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M H Bemelmans

Publications and source records attributed to M H Bemelmans.

17 recordsLinked to original sources
PubMed1996

TNF receptors in murine Candida albicans infection: evidence for an important role of TNF receptor p55 in antifungal defense.

TNF mediates multiple biologic activities through two distinct cell surface receptors, TNFR-p55 and TNFR-p75. TNF plays an important role in nonspecific resistance against the fungus Candida albicans. We used transgenic mice deficient for TNFR-p55 or TNFR-p75 to investigate the role of the TNFR in antifungal defense. Mice deficient for TNFR-p55 have highly impaired ability to clear infection with C. albicans and readily succumb to the infection. Also mice deficient for TNFR-p75 had a significant reduction in their ability to clear the fungus although lethality was not increased. These data demonstrate that TNFR-p55 in particular, but also TNFR-p75, plays a definite role in defense against infection with C. albicans. In NMRI mice, infection with C. albicans resulted in a significant systemic release of soluble (s)TNFR-p75. Cyclophosphamide-induced granulocytopenia led to a reduction of sTNFR-p75 release, whereas levels of bioactive TNF in response to fungal infection were increased. Release of sTNFR-p55 was not affected by induction of granulocytopenia. These observations suggest that granulocytes are a source of sTNFR-p75, possibly contributing to regulation of TNF activity during infection with C. albicans.

Animals↗
PubMed1996

Increased concentrations of tumour necrosis factor (TNF) and soluble TNF receptors in biliary obstruction in mice; soluble TNF receptors as prognostic factors for mortality.

Systemic tumour necrosis factor (TNF) is present in jaundiced mice. Two soluble TNF receptors, sTNFr-P55 and sTNFr-P75 are reported to play a part in the natural defence against TNF. This study investigated the properties of circulating TNF and sTNFr in jaundiced mice. The data show that TNF in these mice is biologically inactive and that an increase of both sTNFr is seen (p < 0.001). Surgical trauma in jaundiced mice is known to be accompanied by a high mortality (36%) and increased TNF concentrations. This study shows that both systemic TNF and sTNFr concentrations are increased after surgical trauma in jaundiced mice and that sTNFr concentrations rather than TNF concentrations were found to be correlated with mortality. In line with this finding this study showed that lactulose pretreatment before a surgical trauma in these mice significantly reduces postoperative concentrations of sTNFr-P75 (p < 0.005) and mortality (0%; p < 0.05) without reducing TNF concentrations, while anti-TNF antibodies were ineffective. In conclusion, these data suggest that TNF in biliary obstruction is rapidly inactivated by increased concentrations of sTNFr. Furthermore, sTNFr concentrations rather than TNF concentrations show a good correlation with mortality after surgery in obstructive jaundice. The positive effect of lactulose on mortality could be caused by a decreased inflammatory status.

Animals↗
PubMed1996

Tumor necrosis factor: function, release and clearance.

Tumor Necrosis Factor (TNF) is a multifunctional cytokine. It plays an important role in the pathophysiology of several diseases. Recently, it has been discovered that TNF is circulating in two different forms, a bioactive form and an immunologically detectable form. These two forms of TNF show different clearance kinetics. The immunological form is supposed to be an inactivated TNF protein. For this inactivation, proteolytic degradation or TNF binding by inactivating proteins is necessary. In this review we have focused on TNF inactivation by TNF binding proteins. Recent data show that there are soluble TNF receptors circulating which can bind and inactivate TNF. These receptors are membrane-bound TNF receptors which have been proteolytically cleaved from the cell membrane. Two TNF receptors are circulating, the soluble TNF receptor of 55 kDa (P55) and the receptor of 75 kDa (P75). The receptors are held responsible not only for inactivation of the TNF, but also for the clearance of TNF. Recent data show that the kidney is the most important organ for TNF clearance, followed by the liver. All other organs are of less importance. In this review, function, release, and clearance of TNF are discussed.

Animals↗
PubMed1995

Differences in the shedding of soluble TNF receptors between endotoxin-sensitive and endotoxin-resistant mice in response to lipopolysaccharide or live bacterial challenge.

TNF-alpha plays a pivotal role in the pathogenesis of septic shock. It exerts its effects by binding two cell surface receptors, designated TNF-R I and II, also referred to as the p55 and p75 receptors, respectively. TNF-Rs are transmembrane proteins, which on cleavage of their extracellular domains, result in the release of soluble fragments (sTNF-R). sTNF-R levels increase markedly during infection, and may serve to modulate TNF-alpha bioactivity. The mechanisms regulating this process are uncertain. To investigate this, we measured sTNF-R release in endotoxin-sensitive C3H/HeN and endotoxin-resistant C3H/HeJ mice given LPS or live Gram-negative bacteria. In C3H/HeN mice, there was a rapid early response during the first 4 h, and a second peak at 8 h, particularly noticeable in the case of the p75 receptor. Prior administration of neutralizing Abs to TNF-alpha or IFN-gamma had no effect on receptor shedding. Surprisingly, C3H/HeJ mice also responded to both bacterial challenge and to LPS by shedding sTNF-R; the magnitude and duration of the early response was not substantially different from C3H/HeN mice, although the second peak was absent. Peritoneal macrophages from C3H/HeN mice responded promptly (5 h) when stimulated with LPS in vitro, and by 22 h levels had increased five- to 10-fold. In contrast, cells from C3H/HeJ mice demonstrated only a very modest response at 22 h following maximal stimulation. The data suggest that there may be at least two separately regulated pathways that control sTNF-R shedding in these mice.

Animals↗
PubMed1995

Granulocytopenia reduces release of soluble TNF receptor p75 in endotoxin-stimulated mice: a possible mechanism of enhanced TNF activity.

This study demonstrates that granulocytopenia alters the TNF response to endotoxin. Significantly higher levels of bioactive TNF were observed in mice rendered granulocytopenic (< 0.05 x 10(9) granulocytes/litre) with cyclophosphamide than in normal mice. Levels of circulating soluble TNF receptor p75 (sTNFR-p75) in response to endotoxin were higher in normal mice than in granulocytopenic mice whereas no difference in levels of circulating soluble TNF receptor p55 (sTNFR-p55) was observed. To investigate further the role of both sTNFR in inactivation of TNF, murine recombinant (r) TNF or human rTNF was injected in to normal and granulocytopenic mice. Higher TNF bioactivity was recovered in granulocytopenic mice than in normal mice after administration of murine rTNF, whereas, no difference in recovered TNF bioactivity was observed after human rTNF. As murine TNFR-p75 does not bind to human TNF, this observation indicates that less sTNFR-p75 available for neutralization of TNF in the circulation in granulocytopenia results in enhanced TNF bioactivity. Furthermore, endotoxin-induced lethality was increased in granulocytopenic mice. In summary, this study shows that endotoxin-induced release of sTNFR-p75 is reduced and TNF bioactivity increased in granulocytopenia. Our data suggest that release of sTNFR-p75 from granulocytes is a mechanism in the regulation of TNF bioactivity.

Agranulocytosis↗
PubMed1994

In vivo T cell activation by anti-CD3 monoclonal antibody induces soluble TNF receptor release in mice. Effects of pentoxifylline, methylprednisolone, anti-TNF, and anti-IFN-gamma antibodies.

Injection of anti-CD3 is accompanied by an increase in systemic TNF, a mediator of the physiologic changes induced by anti-CD3 injection. Various mechanisms have been reported to be responsible for TNF inactivation and clearance. Recently, it has become evident that circulating soluble TNFRs (P55 and P75), which are known to increase in response to TNF inducers such as LPS, represent a natural protection mechanism against circulating TNF. Here we show that triggering the TCR by anti-CD3 injection results in a strong induction of both systemic TNF and soluble TNFR release. Maximal levels of TNF were reached after 2 h (10 ng/ml). Maximum levels of P55 (450 pg/ml) were reached between 0.5 and 8 h, whereas the highest levels of P75 were reached after 2 h (28 ng/ml). Because TNF and IFN-gamma are supposed to be involved in the pathophysiology of the anti-CD3 response, we investigated the influence of in vivo neutralization of TNF and IFN-gamma. Injection of mAb to TNF and IFN-gamma significantly reduced systemic TNF levels and both soluble TNFR levels. Two inhibitors of anti-CD3 induced TNF release; steroids and pentoxifylline both reduced TNF levels and P75 levels without affecting P55 levels. The results show that T cell activation induces both systemic TNF release and release of both soluble TNFRs. Although TNF and IFN-gamma are involved in this mechanism, their role does not seem to be crucial.

Animals↗
PubMed1994

Non-radical therapy for early gastric cancer.

To assess the potential benefit of R2 gastrectomy for patients with early gastric cancer, complications and long-term survival of patients who underwent conventional resection with limited lymphadenectomy (R1 gastrectomy) were analysed retrospectively. Resection margins of all 46 consecutive patients were free from tumour. Tumours were limited to the mucosa in 35 patients and infiltrated the submucosa in 11. Positive lymph nodes were found in two patients. The 30-day mortality was two patients, and cardiac and pulmonary complications occurred in five and six respectively. Anastomotic leakage developed in two patients. During 5 years of follow-up two patients died from tumour recurrence; one of these had lymph node metastases at the initial resection. Resection with limited lymphadenectomy for early gastric cancer results in a 91 per cent 5-year survival rate without the need for R2 gastrectomy with its probably higher morbidity and mortality.

Adult↗
PubMed1994

Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozotocin-diabetic rats.

Advanced glycation end-product-formation is thought to play a role in the development of diabetic angiopathy. By altering the structure of different extracellular matrix components advanced glycation end-products might affect vascular and glomerular permeability. In this study we investigated the effect of treatment with an inhibitor of advanced glycation end-product-formation, aminoguanidine, on vascular permeability and the development of albuminuria in streptozotocin-induced diabetic rats. Male Wistar Rp rats were randomized into a control group, a diabetic group, and an aminoguanidine-treated diabetic group. After 8 weeks, 24-h urine collections were taken and rats were implanted with an arterial and a venous catheter. mean arterial blood pressure was determined by intra-arterial measurement. Regional albumin clearances were assessed in the eye, ileum, lung, skeletal muscle and skin using an isotope technique. Mean arterial pressure in the diabetic group was significantly lower in the control and aminoguanidine-treated groups (p < 0.02). Regional albumin clearances were significantly increased in all tissues of diabetic rats compared to control rats (p < 0.05). Aminoguanidine treatment of diabetic rats resulted in a significant decrease of regional albumin clearance in all tissues except the lung (p < 0.05, lung p = 0.07). The development of albuminuria in diabetic rats however, was not affected by aminoguanidine.

Albuminuria↗
PubMed1994

Mechanism of induction of tolerance to tumour necrosis factor (TNF): no involvement of modulators of TNF bioavailability or receptor binding.

The repetitive administration of low doses of hTNF to mice induces tolerance to the lethal effects of mTNF. The underlying mechanism is unknown. In this study we have investigated whether changes in bioavailability and receptor binding could account for the observed differences. To that end we compared the pharmacokinetics of mTNF, the antibody response to TNF, the levels of soluble TNF receptors and the receptor binding of TNF in tolerant and control mice. No differences in pharmacokinetic parameters were observed. An antibody response towards hTNF occurred but the antibodies did not neutralize the mTNF used as a challenge. Furthermore, tolerance failed to protect mice against lethality induced by TNF in the presence of galactosamine, where 100- to 1000-fold lower dose of TNF is required. Also, tolerance could be induced in athymic nude mice where the antibody response is absent. These results show that the mechanism of induction of tolerance is not due to an antibody response. No differences in levels of soluble receptors or receptor binding could be observed in tolerant vs control mice. We conclude that the induction of tolerance involves mechanisms operating at the post-receptor pathways.

Animals↗
PubMed1994

Tissue distribution and clearance of soluble murine TNF receptors in mice.

In this study, clearance of sTNFR was investigated. The data show that bilateral nephrectomy results in an increase of the levels of both sTNFR after which a new steady state situation develops, suggesting that other organs, apart from the kidneys, are involved in clearing of sTNFR. Bilateral nephrectomy also leads to an increase in circulating TNF. This TNF was detected by ELISA and appeared to be not biologically active. To investigate whether the endotoxin induced increase in sTNFR is dependent of renal function, endotoxin was injected in nephrectomized mice. The data show that nephrectomy followed by endotoxin injection resulted in a further increase of the levels of both sTNFR. However, the endotoxin induced increase in nephrectomized mice was similar to the situation in normal mice after LPS indicating that the endotoxin induced increase is kidney independent in these mice. To investigate the relative participation of various organs in sTNFR clearance, 125I labelled sTNFR-P75 was injected. The data reveal that the majority of the sTNFR is removed from the circulation by the kidneys although indications for involvement of the liver and the lungs were also obtained. Calculation of the parametric clearance revealed that nephrectomy resulted in a 50% reduction of sTNFR-P75 clearance. Furthermore, the data presented strongly suggest that sTNFR release seems to be a continuous process, which is in balance with clearance of the sTNFR by the kidney, although other organs such as the liver and the lungs are involved.

Animals↗
PubMed1994

Increased plasma concentrations of soluble tumor necrosis factor receptors in sepsis syndrome: correlation with plasma creatinine values.

OBJECTIVES: Tumor necrosis factor (TNF) is an important mediator in the complex pathophysiology of sepsis syndrome. Although a positive correlation with mortality rate has been demonstrated, TNF has not been found consistently in sepsis. Since prolonged increases in soluble TNF receptor concentrations were demonstrated after endotoxin and TNF administration, we investigated whether the measurement of TNF receptor concentrations could provide a better indicator of disease than plasma TNF and interleukin (IL)-6 concentrations. DESIGN: Prospective analysis. SETTING: General intensive care unit (ICU) of a university hospital. PATIENTS: Twenty-six patients with sepsis syndrome and proven bacteremia. MEASUREMENTS AND MAIN RESULTS: Plasma peak concentrations of the soluble 55-kilodalton molecular weight TNF receptor were significantly higher (p < .005) in nonsurvivors compared with survivors of sepsis syndrome, whereas the difference in peak concentrations of the soluble 75-kilodalton TNF receptor did not reach significance (p = .06). In contrast to TNF peak concentrations (p = .14), significantly higher (p < .05) IL-6 peak concentrations were measured in nonsurvivors. Besides the positive correlation between the soluble 55-kilodalton TNF receptor and the soluble 75-kilodalton TNF receptor (r2 = .68; p < .0001), peak concentrations of both soluble 55-kilodalton TNF receptor and 75-kilodalton TNF receptor correlated significantly with plasma creatinine values, an indicator of renal function (r2 = .60; p < .0001 and r2 = .44; p < .001, respectively). Plasma creatinine concentrations were significantly higher in nonsurvivors (p < .001). CONCLUSIONS: In the population studied, plasma-soluble TNF receptor concentrations correlated with outcome as well as with plasma creatinine concentrations. The data presented suggest that increased plasma-soluble TNF receptor concentrations in patients with sepsis syndrome are merely the result of renal failure complicating sepsis, and are similarly correlated with mortality rate.

Adult↗
PubMed1993

LPS-induced sTNF-receptor release in vivo in a murine model. Investigation of the role of tumor necrosis factor, IL-1, leukemia inhibiting factor, and IFN-gamma.

TNF, a primary mediator of the response to infection, can be injurious to the organism when present in excessive quantities. Circulating soluble TNF receptors (sTNFR) appear to represent a natural mechanism that protects against circulating TNF. Two soluble TNF receptors (sTNFR-P55 and sTNFR-P75) circulate in vivo and are up-regulated in response to endotoxin. In this study, we investigated the kinetics of LPS-induced sTNFR release and the role of the cytokines TNF, leukemia inhibiting factor, IFN-gamma, and IL-1 in this process. The results show that LPS injection results in a rapid increase in levels of both sTNFR. Although sTNFR-P55 decreases after a peak at 30 min, sTNFR-P75 levels show a peak after 4 to 8 h, after which they slowly diminish. Both human TNF and murine TNF are capable of increasing levels of both sTNFR. Blocking circulating TNF by administration of 3 different anti-TNF agents before LPS injection (mAb to murine TNF, sTNFR55-Fc or sTNFR75-Fc) results in a significant increase of sTNFR-P55 levels, whereas only both sTNFR-Fc constructs also significantly increase sTNFR-P75 levels. Although IL-1 receptor antagonist pretreatment before LPS has no effect on TNF or sTNFR levels, leukemia inhibiting factor pretreatment significantly increases sTNFR-P55 levels. Pretreatment with anti IFN-gamma mAb before LPS results in a significant reduction in TNF and sTNFR-P55 levels, but sTNFR-P75 levels are significantly increased. Our data show that both sTNFR can be up-regulated by LPS and TNF. The influence of TNF, leukemia inhibiting factor, IL-1, and IFN-gamma on the kinetics of LPS-induced circulating sTNFR is discussed in the context of the pathophysiology of LPS-induced disease.

Animals↗
PubMed1993

Influence of nephrectomy on tumor necrosis factor clearance in a murine model.

TNF, a cytokine with multiple properties, is known to be rapidly inactivated in vivo. In patients with septic shock and kidney malfunction, conflicting data have been reported regarding the presence of TNF in the circulation. Recently, we have shown that these differences can be the result of the detection of free TNF vs TNF complexed with soluble TNF-R. Enhanced levels of soluble TNF-R have been reported in patients with kidney malfunction. Because the kidney is thought to play an important role in TNF and TNF-R metabolism, we investigated the influence of bilateral nephrectomy on TNF clearance and TNF-R regulation in a murine model. The data obtained show that bilateral nephrectomy results in circulating levels of immunologically detectable (ELISA), but not biologically active (bioassay), TNF. Injection of endotoxin results in significantly higher levels of immunologically detectable TNF in bilaterally nephrectomized mice, compared with sham-operated mice, whereas biologically active levels were similar. To investigate the roles of TNF-R1 (P55) and TNF-R2 (P75) in this process, clearance of TNF was studied by injection of murine and human TNF. Murine TNF injection leads to comparable clearance of bioactive TNF in nephrectomized and sham-operated mice (t1/2 = approximately 12 min). However, clearance of immunologically detectable murine TNF is significantly slower in nephrectomized mice, compared with sham-operated mice (t1/2 = 96 min vs 26 min, respectively; p < 0.05). Administration of human TNF results in a significantly lower clearance in nephrectomized mice, compared with sham-operated mice (t1/2 = 108 min vs 25 min, respectively; p < 0.05). This is observed for both bioactive human TNF and immunologically detectable human TNF. Based on the fact that murine TNF-R1 (55 kDa) has a similar affinity for murine and human TNF, whereas murine TNF-R2 (75 kDa) shows affinity only for murine TNF, the data obtained suggest an important role for TNF-R2 in inactivation and clearance of TNF by the kidney. Moreover, the data suggest that kidney malfunction affects TNF clearance, leading to increased amounts of circulating TNF-TNF-R complexes, which could function as a slow release reservoir for TNF.

Adrenalectomy↗
PubMed1993

Effect of antitumour necrosis factor treatment on circulating tumour necrosis factor levels and mortality after surgery in jaundiced mice.

Tumour necrosis factor (TNF) may play an important role in the increased incidence of complications after surgery in patients with obstructive jaundice. This study evaluated the effect of three different anti-TNF treatments, a monoclonal anti-TNF antibody (TN3), pentoxifylline and lactulose, on outcome after severe surgical trauma in mice with experimental biliary obstruction. Circulating serum TNF levels and mortality rate were monitored. Severe surgical trauma, such as renal ischaemia, in jaundiced mice resulted in increased levels of circulating TNF (3.5 ng/ml) and a high mortality rate (54 per cent). The three different anti-TNF treatments caused a significant reduction in postoperative levels of circulating TNF (TN3, P < 0.001; pentoxifylline, P < 0.01; lactulose, P < 0.05). Treatment with TN3 and pentoxifylline did not lead to a significantly reduced mortality rate (36 and 44 per cent respectively). Only lactulose treatment produced a significantly reduced mortality rate (7 per cent, P < 0.01). TNF is therefore not the only mediator responsible for death after surgery in jaundiced mice. Other mechanisms affected by lactulose are also involved.

Animals↗
PubMed1992

Cytokines tumor necrosis factor and interleukin-6 in experimental biliary obstruction in mice.

The putative role of the cytokines interleukin-6 and tumor necrosis factor in the pathophysiology of the complications and mortality after surgery in jaundiced patients was studied in a murine model. Cytokine serum levels were determined in mice with experimental biliary obstruction. As an indicator of the activation status of macrophages, cytokine release by mononuclear phagocytes obtained from such mice was assessed. Following surgery, interleukin-6 levels increased to 2 to 3 ng/ml after 3 to 4 hr, but declined rapidly afterward to levels of 60 pg/ml after 10 days. After 12 days, substantial interleukin-6 levels were observed in jaundiced mice (100 pg/ml), whereas levels in sham mice further decreased (p less than 0.001). The cytokine tumor necrosis factor was frequently present in the serum of jaundiced mice. After 22 days, when killed, all jaundiced mice showed significant tumor necrosis factor levels (p less than 0.001). This was in contrast to sham mice in which tumor necrosis factor was never detected. The presence of an activated state of macrophages in jaundiced mice was concluded from the observed high spontaneous cytokine release and significantly higher release after stimulation (p less than 0.05). The presence of circulating cytokines was discussed in the context of the postoperative complications observed in jaundiced patients.

Analysis of Variance↗