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Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release.

Published on Jan 23, 2020in PLOS ONE2.776
· DOI :10.1371/JOURNAL.PONE.0228093
Masayuki Akatsuka2
Estimated H-index: 2
(Sapporo Medical University),
Yoshiki Masuda12
Estimated H-index: 12
(Sapporo Medical University)
+ 1 AuthorsMichiaki Yamakage8
Estimated H-index: 8
(Sapporo Medical University)
Abstract
Multiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.
  • References (30)
  • Citations (1)
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References30
Newest
#1Takashi Ito (Kadai: Kagoshima University)H-Index: 23
#2M Nakahara (Kadai: Kagoshima University)H-Index: 4
Last. Ikuro Maruyama (Kadai: Kagoshima University)H-Index: 38
view all 10 authors...
Background Nuclear histone proteins are released into the extracellular space during sepsis and act as major mediators of death. However, circulating histone levels have not been precisely quantified.
2 CitationsSource
#1Houra Loghmani (UBC: University of British Columbia)H-Index: 1
#2Edward M. Conway (UBC: University of British Columbia)H-Index: 41
Thrombomodulin (TM) is an integral component of a multimolecular system, localized primarily to the vascular endothelium, that integrates crucial biological processes and biochemical pathways, including those related to coagulation, innate immunity, inflammation, and cell proliferation. These are designed to protect the host from injury and promote healing. The “traditional” role of TM in hemostasis was determined with its discovery in the 1980s as a ligand for thrombin and a critical cofactor f...
14 CitationsSource
#1Eleanor Silk (Imperial College London)H-Index: 1
#2Hailin Zhao (Imperial College London)H-Index: 24
Last. MADa-qing (Imperial College London)H-Index: 50
view all 4 authors...
Histones are intra-nuclear cationic proteins that are present in all eukaryotic cells and are highly conserved across species. Within the nucleus, they provide structural stability to chromatin and regulate gene expression. Histone may be released into the extracellular space in three forms: freely, as a DNA-bound nucleosome or as part of neutrophil extracellular traps, and all three can be detected in serum after significant cellular death such as sepsis, trauma, ischaemia/reperfusion injury an...
37 CitationsSource
#1Chihiro Kawai (Kyoto University)H-Index: 5
#2Hirokazu Kotani (Kyoto University)H-Index: 22
Last. Keiji Tamaki (Kyoto University)H-Index: 13
view all 7 authors...
Extracellular histones are a damage-associated molecular pattern (DAMP) involved in the pathogenesis of various diseases. The mechanisms of histone-mediated injury in certain organs have been extensively studied, but an understanding of the pathophysiological role of histone-mediated injury in multiple organ injury remains elusive. To elucidate this role, we systemically subjected C57BL/6 mice to various doses of histones and performed a chronological evaluation of the morphological and function...
31 CitationsSource
#1Wataru Osumi (Osaka Medical College)H-Index: 2
#2Denan Jin (Osaka Medical College)H-Index: 4
Last. Kazuhisa Uchiyama (Osaka Medical College)H-Index: 29
view all 12 authors...
The effect of recombinant human soluble thrombomodulin (TM-α) on acute liver failure (ALF) is unclear, and we elucidated the effect of TM-α in lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced ALF in mice. Placebo (saline) or TM-α (100 mg/kg) was administered 1 h after LPS/GalN administration. Survival rates were evaluated for 24 h after LPS/GalN administration. Plasma and liver samples were evaluated 1, 3, and 7 h after LPS/GalN administration. Survival rates were significantly higher in ...
6 CitationsSource
#1Josée Bouchard (UdeM: Université de Montréal)H-Index: 24
#2Anjali Acharya (Jacobi Medical Center)H-Index: 3
Last. Ravindra L. Mehta (UCSD: University of California, San Diego)H-Index: 67
view all 10 authors...
Background and objectives AKI is frequent and is associated with poor outcomes. There is limited information on the epidemiology of AKI worldwide. This study compared patients with AKI in emerging and developed countries to determine the association of clinical factors and processes of care with outcomes. Design, setting, participants, & measurements This prospective observational study was conducted among intensive care unit patients from nine centers in developed countries and five centers in ...
53 CitationsSource
#1M Nakahara (Kadai: Kagoshima University)H-Index: 4
#2Takashi Ito (Kadai: Kagoshima University)H-Index: 23
Last. Ikuro Maruyama (Kadai: Kagoshima University)H-Index: 38
view all 16 authors...
Introduction Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagula...
70 CitationsSource
In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF...
212 CitationsSource
#1Tobias A. Fuchs (Harvard University)H-Index: 27
#2Ashish A. Bhandari (Boston Children's Hospital)H-Index: 3
Last. Denisa D. Wagner (Harvard University)H-Index: 105
view all 3 authors...
Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. ...
202 CitationsSource
#1Takashi Ito (Kadai: Kagoshima University)H-Index: 23
#2Ikuro Maruyama (Kadai: Kagoshima University)H-Index: 38
Summary. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated activation of protein C. Recently, we conducted a multicentre, double-blind, randomized trial to evaluate the efficacy and safety of recombinant human soluble thrombomodulin (rhsTM, also known as ART-123) for the treatment of disseminated intravascular coagulation (DIC), and found that rhsTM therapy is more effective and safer than low-dose heparin therapy. Thus, in 2008, rhsTM (Recomodulin) was...
99 CitationsSource
Cited By1
Newest
#1Luciana Costa Faria (UFMG: Universidade Federal de Minas Gerais)H-Index: 9
#2Antônio Márcio F Andrade (UFMG: Universidade Federal de Minas Gerais)
Last. Marcus Vinícius M Andrade (Faculdade de Medicina da Universidade Federal de Minas Gerais)
view all 7 authors...
BACKGROUND: Liver transplant (LT) presents early complications, such as allograft dysfunction and acute kidney injury, which contribute significantly to morbidity and mortality. High mobility group box 1 protein (HMGB1) has been identified as mediator in ischemia-reperfusion injury. Nucleosomes are complexes formed by DNA and histone proteins, and histones contribute to organ failure and death during sepsis. METHODS: HMGB1 and nucleosome plasma levels were measured, by enzyme-linked immunosorben...
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