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H van Vugt

Publications and source records attributed to H van Vugt.

At least 19 recordsLinked to original sources
PubMed2001

Genotype versus phenotype: conflicting results in mapping a lung tumor susceptibility locus to the G7c recombination interval in the mouse MHC class III region.

Susceptibility to chemically induced lung tumorigenesis has previously been mapped to a genomic interval of 27 kb in the MHC class III region of the mouse using two H2 (a/b) intra- H2 recombinants, B10.A(1R) and B10.A(2R). Three genes are located within this interval, G7e (encoding a viral envelope protein), G7a/ Vars2 (encoding valyl-tRNA synthetase), and G7c (a gene with unknown function). A 70 kb contig, spanning the 27 kb region and extending 20 kb either side, was constructed from lambda phage libraries with genomic inserts derived from mouse strains B10.A(1R) and B10.A(2R). The region was analyzed for single-nucleotide polymorphisms, which would facilitate further fine mapping of the interval. Analysis of the expression levels of the candidate genes did not reveal any difference between B10.A(1R) and B10.A(2R). In addition, no differences were found at the sequence level in the 27 kb interval except for an A to T transition in intron 7 of G7c. A database comparison of the sequence surrounding this polymorphism did not identify any DNA-binding or enhancer consensus sequence. In conclusion, the previously observed phenotype could not be associated with or assigned to any of the candidate genes G7e, G7a/ Vars2, or G7c, nor could any of the other susceptibility loci, which have been reported to map to this region ( Cps1, Acp, Orch1, and Igis1).

Animals↗
PubMed1998

Molecular analysis of the major MHC recombinational hot spot located within the G7c gene of the murine class III region that is involved in disease susceptibility.

Recombination within the MHC does not occur at random, but crossovers are clustered in hot spots. We previously described a recombinational hotspot within the 50-kb Hsp70.3-G7 interval in the class III region of the mouse MHC. The parental haplotypes of recombinants with crossovers in this region represent the majority of the laboratory haplotypes (a, b, d, dx, k, m, p, px, q, s, and u). Using microsatellite markers and sequence-based nucleotide polymorphisms, the breakpoint intervals of 30 recombinants were mapped to a 5-kb-long interval within the G7c gene adjacent to G7a. Recombination within the G7c hot spot does not appear to be restricted to certain haplotypes. Sequence motifs that had been suggested to be associated with site-restricted meiotic recombination were absent in the vicinity of the G7c hot spot, and hence, these sequence motifs are no prerequisite for meiotic recombination. The G7c hot spot resides in a region to which a number of disease susceptibility loci have been mapped, including susceptibility to cleft palate, experimental autoimmune allergic orchitis, and chemically induced alveolar lung tumors. The exact localization of crossovers in recombinants that have been used in functional studies is important for mapping susceptibility genes and limits the number of candidate genes.

Animals↗
PubMed1996

A novel gene, G7e, resembling a viral envelope gene, is located at the recombinational hot spot in the class III region of the mouse MHC.

DNA sequence analysis of a segment of 15 kb, situated between G7b and G7a and present in the mouse but absent in human, revealed about 11 kb of DNA harboring a large number of repetitive sequences and 4 kb harboring a novel gene, G7e. This gene is transcribed in lymphoid tissues, having a 3-kb mRNA. The cDNA sequence of G7e shows stretches of nucleotide homology with murine leukemia virus (MuLV) envelope genes, and the predicted protein encompasses viral envelope motifs. The finding of a gene resembling MuLV envelope genes, flanked by a long terminal repeat and gag- and pol-like sequences, leads to the assumption that G7b and G7a in the mouse were separated through the insertion of a provirus, an event that might have taken place even before speciation of rat and mouse. The 15-kb interval forms a part of a 50-kb region, between Hsp70.3 and G7, where recombination preferentially takes place. Several disease susceptibility genes have been mapped to this same interval. The position of G7e in or in the vicinity of a recombinational hot spot might not be coincidental. The presence of adjacent putative recombination regulatory sequences is suggestive for the location of the crossover sites of recombination in this interval.

Amino Acid Sequence↗
PubMed1993

Three Hsp70 genes are located in the C4-H-2D region: possible candidates for the Orch-1 locus.

The central region of the mouse MHC harbors a recombinational hot spot area. Most recombinations in this part of the complex take place between the Hsp70.1 gene and the G7 gene. This interval is of interest since structurally indistinguishable recombinant haplotypes do differ in functional behavior. Susceptibility to experimental allergic orchitis, which is controlled by the Orch-1 locus, is one example. We have analyzed the hot spot region at the molecular level in order to understand the molecular organization of this chromosomal segment. From a C57BL genomic library we constructed a cosmid contig bridging the interval between Hsp70.1 and G7. The Orch-1 gene maps to a 60-kb segment of DNA in which we found a new Hsp70 homologue, Hsp70.3. Thus, as in the human MHC, the central region of the mouse MHC harbors a cluster of three Hsp70 genes; Hsp70.1, Hsp70.3, and Hsc70t. Two other genes are located in this critical interval (G7b and G7a/Bat-6), and there might still be other undetected genes present in the region. Heat shock proteins play an important role in a large number of physiological processes and it is tempting to speculate that Hsc70t, which exhibits testis-specific expression, may be identical to Orch-1.

Animals↗
PubMed1990

Alpha 2-macroglobulin and fibrinogen modulate inflammatory edema in man.

Animal experiments suggest that the response of acute-phase proteins (APPs) modulates the inflammatory reaction following tissue injury. To study this in man we investigated the relation between a number of APPs, including fibrinogen and alpha 2-macroglobulin, and the inflammatory edema induced by a primary immunization against cholera, typhoid, and yellow fever. Vaccination induces a significant APP response; however, only alpha 2-macroglobulin and fibrinogen were of importance to the amount of edema, measured 24 h after vaccination. High plasma levels of alpha 2-macroglobulin strongly inhibit the amount of edema, whereas a high level of fibrinogen proved to be a stimulating factor. This holds both for the basal prevaccination levels and the postvaccination levels. The normal variation of the plasma concentration of these proteins in healthy subjects seems to be a determining factor to the amount of edema in this kind of injury.

Acute-Phase Proteins↗
PubMed1990

The relation among stress, adrenalin, interleukin 6 and acute phase proteins in the rat.

Stress reactions exist in many conditions in which plasma interleukin 6 (IL-6) is elevated. Examples are burns and sepsis. In these situations fever is often present. These stress situations are always accompanied with high levels of adrenalin and corticosteroids. These hormones, especially when given together, elicit a definite response of acute phase proteins in normal rats. In two stress models, (i) laparotomy and (ii) fever induced by administration of PGE2 in the lateral intracerebral ventricle, we observed a rise of adrenalin and corticosteron followed by an elevated level of plasma IL-6. Therefore, we studied the effect of adrenalin and corticosteron on the plasma level of IL-6. Adrenalin evokes high levels of IL-6, and this effect can be blocked by propranolol. When IL-6 release is blocked in this way, the response of alpha 2 macroglobulin and the cysteine protease inhibitor, both fast-reacting acute phase proteins in rat, is strongly depressed. Isoprenalin, an adreno beta 2 agonist, also causes very high levels of IL-6, indicating that the release of IL-6 can be mediated by an adreno beta 2 receptor whose presence has been demonstrated in monocytic cells. The results suggest a relation between stress situations and IL-6 and may be another factor besides the presence of endotoxins, virus, etc. explaining the high levels of IL-6 observed in many serious clinical situations.

Acute-Phase Proteins↗
PubMed1989

[The effect of acute-phase proteins on inflammation edema due to vaccination].

The authors describe the profiles of a series of acute phase plasma proteins induced by vaccination (VAC) for cholera, typhoid, yellow fever and combinations of these with DTP. Cholera and typhoid VAC as single vaccinations induce the strongest reaction, yellow fever the weakest. The reaction pattern depends also on the kind of vaccination: DTP, especially, raises haptoglobin levels. Great individual variability in reaction exists. The authors also investigated the relation between the levels of these acute phase proteins, including alpha 2-macroglobulin, and the amount of inflammatory oedema that developed at the vaccination site. It was found that the pre-vaccination levels of alpha 2-macroglobulin and haptoglobin were correlated negatively with the oedema developed 24 hrs later, while fibrinogen showed a positive relationship. The acute phase reaction of these proteins did not alter these correlations. The other acute phase proteins had no influence on the oedema in this model. It is concluded that the existing substantial individual differences in plasma levels of alpha 2-macroglobulin, fibrinogen and haptoglobin in part govern the degree of oedema developing after a vaccination; they are to be regarded as factors of the so called 'innate immunity'.

Acute-Phase Proteins↗
PubMed1988

Relation between acute-phase proteins and enhanced bleomycin-induced pulmonary fibrosis in the rat.

Intratracheal application of Bleomycin (Bleo) in rats induces interstitial pneumonitis followed by progressive fibrosis. As the presence of high levels of acute-phase proteins (= reactants = APR), especially alpha 2-macroglobulin of the rat (alpha 2M), enhances liver fibrosis, we investigated whether this phenomenon also occurs in rats with Bleo-induced lung fibrosis. The experiments showed that this is the case; lung fibrosis assessed by measuring hydroxyproline, hexosamine, and prolyl-4-hydroxylase was enhanced when just before Bleo application an acute-phase reaction was induced. This effect can be explained by the inhibitory effect of alpha 2M on collagenase. The experiments showed a significant positive correlation between alpha 2M and parameters of fibrosis. This is especially the case in the third week after Bleo application. Bleo itself does not induce a strong acute-phase reaction, notwithstanding the pneumonitis during the first weeks. The increased fibrosis is accompanied by progressive ventilatory disturbances demonstrated by high arterial pCO2 and low pO2. In patients undergoing Bleo treatment, varying levels of APR can be expected, and this could explain the rapid development of fibrosis in individual cases.

Acute-Phase Proteins↗
PubMed1988

Fever and acute phase reactants in the rat.

In rats synthesis of some acute phase reactants can be induced by a combination of corticosteroids and adrenaline. During fever both hormones show high plasma levels. We studied the effect of fever induced by intra-cerebroventricular (i.c.v.) injection of PGE2 on the acute phase response. Fever was continuously recorded and 24 h after induction acute phase reactant (APR) response was measured as indicated by the rise of alpha-macrofetoprotein (alpha M FP, alpha 2 macroglobulin of the rat). Controls received 0.9% saline i.c.v. Controls did not develop fever (dTmax less than or equal to 1 degree C) nor did they show significant APR response. The maximal rise in body temperature after PGE2 (2.6 +/- 0.7 degrees C) correlated significantly with the rise in alpha M FP concentration 24 h later. Adrenalectomy prevented the APR response completely but the magnitude of the fever reaction remained the same (2.1 +/- 0.3 degrees C). alpha-Blockade gave a smaller fever response but had no effect on the APR response. In alpha- and beta-blockade, fever response was normal but no APR response was obtained. Destroying the sympathetic nerve supply to the liver with 6-OH dopamine retarded the fever response but again APR response was not impeded. In order to differentiate between the role of fever as such and the effect of PGE2 on APR synthesis, we used heat exposure to induce hyperthermia in normal rats who showed an APR response comparable with that after i.c.v. PGE2. Pretreatment with sodium salicylate before inducing hyperthermia led to a variable rise in alpha M FP. Fever as such, without tissue injury, induces an APR response. The pathway to this effect probably involves circulating corticosterone and adrenaline, possibly via a beta-receptor mediated stimulation.

Acute-Phase Proteins↗
PubMed1986

Acute phase reactants enhance CCl4 induced liver cirrhosis in the rat.

High levels of acute phase proteins (acute phase reactants, APR) suppress acute inflammatory reactions in the rat. As many APR have antiprotease properties, including an anticollagenase activity, the effect of APR on the development of CCl4-induced liver fibrosis was investigated in rats. APR were provoked by repeated injections of epinephrine, inducing a broad spectrum of APR. This reaction can be monitored measuring alpha 2-macroglobulin levels in the rat (alpha 2-macrofetoprotein, alpha M FP). This protein was found to inhibit both acute galactosamine hepatitis and acute CCl4-induced liver toxicity. The animals with high levels of APR at the start of CCl4 treatment developed a more severe degree of fibrosis and cirrhosis than the control group in which no acute phase reaction was induced. Epinephrine alone had no such effects. Additionally, the APR positive group showed an initially lower degree of hepatocellular damage when compared to control animals. This uncoupling of liver cell damage and subsequent fibrosis may demonstrate that higher levels of APR might be important as to the development of cirrhosis, possibly based on the anticollagenase activity of these proteins.

Alanine Transaminase↗
PubMed1986

Pathways of enzyme transfer in sodium taurocholate-induced acute hemorrhagic pancreatitis.

The pathways of enzyme transfer from the pancreas into the systemic circulation were analyzed in sodium taurocholate-induced acute hemorrhagic pancreatitis in the rat by estimating lipase concentrations in blood, lymph and ascites. During the first few hours of pancreatitis high enzyme levels were observed in thoracic duct lymph. However, cannulation of the thoracic duct did not prevent a significant increase in the lipase concentration in peripheral blood. The portal vein lipase concentration was found to exceed the peripheral values by approximately 10%. Extremely high concentrations of lipase were measured in the ascites collected during pancreatitis. When the ascites was transferred to the peritoneal space of healthy rats, a significant increase in the lipase concentration in peripheral blood was measured. This increase could not be prevented by transection of the parasternal lymphatics. It was concluded that the hematogenous rather than the lymphatic transport of lipase from the pancreas and the peritoneal surface is the most important pathway. In this respect, this study does not support thoracic duct drainage but advocates peritoneal lavage as a logical therapeutic measure to reduce the concentration of circulating toxic substances from the pancreas in acute pancreatitis.

Acute Disease↗
PubMed1986

Alpha 2 macroglobulin of the rat, an acute phase protein, mitigates the early course of endotoxin shock.

Normal rats and rats with high levels of alpha 2 macrofetoprotein (alpha M FP), an acute phase globulin induced by pretreatment with BaSO4 i.p., were injected with sublethal doses of endotoxin. One hour survival was better in the group with high levels of alpha M FP (36%) than in controls (9%). All rats receiving purified alpha M FP i.p. survived. Recovery of mean arterial blood pressure, expressed as the surface area under the curve, was significantly better in the groups with high alpha M FP levels. Leakage of i.v. administered human albumin was the same in control and BaSO4 pretreated rats. BaSO4 induces peritonitis which could explain the albumin leakage. Experiments were repeated therefore in rats pretreated with adrenaline which also initiates the production of alpha M FP. In this group, I h survival after endotoxin administration was 100% and albumin leakage was significantly less than in rats receiving either endotoxin only or BaSO4-pretreatment. In early endotoxin shock prostaglandins, including PGE2 a potent vasodilatator, are released into the circulation. From previous data it is known that alpha M FP prevents the vasodilatation and increased vascular permeability caused by PGE2. Rats with high levels of alpha M FP had a smaller fall in diastolic blood pressure after PGE2 administration than did controls with normal alpha M FP levels. The effects of alpha M FP on the haemodynamic events in early endotoxin shock could well be due to inhibition of PGE2 activity.

Animals↗
PubMed1986

The effects of alpha M-foetoprotein, an acute phase protein, and BaSO4-induced injury on IgE-mediated, systemic anaphylaxis in the rat.

A recently developed method for inducing fatal, IgE-mediated, bronchial and cardiovascular anaphylaxis in the rat was used to compare the effects of exogenously administered, purified alpha M-foetoprotein (alpha M FP) and BaSO4 pretreatment (as mean to induce an acute phase reaction with increased alpha M FP serum levels) with regard to mortality, bronchoconstriction and cardiovascular events. The BaSO4 pretreatment protected the rats almost completely against mortality, whereas exogenously administered alpha M FP offered no protection at all. With respect to the antigen-induced bronchoconstriction alpha M FP greatly inhibited the increase of the pulmonary resistance (RI), whereas the BaSO4 pretreatment suppressed either the dynamic lung compliance (Cdyn) or RI considerably. The cardiovascular events were only influenced by the BaSO4 pretreatment demonstrating a small but highly significant reduction of the initial fall in blood pressure together with a remarkable recovery within almost I h in the majority (91%) of the animals. Both exogenously administered alpha M FP and BaSO4 pretreatment increased the alpha M FP serum levels from a normal value of 59 +/- 4 micrograms/ml (n = 22), to 2732 +/- 252 micrograms/ml (n = 9) and 855 +/- 200 micrograms/ml (n = 22), respectively. From these data we conclude that the antianaphylactic activity of alpha M FP is limited to bronchoprotection of the more central parts of the lungs, whereas BaSO4 pretreatment covers a much broader antianaphylactic profile. This implies that BaSO4 pretreatment does not only induce alpha M FP but also other endogenous antianaphylactic factors.

Anaphylaxis↗