COMP-Angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury

Kim, Duk Hoon; Jung, Yu Jin; Lee, Ae Sin; Lee, Sik; Kang, Kyung Pyo; Lee, Tae Hwan; Lee, Sang Yong; Jang, Kyu Yun; Moon, Woo Sung; Choi, Kyoo Wan; Yoon, Kwon‐Ha; Sung, Mi Jeong; Park, Sung Kwang; Kim, Won

doi:10.1038/ki.2009.387

Cited by 80 publications

(56 citation statements)

References 40 publications

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“…The reason why no influence of the CYP down-regulation was noted in toxicokinetics of DCF remains unclear although the time lag up to the onset of CYP down-regulation may have contributed. Moreover, regarding the delayed elimination of 5-OH-DCF from plasma, the decreased clearance by LPS-induced alterations in blood flow (Kim et al, 2009), transporters or phase II enzymes (Yano et al, 2010) may explain the differences observed between the results of in vitro and in vivo experiments. For example, LPS is known to downregulate the multidrug resistance-associated protein 2 (Mrp2) that mediates canalicular secretion of several amphiphilic organic anions including glucuronides and GSH conjugates (Yano et al, 2010).…”

Section: Discussionmentioning

confidence: 92%

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

et al. 2012

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-Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is well known to induce idiosyncratic hepatotoxicity. Although there remains much to be elucidated about its onset mechanism, it is widely accepted as a hypothesis that idiosyncratic hepatotoxicity arises from a specific immune response to a hapten formed by covalent binding of drugs or their reactive metabolites to hepatic tissues. In this study, we investigated the effects of covalent binding of DCF reactive metabolites to hepatic tissues using a rat model of liver injury induced by co-treatment with lipopolysaccharide (LPS) at a non-hepatotoxic dose. In studies done in vitro using hepatic microsomes prepared from rats treated with LPS alone, 4'-and 5-hydroxylation activities on DCF metabolism and adducts of reactive metabolites to dansyl glutathione (dGSH) were markedly decreased associated with a decrease in total P450 content. However, in studies done in vivo, the LPS/DCF co-treatment significantly increased adducts of 5-hydroxydiclofenac (5-OH-DCF) to rat hepatic tissues and delayed the elimination of 5-OH-DCF from plasma. Furthermore, we investigated the effects of co-treatment on hepatic GSH level in rats. A decrease of hepatic GSH was observed with the LPS/DCF co-treatment but not with LPS or DCF alone. The results suggest that covalent binding of reactive metabolites via 5-OH-DCF to hepatic tissues may play an important role in the onset of DCF-induced idiosyncratic hepatotoxicity, especially under decreased GSH conditions.

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Section: Discussionmentioning

confidence: 92%

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

et al. 2012

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“…Ang-1 attenuates thrombin-induced permeability in human pulmonary microvascular endothelial cells (HPMVECs) by enforcing the VE-cadherin organization [10]. Ang-1 could counteract the inflammatory effects of vascular endothelial growth factor (VEGF) on endothelial cells [11], ameliorate ROS-induced acute lung injury [12] and lipopolysaccharide-induced acute kidney injury [13] by reducing the induction of ICAM-1 and VCAM-1, causing a reduction in leukocyte adhesion and subsequent inflammation. While Ang-1 has been shown to have a protective effect against inflammation, Ang-2 has been shown to have the opposite effect.…”

Section: Pathophysiologic Mechanisms Of Myocardial I/r Injury and Thementioning

confidence: 99%

Angiopoietin-1, Angiopoietin-2 and Myocardial Ischemia-Reperfusion Injury

Chen¹

2012

J Hypertens

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“…During endotoxemia, the vascular endothelial cells are affected by the inflammatory cytokines that induce the expression of cell adhesion molecules, such as ICAM-1, VCAM-1, and fractalkine (9,16). Following the expression of cell adhesion molecules, inflammatory cells, such as neutrophil and polymorphonuclear cells migrate into the tissue and are activated at the site of inflammation (18).…”

Section: Discussionmentioning

confidence: 99%

“…As endotoxemia is associated with increased myocardial vascular permeability, we examined the effect of JANEX-1 on the endotoxemia-induced vascular leakage of Evans blue dye (16). Endotoxemia significantly increased the vascular leakage, and this effect was significantly reduced by pretreatment with JANEX-1 (Fig.…”

Section: Janex-1 Improves Myocardial Vascular Leakage By Decreasing Smentioning

confidence: 99%

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Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor‑α‑induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice

Lee

Kim

et al. 2012

Int J Mol Med

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Abstract. Vascular endothelial cells play an important role in leukocyte trafficking during the inflammatory process. Proinflammatory cytokines activate the expression of cell adhesion molecules in endothelial cells. Janus kinase (JAK) and signal transducer and activator of transcription (STAT) are important intracellular cytokine signaling molecules that are involved in immune responses. The purpose of this study was to investigate the effect of JAK3 inhibition on the expression of tumor necrosis factor (TNF)-α-induced cell adhesion molecules in vascular endothelial cells and to evaluate the therapeutic potential of JAK3 for myocardial vascular permeability in endotoxemic mice. A JAK3 inhibitor, JANEX-1, decreased the TNF-α-induced expression of intercellular adhesion molecule (ICAM)-1, VCAM (vascular cell adhesion molecule)-1 and fractalkine in human umbilical vein endothelial cells (HUVECs). The downregulation of the expression of these cell adhesion molecules by JANEX-1 was mediated via suppression of STAT3 phosphorylation and nuclear factor-κB (NF-κB) activation. In endotoxemic mice, pretreatment with JANEX-1 prevented not only an increase in the cardiac ICAM-1 expression by LPS in the arteriolar and capillary endothelial cells, but also myocardial vascular leakage. These results suggest that inhibition of the JAK/STAT pathway by JANEX-1 ameliorates the expression of TNF-α-induced cell adhesion molecules in HUVECs and improves myocardial vascular permeability. IntroductionSepsis is a systemic inflammatory response to severe infection and is characterized by multi-organ dysfunction and hemodynamic compromise (1). A pathophysiological feature of sepsis is the production of proinflammatory mediators, such as cellular adhesion molecules, cytokines, and chemokines by vascular endothelial and inflammatory cells (2). Among these cells, the vascular endothelial cells play important roles both in forming a structural barrier between circulating blood and the underlying tissue and in generating vasoactive mediators, such as nitric oxide, prostacyclin, endothelin, and platelet-activating factor in response to physiological or pathological conditions (3). Infiltration of leukocytes from the circulatory system to the inflammatory site requires the expression of adhesion molecules and multiple signaling cascades in endothelial cells (3,4). Therefore, therapeutic strategies focused on the regulation of the interaction between circulating leukocytes and endothelial cells might be a plausible approach to treat sepsis-induced organ dysfunction.The first step in the initiation of inflammatory cascades is the binding of a cytokine to its corresponding receptor, leading to a change in gene expression. Among these signaling pathways, the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway participates in the signaling of many cytokines and is involved in stress-responsive gene expression, immune response, myocardial ischemic preconditioning and the remodeling of post-myocardial infarction (5-8). ...

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COMP-Angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury

Cited by 80 publications

References 40 publications

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

Angiopoietin-1, Angiopoietin-2 and Myocardial Ischemia-Reperfusion Injury

Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor‑α‑induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice

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