Pretreatment with Soluble Thrombomodulin Prevents Intrasinusoidal Coagulation and Liver Dysfunction following Extensive Hepatectomy in Cirrhotic Rats

Kaido, Toshimi; Yoshikawa, Akira; Seto, Shiro; Shoji, Yasuhiro; Furuyama, Hiroaki; Arii, Shigeki; Takahashi, Yasuo; Imamura, Masayuki

doi:10.1055/s-0037-1614380

Cited by 14 publications

(11 citation statements)

References 20 publications

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“…Another aspect of the biology of TM was suggested by infusion studies in which rhs-TM demonstrated protective properties in a range of models, including glomerulonephritis, sepsis, and ischemic settings (8)(9)(10)(11). In these models, anticoagulation alone does not reproduce the effects of TM infusion (32,33).…”

Section: Discussionmentioning

confidence: 99%

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The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Abeyama

Stern²,

Ito³

et al. 2005

J. Clin. Invest.

479

229

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Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation-induced cutaneous inflammation, and in vivo lipopolysaccharide-induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.

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Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that TM also plays an important role in attenuation of the inflammatory response in settings such as endotoxin-induced tissue damage, cytokine production, glomerulonephritis, and atherosclerosis (7)(8)(9)(10)(11)(12). One mechanism for TM's antiinflammatory effects relates to properties of APC.…”

Section: Introductionmentioning

confidence: 99%

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Abeyama

Stern²,

Ito³

et al. 2005

J. Clin. Invest.

479

229

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“…Accordingly, recombinant thrombomodulin is capable of attenuating increased levels of serum fibrin degradation products, fibrin deposition within liver sinusoids, injury of SEC, and liver dysfunction after endotoxin exposure (431). Also, urine thrombomodulin administration prevents intrasinusoidal fibrin depositions and attenuates posthepatectomy liver dysfunction in endotoxin-challenged cirrhotic rats (359). The localization of endotoxin in KC and SEC correlates with the incidence of sinusoidal thrombosis both temporarily and spatially within the septic liver tissue (787), which, among many other factors, explains the prothrombotic state in sepsis.…”

Section: A Sinusoidal Endothelial Cell Activationmentioning

confidence: 99%

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

Vollmar

Menger²

2009

Physiological Reviews

426

368

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The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.

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“…In our study the mean level of U-TM was 28 folds higher than P-TM in the normal control group. The difference in the level of TM in plasma and urine in normal subjects could be attributed to their different origin [11,12].…”

Section: Discussionmentioning

confidence: 99%

“…[24]. Hossaka et al on 2000 reported that soluble TM isolated from human urine affects the invasion and metastasis, while Kaido et al 1999 used U-TM to ameliorate fibrin deposition, hepato-cellular necrosis and improve the survival rate of control rats [10,11].…”

Section: Discussionmentioning

confidence: 99%

Urinary thrombomodulin is down regulated in schistosomiasis associated bladder cancer

Refaat

Ali

Hassan

et al. 2012

Journal of Genetic Engineering and Biotechnology

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Background: Thrombomodulin (TM) is a surface glycoprotein and expressed in many cancers. The aim of the present study was to detect the expression levels of TM in plasma and urine of bladder cancer patients and to compare these levels to the clinicopathological data of the patients as well as the ploidy status of their exfoliated urinary cells. We studied the levels of TM in plasma and urine samples of 57 bladder cancer patients and 10 controls using the (ELISA) assay and compared the results to the ploidy status of the cells taken from the patents urine samples as well as their clinicopathological profile.Results: Urinary TM was significantly down regulated while plasma TM was significantly up regulated in bladder cancer patients. Plasma TM was significantly higher in SCC than TCC patients. The sensitivity and specificity of urinary TM were 90% and 86%, respectively. While the sensitivity and specificity of plasma TM were 76% and 80%, respectively.Conclusion: Urinary TM is significantly down regulated, while plasma TM is significantly up regulated in bladder cancer as compared to the control group. Urinary TM has superior sensitivity and specificity over plasma TM. Urinary TM could be used as a predictive marker in bladder cancer. Further studies are needed to detect the prognosis significance of thrombomodulin in schistosomiasis associated bladder cancer.

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Pretreatment with Soluble Thrombomodulin Prevents Intrasinusoidal Coagulation and Liver Dysfunction following Extensive Hepatectomy in Cirrhotic Rats

Cited by 14 publications

References 20 publications

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

Urinary thrombomodulin is down regulated in schistosomiasis associated bladder cancer

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