Adenoviral gene transfer of ABIN-1 protects mice from TNF/galactosamine-induced acute liver failure and lethality.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a central role in acute and chronic hepatitis B and C infection and alcoholic liver disease as well as fulminant liver failure. TNF-induced liver failure is characterized by parenchymal cell apoptosis and inflammation leading to liver cell necrosis. The transcription factor NF-kappaB is believed to mediate at least part of the proinflammatory effects of TNF, and is therefore a favorite drug target.

Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes.

The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti- or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively).

Exogenous alpha-1-acid glycoprotein protects against renal ischemia-reperfusion injury by inhibition of inflammation and apoptosis.

Background: Although ischemia-reperfusion (I/R) injury represents a major problem in posttransplant organ failure, effective treatment is not available. The acute phase protein alpha-1-acid glycoprotein (AGP) has been shown to be protective against experimental I/R injury. The effects of AGP are thought to be mediated by fucose groups expressed on the AGP protein inhibiting neutrophil infiltration.

Transpupillary thermotherapy of occult CNV with no or minimally classic CNV in age-related macular degeneration.

Transpupillary thermotherapy (TTT) has been suggested as a putative treatment for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). This prospective study comprised 66 consecutive patients referred for exudative AMD with predominantly occult subfoveal CNV. Based on fluorescein angiography, there were 38 cases with occult CNV only, and 28 eyes with minimally classic CNV as well.

Response of TNF-hyporesponsive SPRET/Ei mice in models of inflammatory disorders.

Most inflammatory disorders are becoming more prevalent, especially in Western countries. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF) plays a prominent role in many of these inflammatory disorders. We have previously shown that SPRET/Ei mice exhibit an extreme and dominant resistance to high doses of TNF.

Breaking the species barrier: derivation of germline-competent embryonic stem cells from Mus spretus x C57BL/6 hybrids.

Embryonic stem (ES) cells, which can differentiate into almost all types of cells, have been derived from the house mouse Mus musculus, rat, rabbit, humans, and other species. Transmission of the genotype to the offspring of chimeras has been achieved only with M. musculus ES cells, limiting targeted mutagenesis using ES cells to this species.

Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation?

Matrilysin or MMP-7, one of the smallest of all known matrix metalloproteinases (MMPs), has been studied extensively in many different tumor types, since its discovery more than 20 years ago. However, research during the past several years has revealed that this protease also plays an essential role in innate immunity, and, more particularly, in inflammatory disorders.

MMP-2 and MMP-9 synergize in promoting choroidal neovascularization.

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls.

Bilirubin release induced by tumor necrosis factor in combination with galactosamine is toxic to mice.

Application of tumor necrosis factor (TNF) in combination with galactosamine (GalN) in mice causes severe apoptosis of hepatocytes, resulting in complete destruction of the liver. Administration of high levels of unconjugated bilirubin and abnormally high production of unconjugated bilirubin have been reported to cause liver damage and are associated with several human pathologies. Serum alanine aminotransferase as well as total and direct bilirubin levels in mice were determined.

Serine proteases of the fibrinolysis pathway are not involved in lethal hepatitis and fibrinogen breakdown induced by tumor necrosis factor.

Tumor necrosis factor (TNF) plays a key role in several types of fulminant and acute hepatitis, and induces massive apoptosis and necrosis of hepatocytes. Our previous studies described the central role played by several matrix metalloproteinases (MMPs) and one or more unknown serine proteases. The aim of this study was to investigate the involvement of serine proteases of the fibrinolytic pathway, known to be activators of several MMPs, in TNF-induced hepatitis and fibrinogen (FG) breakdown.

Transpupillary thermotherapy of predominantly occult choroidal neovascularization in age-related macular degeneration with 12 months follow-up.

Purpose: To perform a phase I/II safety and efficacy study in order to assess the outcome following transpupillary thermotherapy (TTT) for occult choroidal neovascularization (CNV) with no or minimally classic CNV in age-related macular degeneration.

Methods: The study comprised 113 referred patients (79 females, 34 males) aged 59-89 years (mean 77.7 years) with predominantly occult CNV.

Alpha(1)-acid glycoprotein: an acute phase protein with inflammatory and immunomodulating properties.

alpha(1)-Acid glycoprotein (AGP) is a protein with a molecular weight of 41-43 kDa and is heavily glycosylated (45%). Due to the presence of sialic acids, it is negatively charged (pI=2.7-3.

TNF-mediated toxicity after massive induction of specific CD8+ T cells following immunization of mice with a tumor-specific peptide.

We immunized mice with antigenic peptide P815E, which is presented by H-2K(d) and recognized by tumor-specific CTL raised against P815 tumor cells. This peptide is encoded by the ubiquitously expressed gene MsrA and carries a mutated residue conferring tumor specificity. Unexpectedly, we observed a severe toxicity occurring in the early hours after the third injection, resulting in the death of most mice within 24 h.

Overexpression of alpha(1)-acid glycoprotein in transgenic mice leads to sensitisation to acute colitis.

Background: alpha(1)-Acid glycoprotein (alpha(1)-AGP) is an acute phase protein in most mammalian species whose concentration rises 2-5-fold during an acute phase reaction. Its serum concentration has often been used as a marker of disease, including inflammatory bowel disease (IBD). High alpha(1)-AGP levels were found to have a prognostic value for an increased risk of relapse in IBD.

Hyporesponsiveness of SPRET/Ei mice to lethal shock induced by tumor necrosis factor and implications for a TNF-based antitumor therapy.

Tumor necrosis factor (TNF) is a central mediator in lethal shock and an interesting cytokine for anticancer therapy. To inhibit TNF-induced lethal shock, it is important to identify protective genes. Here we demonstrate that the SPRET/Ei mouse strain, derived from Mus spretus, exhibits an extremely dominant resistance to TNF-induced lethal inflammation.

HSP70 protects against TNF-induced lethal inflammatory shock.

The heat shock (HS) response is a universal response activated after exposure to various stimuli. The major HS protein (HSP) is the 72 kDa HSP70 with strong homology in different eukaryotic species. We demonstrate that HS treatment of mice leads to a strong induction of HSP70 in several organs and confers significant protection against lethality induced by tumor necrosis factor (TNF).

Mice lacking alpha(2)-macroglobulin show an increased host defense against Gram-negative bacterial sepsis, but are more susceptible to endotoxic shock.

The onset of an acute phase response is one of the initial steps in the defense against an infectious organism. Alpha(2)-macroglobulin (alpha(2)M), an acute phase protein in most mammalian species, is known to have a broad antiprotease activity, but it can also bind a number of growth factors, cytokines, ions and lipid factors. We have shown that alpha(2)M-deficient (MAM-/-) mice are more resistant to a lethal Gram-negative infection compared to control mice.

A mediator role for metallothionein in tumor necrosis factor-induced lethal shock.

Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is centrally involved in several inflammatory disorders. Administration of TNF leads to a potentially lethal systemic inflammatory response syndrome (SIRS). We observed that (a) mice lacking functional genes for metallothionein 1 and 2 (MT-null) were protected compared with wild-type controls (P = 0.

Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy.

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival.

Involvement of a serine protease, but not of neutrophil elastase, in tumor necrosis factor-induced lethal hepatitis and induction of platelet-activating factor.

Background/aims: Tumor necrosis factor (TNF) plays an essential role in several types of acute and chronic hepatitis. Our aims in the present study were to elucidate the mechanism by which TNF leads to acute lethal hepatitis, thereby focusing on the role of serine proteases and platelet-activating factor (PAF).

Methods: All experiments were performed in a model of acute hepatitis, induced by TNF in combination with D-(+)-galactosamine (GalN).

Antisense knockdown of inducible nitric oxide synthase inhibits the relaxant effect of VIP in isolated smooth muscle cells of the mouse gastric fundus.

1. Our previous results showed that the non-selective nitric oxide synthase (NOS) inhibitor L-N(G)-nitroarginine (L-NOARG) and the selective inducible NOS (iNOS) inhibitor N-(3-(acetaminomethyl)-benzyl)acetamidine (1400W) inhibited the relaxant effect of vasoactive intestinal polypeptide (VIP) in isolated smooth muscle cells of the mouse gastric fundus, suggesting the involvement of iNOS. The identity of the NOS isoform involved in the VIP-induced relaxation in isolated smooth muscle cells of the mouse gastric fundus was now further investigated by use of antisense oligodeoxynucleotides (aODNs) to iNOS.

Detection, characterisation and purification of a murine liver factor capable of desensitising towards the lethal activity of tumour necrosis factor.

Tumour necrosis factor (TNF) is a major mediator in septic shock and several inflammatory diseases such as hepatitis. Galactosamine (GalN) sensitises experimental animals for TNF and the combination TNF/GalN leads to a lethal inflammatory hepatitis. We describe that a single injection of lipopolysaccharide (LPS), interleukin-1 (IL-1) or TNF can desensitise against the lethality induced by TNF/GalN, but also against changes in metabolic parameters such as hypothermia and transaminase release, in a dose responsive way.