Analysis of Arg-Gly-Asp mimetics and soluble receptor of tumour necrosis factor as therapeutic modalities for concanavalin A induced hepatitis in mice.

Bruck, Rafael; Shirin, Haim; Hershkoviz, Rami; Lider, Ofer; Kenet, G.; Aeed, Hussein; Matas, Zipora; Zaidel, Liliana; Halpern, Zamir

doi:10.1136/gut.40.1.133

Cited by 33 publications

(22 citation statements)

References 17 publications

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“…A prerequisite for the direct action of effector cells is their adhesion to and transmigration through the endothelial barrier. The protective effect of anti-ICAM-1 mAbs (18) and Arg-Gly-Asp mimetics (which block binding of ␤ 1 integrins to several extracellular matrix glycoproteins) (20) from Con A hepatitis confirmed this assumption.…”

Section: Tnf-␣-induced Expression Of Adhesion Molecules In the Liver supporting

confidence: 61%

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Wolf

Hallmann

Sass

et al. 2001

The Journal of Immunology

108

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TNF-α has been clearly identified as central mediator of T cell activation-induced acute hepatic injury in mice, e.g., Con A hepatitis. In this model, liver injury depends on both TNFRs, i.e., the 55-kDa TNFR1 as well as the 75-kDa TNFR2. We show in this report that the hepatic TNFRs are not transcriptionally regulated, but are regulated by receptor shedding. TNF directly mediates hepatocellular death by activation of TNFR1 but also induces the expression of inflammatory proteins, such as cytokines and adhesion molecules. Here we provide evidence that resistance of TNFR1−/− and TNFR2−/− mice against Con A hepatitis is not due to an impaired production of the central mediators TNF and IFN-γ. Con A injection results in a massive induction of ICAM-1, VCAM-1, and E-selectin in the liver. Lack of either one of both TNFRs did not change adhesion molecule expression in the livers of Con A-treated mice, presumably reflecting the fact that other endothelial cell-activating cytokines up-regulated adhesion molecule expression. However, treatment of TNFR1−/− and TNFR2−/− mice with murine rTNF revealed a predominant role for TNFR1 for the induction of hepatic adhesion molecule expression. Pretreatment with blocking Abs against E- and P-selectin or of ICAM−/− mice with anti-VCAM-1 Abs failed to prevent Con A hepatitis, although accumulation of the critical cell population, i.e., CD4+ T cells was significantly inhibited. Hence, up-regulation of adhesion molecules during acute hepatitis unlikely contributes to organ injury but rather represents a defense mechanism.

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Section: Tnf-␣-induced Expression Of Adhesion Molecules In the Liver supporting

confidence: 61%

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Wolf

Hallmann

Sass

et al. 2001

The Journal of Immunology

108

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“…Consistent with these findings, liver histology in the mice treated with the free-radical scavengers was significantly improved. The time course of TNFa increase in Con A hepatitis has been documented in numerous previous studies including our own that described this model [1,2,[5][6][7][8]. The peak of TNFa elevation is 2 h after Con A injection and thereafter TNFa levels demonstrate a steady decline, thus the determination of TNFa levels in multiple time points is not essential.…”

Section: Discussionmentioning

confidence: 87%

“…Liver injury in this model occurs following the production of lymphokines and monokines such as tumor necrosis factor alpha (TNFa), interferon gamma (INFc), interleukin-6 (IL-6), and IL-1 [1][2][3][4][5]. The T-cell-induced apoptotic liver injury has been prevented by polyclonal TNFa antiserum [6], pretreatment with soluble receptor of TNFa [7], and pentoxifylline [8], indicating that the liver damage is mediated primarily by TNFa. On the other hand, protective effect of certain cytokines such as IL-6, IL-10, and IL-8 was also demonstrated [6,9].…”

Section: Introductionmentioning

confidence: 95%

Inhibition of Immune-Mediated Concanavalin A-Induced Liver Damage by Free-Radical Scavengers

et al. 2009

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“…3) or the survival of the TAA-treated rats. Thus, the administration of sTNF-R, that prevents immune-mediated hepatic damage in mice in response to concanavalin A 23 and toxic liver injury in rats induced by CCl 4 , 20 had no protective effect in this model of TAA-induced FHF.…”

Section: Effect Of Soluble Receptor Of Tnf-␣ ␣ ␣ ␣mentioning

confidence: 89%

Hypothyroidism minimizes liver damage and improves survival in rats with thioacetamide induced fulminant hepatic failure

et al. 1998

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Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats. The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P F .01); the histologic examination of their livers showed less necrosis and inflammation (P F .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P F .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-␣), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 g/rat) did not prevent the induction of fulminant liver failure by TAA. Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypothyroid rats (P F .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism. (HEPATOL-OGY 1998;27:1013-1020.)

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Analysis of Arg-Gly-Asp mimetics and soluble receptor of tumour necrosis factor as therapeutic modalities for concanavalin A induced hepatitis in mice.

Abstract: Background/Aims-It has been shown that synthetic non-peptidic analogues of Arg-Gly-Asp, a major cell adhesive ligand of extraceliular matrix, prevented an

Cited by 33 publications

References 17 publications

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Inhibition of Immune-Mediated Concanavalin A-Induced Liver Damage by Free-Radical Scavengers

Hypothyroidism minimizes liver damage and improves survival in rats with thioacetamide induced fulminant hepatic failure

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