Bacterial lipopolysaccharide decreases thrombomodulin expression in the sinusoidal endothelial cells of rats – a possible mechanism of intrasinusoidal microthrombus formation and liver dysfunction

Kume, Masane; Hayashi, Tatsuya; Yuasa, Hiroyuki; Tanaka, Hitoshi; Nishioka, Junji; Ido, Masaru; Gabazza, Esteban C.; Kawarada, Yoshifumi; Suzuki, Koji

doi:10.1016/s0168-8278(02)00324-0

Cited by 31 publications

(33 citation statements)

References 42 publications

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“…To address this question, the technique of CLP was used to induce sepsis in rat model, and the liver tissue was used for the examination of intracellular distributions of both HuR and TM. From Figure 6A, we found the TM protein expression was reduced in the liver tissue of septic rat as other groups reported (Kume et al, 2003). In sham group, HuR was expressed in Figure 6.…”

Section: Increases Of Interaction Between Hur and Tm Mrna In The Livesupporting

confidence: 68%

“…Furthermore, it was observed that TM protein expression level was significantly decreased at 3 and 6 h, but recovered 12 h after lipopolysaccharide (LPS) treatment in rat sinusoidal endothelial cells. In contrast, the TM mRNA levels were reduced at 6 and 12 h yet slightly recovered 24 h after LPS treatment (Kume et al, 2003). Lack of correlation between protein and mRNA expression patterns indicates the translational regulation mechanism involved in TM protein expression.…”

Section: Introductionmentioning

confidence: 84%

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RNA-binding Protein HuR Interacts with Thrombomodulin 5′Untranslated Region and Represses Internal Ribosome Entry Site–mediated Translation under IL-1β Treatment

Yeh¹,

Hung²,

Hsu

et al. 2008

MBoC

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Reduction in host-activated protein C levels and resultant microvascular thrombosis highlight the important functional role of protein C anticoagulant system in the pathogenesis of sepsis and septic shock. Thrombomodulin (TM) is a critical factor to activate protein C in mediating the anticoagulation and anti-inflammation effects. However, TM protein content is decreased in inflammation and sepsis, and the mechanism is still not well defined. In this report, we identified that the TM 5 untranslated region (UTR) bearing the internal ribosome entry site (IRES) element controls TM protein expression. Using RNA probe pulldown assay, HuR was demonstrated to interact with the TM 5UTR. Overexpression of HuR protein inhibited the activity of TM IRES, whereas on the other hand, reducing the HuR protein level reversed this effect. When cells were treated with IL-1␤, the IRES activity was suppressed and accompanied by an increased interaction between HuR and TM 5UTR. In the animal model of sepsis, we found the TM protein expression level to be decreased while concurrently observing the increased interaction between HuR and TM mRNA in liver tissue. In summary, HuR plays an important role in suppression of TM protein synthesis in IL-1␤ treatment and sepsis. INTRODUCTIONThere is ample evidence that inflammation and coagulation are intricately related processes, whereby inflammation not only leads to activation of coagulation, but coagulation also markedly affects inflammation activity (Esmon, 2005;Levi and Van der Poll, 2005). Inflammation-induced coagulation contributes to vascular thrombotic disease and is also the major consequence in the pathogenesis of microvascular failure and subsequent multiple organ failure in severe sepsis (Diehl and Borgel, 2005). Both preclinical and clinical studies have suggested that excessive microvascular thrombosis during sepsis results in part from depletion of endogenous anticoagulant systems, such as the heparin-antithrombin system, the protein C anticoagulant pathway, and the tissue factor pathway inhibitor system (Haley et al., 2004).Thrombomodulin (TM) is an important anticoagulant protein present on the surface of vascular endothelial cells (Dittman and Majerus, 1990). TM forms a high-affinity complex with thrombin and results in approximately a 100-fold increase in the activation of protein C to execute anticoagulant effects (Esmon, 1993). Recent studies have shown that TM also plays an important role in attenuation of the inflammatory response (Van de Wouwer and Conway, 2004). One mechanism for TM's anti-inflammatory effect relates to the properties of activated protein C (APC). For example, APC has been found to inhibit endotoxin-induced production of tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1␤, IL-6, and IL-8 in cultured monocytes/macrophages (Okajima, 2001). TM is also a critical cofactor for thrombin-mediated activation of the thrombin-activatable fibrinolysis inhibitor (TAFI), which is responsible for inactivation of complement factors C3a and C5a to protect against co...

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Section: Increases Of Interaction Between Hur and Tm Mrna In The Livesupporting

confidence: 68%

Section: Introductionmentioning

confidence: 84%

RNA-binding Protein HuR Interacts with Thrombomodulin 5′Untranslated Region and Represses Internal Ribosome Entry Site–mediated Translation under IL-1β Treatment

Yeh¹,

Hung²,

Hsu

et al. 2008

MBoC

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“…Expression of Tm decreases on vascular endothelium in vitro and in vivo 66,67 after treatment with endotoxin via TNF-␣ up-regulation and signaling. Increased soluble Tm (sTm) values were observed in septic DIC models, 68 which supports our observations.…”

Section: Discussionmentioning

confidence: 97%

A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Ganopolsky

Castellino

2004

The American Journal of Pathology

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During the systemic inflammatory state induced by sepsis, the potential for coagulopathy exists because of up-regulation of natural procoagulants and antifibrinolytics, and down-regulation of natural anti-coagulants, with protein C (PC) being a critical example of the latter case. PC functions as an anti-coagulant, profibrinolytic, and anti-inflammatory agent, and, thus, its administration or deficiency may affect the course and outcome of sepsis in patients. In this study, a cecal ligation and puncture model of septic peritonitis was applied to wild-type mice and littermates with a targeted heterozygous deficiency of PC (PC ؉/؊ ) to characterize the importance of a PC-deficiency on polymicrobial sepsis. An enhanced mortality rate was found to accompany a PC deficiency. Plasma cytokines, as well as organ-specific expression of cytokine transcripts, were elevated in PC ؉/؊ mice. No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC ؉/؊ mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture. Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC ؉/؊ mice. Renal and organ muscle damage was enhanced in PC ؉/؊ mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase. Hypotension and bradycardia were more enhanced in PC ؉/؊ mice than in wild-type mice, thus provoking a more severe septic shock response. Thus, the hemodynamic role of PC during sepsis is of critical importance to the outcome of the

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“…For example, endotoxemia resulted in reduced thrombomodulin expression in rat liver sinusoidal ECs. 106 In patients with meningococcemia, thrombomodulin and EPCR protein levels were decreased in the endothelial lining of dermal microvessels. 107 However, in rats injected with Escherichia coli, there were no changes in thrombomodulin antigen levels or activity.…”

Section: Hemostasismentioning

confidence: 97%

Phenotypic Heterogeneity of the Endothelium

Aird

2007

Circulation Research

1,479

862

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Abstract-Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium. (Circ Res. 2007;100:158-173.)

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Bacterial lipopolysaccharide decreases thrombomodulin expression in the sinusoidal endothelial cells of rats – a possible mechanism of intrasinusoidal microthrombus formation and liver dysfunction

Cited by 31 publications

References 42 publications

RNA-binding Protein HuR Interacts with Thrombomodulin 5′Untranslated Region and Represses Internal Ribosome Entry Site–mediated Translation under IL-1β Treatment

RNA-binding Protein HuR Interacts with Thrombomodulin 5′Untranslated Region and Represses Internal Ribosome Entry Site–mediated Translation under IL-1β Treatment

A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Phenotypic Heterogeneity of the Endothelium

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