Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphocyte infiltration is a manifest feature of hepatitis. To reveal the main site and mechanism of lymphocyte adhesion/extravasation in the hepatic vasculature during inflammation, we morphometrically and histologically analyzed these events in relation to adhesion molecule expression using a murine model of T-cell mediated hepatitis induced by concanavalin A (Con A). Although lymphocyte adhesion was restricted to the sinusoids in untreated mice, it increased in all the segments of porto-sinusoidal-hepatic venous system 8 hours after Con A injection; the number of adhering lymphocytes per unit vascular circumference was the largest in the sublobular veins, relatively large in the central veins and small hepatic veins, and relatively small in the sinusoids and negligible in the portal veins. At 20 hours, extravascular lymphocytes showed similar distribution to lymphocyte adhesion at 8 hours except in the portal veins, around which they were possibly accumulated by the translocation of extrasinusoidal lymphocytes. E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were transiently expressed at 4 to 6 hours, whereas P-selectin and intercellular adhesion molecule-1 were not changed between 0 and 48 hours. In particular, E-selectin expression coincided with that of lymphocyte adhesion in distribution. Lymphocyte attachment was inhibited by pretreatment with anti-E-selectin monoclonal antibody (MAb) or anti-VCAM-1 MAb, and expression of E-selectin and VCAM-1 was suppressed by pretreatment with anti-tumor necrosis factor-alpha (TNF-alpha) MAb. Electron microscopically, lymphocytes were trapped by endothelial lamellipodia and traversed the endothelium by diapedesis. These results indicate that lymphocyte adhesion/transmigration preferentially takes place in the sublobular veins in association with TNF-alpha-induced endothelial activation, i.e., E-selectin and VCAM-1 expression and lamellipodia formation.
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PMID:Sublobular veins as the main site of lymphocyte adhesion/transmigration and adhesion molecule expression in the porto-sinusoidal-hepatic venous system during concanavalin A-induced hepatitis in mice. 1061 32

TNF-alpha 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-gamma. 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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PMID:TNF-alpha-induced expression of adhesion molecules in the liver is under the control of TNFR1--relevance for concanavalin A-induced hepatitis. 1114 13

E-selectin-targeted contrast enhancement of blood vessels in inflamed tissues was investigated with a new contrast agent, Gd-DTPA-B(sLe(x))A, which was recently obtained by grafting a synthetic mimetic of sialyl-Lewis(x), an E-selectin ligand, onto Gd-DTPA. The pharmacokinetics, biodistribution, and potential to image inflammation by MRI of this E-selectin-targeted contrast agent were evaluated. The inhibition (by 15-34%) produced by Gd-DTPA-B(sLe(x))A on Sialyl Le(x)-PAA-biotin binding to E-selectin confirmed the specific interaction of the new contrast agent with this adhesion molecule. Gd-DTPA-B(sLe(x))A was tested at a dose of 0.1 mmol/kg b.w. on mice and rats in a fulminant hepatitis model induced by the co-administration of D-galactosamine and E. coli lipopolysaccharide. A significant and prolonged contrast enhancement between blood vessels and liver parenchyma was obtained in pathological conditions, which attests to the specificity of the agent for E-selectin. The prolonged vascular residence (48.9 min in hepatitis vs. 29.8 min in healthy animals), as evidenced by the pharmacokinetic characterization, suggests that Gd-DTPA-B(sLe(x))A interacts with the specific receptors expressed during inflammation. The biodistribution of the compound indicates its retention in inflamed liver by both specific mechanisms and nonspecific accumulation due to the necrotic lesions. The same mechanisms are invoked to account for its retention in the spleen.
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PMID:Magnetic resonance imaging of inflammation with a specific selectin-targeted contrast agent. 1579 62

Massive liver cell death provoked in silica-treated mice subsequently infected with herpes simplex virus (HSV)-1 is very similar pathohistologically to the cell death observed in human fulminant hepatitis. Previously, we have shown this liver cell death to be extensive apoptosis. In the present study, we examined various factors related to liver damage patho- and immunologically, as well as by reverse transcription-polymerase chain reaction. Tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), interferon (IFN)-alpha, and interleukin-6 mRNAs were detected to a much greater extent in silica-treated mice compared with control mice after HSV-1 infection, and excessive expression of iNOS mRNA and cytokine mRNAs in the liver may be closely related to massive liver cell apoptosis. The apoptosis was less related to the fas ligand than to TNF-alpha. Silica blockage of macrophages makes the liver cell extremely vulnerable to HSV-1 infection, and it induced expression of E-selectin and neutrophil margination in the liver. Subsequent HSV-1 infection induced excessive production of iNOS and cytokines, particularly TNF-alpha, but administration of anti-TNF-alpha antibody or NG-monomethyl-L-arginine was not completely efficacious for the survival of the mice. Overproduction of free radicals in combination with cytokines, such as TNF-alpha, IL-6 and IFN-alpha, may result in hepatic cell apoptosis.
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PMID:Pathogenesis of herpes simplex hepatitis in macrophage-depleted mice: possible involvement of tumor necrosis factor-alpha and inducible nitric oxide synthase in massive apoptosis. 1633 16

Targeting of the endothelial inflammatory adhesion molecule E-selectin by magnetic resonance imaging (MRI) was performed with a superparamagnetic contrast agent in the context of in vitro and in vivo models of inflammation. The specific contrast agent was obtained by grafting a synthetic mimetic of sialyl Lewis(x) (sLe(x)), a natural ligand of E-selectin expressed on leukocytes, on the dextran coating of ultrasmall particles of iron oxide (USPIO). This new contrast agent, called USPIO-g-sLe(x), was tested, in vitro, on cultured human umbilical vein endothelial cells (HUVECs) stimulated to express inflammatory adhesion molecules, and in vivo, on a mouse model of hepatitis. In vitro, HUVECs were stimulated with the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and were then incubated with USPIO-g-sLe(x) or ungrafted USPIO. In vivo, hepatitis was induced on NMRI mice by injection of concanavalin A (Con A). USPIO-g-sLe(x) and ungrafted USPIO were injected intravenously. In vitro results showed an extensive retention of USPIO-g-sLe(x) on TNF-alpha stimulated HUVECs. Image intensity and R(2) measurements performed on T(2)-weighted MR images demonstrated a significantly higher binding of USPIO-g-sLe(x) on stimulated HUVECs. In vivo, USPIO are known to pass through the fenestrae of the liver and to be captured by Kupffer cells, inducing a loss of signal intensity on T(2)-weighted MR images. Unexpectedly, when injected to Con A-treated mice, USPIO-g-sLe(x) induced a significantly lower attenuation of liver signal intensity than USPIO or USPIO-g-sLe(x) injected to healthy mice, or USPIO injected to Con A-treated mice, suggesting that the specific contrast media is retained extracellularly by an interaction with E-selectin overexpressed on the vascular endothelium. Both in vitro and in vivo results therefore indicate that USPIO-g-sLe(x) is recognizing endothelial E-selectin. USPIO-g-sLe(x) is thus well suited for the MRI diagnosis of inflammation and for the in vitro evaluation of endothelial cells activation.
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PMID:Specific E-selectin targeting with a superparamagnetic MRI contrast agent. 1719 96