Recombinant human soluble thrombomodulin improved lipopolysaccharide/d-galactosamine-induced acute liver failure in mice. J Pharmacol Sci. 2015;129:233–9.CrossRefPubMed
11.
Rajashekhar G, Gupta A, Marin A, Friedrich J, Willuweit A, Berg DT, et al. Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice. Am J Physiol Renal Physiol. 2012;302:703–12.CrossRef
12.
Barlow B, Santulli TV. Importance of multiple episodes of hypoxia or cold stress on the development of enterocolitis in an animal model. Surgery. 1975;77:687–90.PubMed
13.
Nakame K, Kaji T, Mukai M, Shinyama S, Matsufuji H. The protective and anti-inflammatory effects of glucagon-like peptide-2 in an experimental rat model of necrotizing enterocolitis. Peptides. 2016;75:1–7.CrossRefPubMed
14.
Feng J, El-Assal ON, Besner GE. Heparin-binding EGF-like growth factor (HB-EGF) and necrotizing enterocolitis. Semin Pediatr Surg. 2005;14:167–74.CrossRefPubMed
15.
Dvorak B, Halpern MD, Holubec H, Williams CS, McWilliam DL, Dominguez JA, et al. Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal ratmodel. Am J Physiol Gastrointest Liver Physiol. 2002;282:156–64.CrossRef
16.
Ares GJ, McElroy SJ, Hunter CJ. The science and necessity of using animal models in the study of necrotizing enterocolitis. Semin Pediatr Surg. 2018;27:29–33.CrossRefPubMed
17.
Rentea RM, Welak SR, Fredrich K, Donohoe D, Pritchard KA, Oldham KT, et al. Early enteral stressors in newborns increase inflammatory cytokine expression in a neonatal necrotizing enterocolitis rat model. Eur J Pediatr Surg. 2013;23:39–47.PubMed
18.
Ikeguchi H, Maruyama S, Morita Y, Fujita Y, Kato T, Natori Y, et al. Effects of human soluble thrombomodulin on experimental glomerulonephritis. Kidney Int. 2002;61:490–501.CrossRefPubMed
19.
Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulincomplexes. Arterioscler Thromb Vasc Biol. 2008;28:1825–30.CrossRefPubMed
20.
Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ. HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med. 2001;164:1768–73.CrossRefPubMed
21.
Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5.CrossRefPubMed
22.
Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest. 2001;108:949–55.CrossRefPubMedPubMedCentral
23.
Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest. 2005;115:1267–74.CrossRefPubMedPubMedCentral
24.
Zamora R, Grishin A, Wong C, Boyle P, Wang J, Hackam D, et al. High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod. Am J Physiol Gastrointest Liver Physiol. 2005;289:G643–652.CrossRefPubMed
25.
Feng J, El-Assal ON, Besner GE. Heparin-binding epidermal growth factor-like growth factor decreases the incidence of necrotizing enterocolitis in neonatal rats. J Pediatr Surg. 2006;41:144–9.CrossRefPubMed
26.
Downard CD, Grant SN, Matheson PJ, Guillaume AW, Debski R, Fallat ME, et al. Altered intestinal microcirculation is the critical event in the development of necrotizing enterocolitis. J Pediatr Surg. 2011;46:1023–8.CrossRefPubMed
27.
Zhang HY, Wang F, Feng JX. Intestinal microcirculatory dysfunction and neonatal necrotizing enterocolitis. Chin Med J (Engl). 2013;126:1771–8.PubMed
28.
Metadata
Title
Recombinant human soluble thrombomodulin reduces the severity and incidence of necrotizing enterocolitis in a newborn rat model
Authors
Bo Li
Ryuta Saka
Yuichi Takama
Takehisa Ueno
Yuko Tazuke
Hiroomi Okuyama
Publication date
01-11-2019
Publisher
Springer Singapore
Keyword
Cytokines
Published in
Surgery Today / Issue 11/2019
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-019-01832-7

Other articles of this Issue 11/2019

Surgery Today 11/2019 Go to the issue

Review Article

Conversion surgery for initially unresectable pancreatic cancer: current status and unresolved issues

Original Article

Efficiency of thoracoscopic palpation in localizing small pulmonary nodules

Original Article

Prone “computed tomography hernia study” for the diagnosis of inguinal hernia

Original Article

The quality of life after laparoscopic ventral and incisional hernia repair with closure and non-closure of fascial defect

How To Do It

Totally extraperitoneal approach to laparoscopic lateral lymph node dissection for patients with recurrent lateral pelvic lymph nodes after rectal cancer surgery: a novel technique—M TEP LLND

How To Do It

Laparoscopic extraperitoneal sigmoid colostomy using the totally extraperitoneal hernia repair technique after abdominoperineal resection for rectal cancer