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Biomedical subjects

J L Mege

Publications and source records attributed to J L Mege.

At least 55 records · Page 3Linked to original sources
PubMed1994

Prognostic values of serum cytokines in septic shock.

OBJECTIVE: To prospectively evaluate the prognostic values of two serum cytokine levels, TNF alpha and IL6 serially measured at predetermined intervals in septic shock patients unresponsive to correction of hypoxaemia and plasma volume expansion and treated according to a strict protocol designed to meet specific therapeutic goals (goal-directed therapy). The evolution of serum lactate levels and oxygen-derived parameters was also investigated. DESIGN: A prospective case series study. Patients were followed-up until they were discharged from the hospital, or died. SETTING: ICU of a university hospital. PATIENTS: 30 consecutive patients with septic shock of various origins. INTERVENTIONS: The therapy was aimed at achieving and maintaining for at least 24 h supranormal values CI (> or = 4.0 l.min-1.m-2), oxygen delivery (DO2 > or = 550 ml.min-1.m-2) and oxygen uptake (VO2 > or = 150 ml.min-1.m-2) using a combination of fluid loading, norepinephrine, dobutamine and dopamine. A significant decrease in TNF alpha levels was associated with a favourable outcome while TNF alpha levels remained elevated in the patients who died in shock or of multiple organ failure. No prognostic value was associated with changes in IL 6 concentrations. In a stepwise logistic regression analysis, only TNF alpha levels contributed significantly to prediction of patients' outcome. A significant decrease in serum lactate concentrations was observed both in survivors and in patients who survived the episode of septic shock, but subsequently died of multiple organ failure. A positive DO2/VO2 relationship was observed only in survivors but did not contribute significantly to prediction of patient outcome. CONCLUSIONS: TNF alpha is a major mediator involved in the pathogenesis of septic shock and its decrease was significantly associated with a favourable outcome. IL 6 is certainly involved in the pathophysiology of septic shock but further studies are required to determine whether or not it is directly involved in the mediation of late and lethal complications of septic shock. Serum lactate levels and oxygen-derived variables were of less interest as prognostic factors.

Adult↗
PubMed1994

Monitoring of alveolar macrophage production of tumor necrosis factor-alpha and interleukin-6 in lung transplant recipients. Marseille and Montreal Lung Transplantation Group.

Bronchiolitis obliterans (BO), a common complication in lung transplant recipients, is a fibrotic process probably related to acute rejection (AR) and cytomegalovirus pneumonitis (CMVP). Because the pathogenesis of pulmonary fibrotic diseases involves activation of alveolar macrophages (AM), the present study was carried out to determine if AM were activated during AR, CMVP, and BO. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured in 157 AM supernatants obtained from 29 transplant recipients by immunoradiometric assay. Five groups were analyzed: AR (n = 21), CMVP (n = 12), BO (n = 15), bacterial pneumonia (BP) (n = 8), and control subjects (n = 70). Cytokines were also assayed 15 d (n = 15) and 30 d (n = 9) after AR and 30 d (n = 9) after CMVP. Cytokine secretion was elevated during AR (TNF-alpha = 3,709 +/- 1,409 pg/10(6) cells, IL-6 = 5,482 +/- 2,058 pg/10(6) cells, p < 0.005), and they returned to control values within 15 d. A similar pattern was observed during CMVP (TNF-alpha = 5,000 +/- 2,773 pg/10(6) cells, IL-6 = 12,280 +/- 3,939 pg/10(6) cells, p < 0.005), and values returned to control levels within 30 d. During BP, cytokine production values were higher than control values, but to a lesser extent than in AR and CMVP (TNF-alpha = 2,502 +/- 1,072, p < 0.05; IL-6 = 3,734 +/- 1,440, p < 0.005). In contrast, cytokine secretion during BO was not statistically different from that of control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease.

Unexplained weight loss is common in chronic obstructive pulmonary disease (COPD). Blood levels of tumor necrosis factor-alpha (TNF-alpha), a cytokine causing cachexia in laboratory animals, are elevated in various human diseases associated with weight loss. We therefore prospectively measured TNF-alpha serum levels (immunoradiometric assay) in patients with clinically stable COPD (n = 30; all male; mean age, 65 yr) whose weight was less (Group I; n = 16) or more (Group II; n = 14) than the lower limit of normal taken from Metropolitan Life Insurance Company tables. The patients had no cause known to elevate TNF-alpha serum levels; notably, they were not infected. Group I patients had unintentionally lost weight during the previous year, whereas the weight of Group II patients had not changed during the same period. The two groups had similar chronic airflow obstruction and arterial blood gas impairment; hyperinflation and reduction in diffusing capacity were more pronounced in Group I, but differences were not significant. TNF-alpha serum levels (pg/ml; mean [SD]) were significantly higher in Group I than in Group II (70.2 [100.0] versus 6.7 [6.4]; p < 0.001). Group II TNF-alpha serum levels did not differ significantly from those of healthy subjects (7.8 [3.9]), whereas those of Group I were significantly higher (p < 0.001). Because renal function was in the normal range, we conclude that increased TNF-alpha production--and not decreased TNF-alpha clearance--is a likely cause of weight loss in patients with COPD.

Aged↗
PubMed1994

Non-endotoxinic tumour necrosis factor-alpha-inducing factors in haemodialysis.

A transmembrane passage of endotoxins may account for the dysfunction of cytokine production which has been often reported in haemodialysis. We developed an assay based on the ability of patient serum to stimulate tumour necrosis factor alpha (TNF alpha) secretion in normal peripheral blood mononuclear cells. Three groups of subjects were investigated: normal controls (n = 14), patients with chronic renal failure, CRF (n = 15), and patients dialysed with polyacrylonitrile (n = 7), polysulphone (n = 8), and cellulose acetate (n = 7). Sera from dialysed patients displayed a significantly higher TNF alpha-inducing activity than those of controls and CRF patients. The ability of serum to elicit TNF alpha secretion was neither modified during the dialysis session nor influenced by the type of haemodialysis membrane. TNF alpha-inducing activity in serum was not inhibited by polymyxin B, known to impair endotoxin-dependent cell responses, thus suggesting that it was not related to circulating endotoxins. We conclude that non-endotoxinic factors are present in serum from dialysed patients and are able to induce cytokine secretion.

Antigens, CD↗
PubMed1993

Zymosan-induced tyrosine phosphorylations in human monocytes. Role of protein kinase C.

Protein tyrosine phosphorylations are involved in the proliferation and secretory responses of immune cells, but their role in phagocytes is poorly understood. The ability of unopsonized zymosan to induce protein tyrosine phosphorylations was investigated in human monocytes. The addition of zymosan to monocytes resulted in an increase in tyrosine phosphorylation of several endogenous proteins including 28-, 33-, 38-, 42-, 47-, 55- to 60-, 62-, 68-, 90-, 105-, 116-, and 120-kDa proteins; 55- to 60-kDa proteins were the predominant phosphoproteins. Moreover, we studied the effects of tyrphostin 23, a specific tyrosine kinase inhibitor, on stimulated tyrosine phosphorylations and early secretory responses of monocytes, i.e., arachidonic acid release and oxidative metabolism. We showed that tyrphostin inhibited zymosan-stimulated tyrosine phosphorylations and arachidonic acid release, but that it did not affect superoxide generation induced by zymosan. Zymosan binds mainly to CR3 receptor on human monocytes, and CR3 is devoid of intrinsic tyrosine kinase activity. It was predictable that zymosan stimulated a tyrosine kinase distal to the receptor or associated with it. We observed that PMA mimicked zymosan-induced tyrosine phosphorylations, thus suggesting that both agonists used a common transductional pathway implicating the serine/threonine kinase, protein kinase C. The antagonists of protein kinase C, sphingosine and calphostin C, inhibited zymosan-stimulated tyrosine phosphorylations. We suggest that, in human monocytes, zymosan-induced tyrosine phosphorylations are involved in cell responses such as the release of arachidonic acid, and that they require the sequential activation of protein kinase C and cellular protein tyrosine kinases.

Catechols↗
PubMed1993

Nocardia fractions, NLD and NWSM, induce tumor necrosis factor-alpha secretion in human monocytes: role of protein kinase C.

Nocardia lysozyme digest (NLD) and Nocardia water-soluble mitogen (NWSM) are two fractions derived from Nocardia opaca. In this report, we demonstrated that both fractions elicited significant secretion of tumor necrosis factor-alpha (TNF-alpha) in human monocytes. Supernatants from monocytes stimulated with NWSM and low concentrations of NLD displayed a cytotoxic activity against TNF-alpha-sensitive L929 cells, but supernatants from monocytes stimulated with high concentrations of NLD failed to lyse L929 cells. This latter phenomenon might be related to the secretion of an inactive form of TNF-alpha or the release of an inhibitor of TNF-alpha cytotoxic activity. Since it is well established that protein kinase C (PKC) plays a major role in the signaling of several monocyte activators, we investigated the putative role of PKC in cytokine synthesis induced by NLD and NWSM fractions. TNF-alpha secretion in response to both Nocardia fractions was inhibited by sphingosine, staurosporine and calphostin C, known PKC inhibitors, as well as by a PKC depletion procedure. In addition, NLD and NWSM induced a transient increase in [3H]phorbol dibutyrate binding, which assessed the activation of PKC. The data suggest the involvement of PKC in the signaling of NLD and NWSM fractions leading to the synthesis and the secretion of TNF-alpha by human monocytes.

Adjuvants, Immunologic↗
PubMed1993

Anti-neutrophil cytoplasmic antibodies (ANCA) and infection.

As ANCA are occasionally noted in patients with infectious disorders independently of any vasculitis process, we examined serum from patients with acute infection (n = 22) and septic shock (n = 57). Only two patients with acute infection were ANCA positive as determined by indirect immunofluorescence and western blot analysis. The clinical recovery of both patients was associated with negative immunofluorescence and western blot tests.

Adult↗
PubMed1993

F-actin content and spatial distribution in resting and chemoattractant-stimulated human polymorphonuclear leucocytes. Which role for intracellular free calcium?

Intracellular free calcium concentration ([Ca2+]i) plays a pivotal role for many responses in polymorphonuclear leucocytes (PMNs) stimulated by chemoattractants such as N-formylmethionyl-leucyl-phenylalanine (fMet-Leu-Phe). The importance of [Ca2+]i in the morphological polarization was investigated by using calcium-manipulated PMNs. We loaded human PMNs with BAPTA/AM to buffer or chelate [Ca2+]i in the presence or the absence of extracellular calcium by using fluo-3/AM as calcium indicator. The shape changes of PMNs were determined by microscopic examination, and membrane ruffling by right-angle light-scatter changes. Actin polymerization and F-actin distribution were recorded by staining PMNs with bodipy-phallacidin and quantified by quantitative fluorescence microscopy. We found that calcium-free incubation of PMNs loaded or not with 50 microM BAPTA/AM did not modify morphological polarization, membrane ruffling, actin assembly and F-actin distribution of PMNs stimulated with fMet-Leu-Phe, suggesting that these responses were probably functionally linked. It should be noted that incubation of PMNs in calcium-free conditions resulted in a radial distribution of F-actin and a moderate polymerization of actin, but not in morphological polarization of PMNs. Moreover, both calcium-sensitive and calcium-insensitive mechanisms of actin polymerization were additive, and inhibitable by 5 micrograms/ml cytochalasin B.

Actins↗
PubMed1993

Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects.

OBJECTIVE: The etiopathogenesis of Behçet's disease (BD) has not yet been clarified but might involve immune dysfunction. As cytokines are involved in the regulation of immune responses and inflammatory reactions, we investigated whether they may play a role in the pathogenesis of BD. METHODS: We investigated spontaneous and lipopolysaccharide (LPS) stimulated production of tumor necrosis factor alpha (TNF alpha), interleukin (IL) 1, IL-6, IL-8 and granulocyte monocyte macrophage colony stimulating factor (GM-CSF) by peripheral blood monocytes from 21 patients with BD, 10 healthy controls and 10 patients with familial Mediterranean fever (FMF), another chronic inflammatory disease. We also studied superoxide generation and surface antigen expression by polymorphonuclear neutrophils (PMN). RESULTS: The spontaneous secretion of TNF alpha, IL-6 and IL-8 by monocytes was significantly increased in patients with active BD. The secretion of TNF alpha, IL-1, IL-6 and IL-8 was found to be in normal range in asymptomatic patients with FMF. The LPS stimulated production of TNF alpha, IL-6, IL-1 and IL-8 was significantly increased in patients with BD, without any correlation with BD activity. In vitro, PMN spontaneously generated significant amounts of superoxide in patients with active BD. CONCLUSION: Taken together, our results suggest that monocyte and PMN dysfunctions may play a role in the pathogenesis of BD.

Adult↗
PubMed1992

Zymosan-stimulated tumor necrosis factor-alpha production by human monocytes. Down-modulation by phorbol ester.

In this study, we showed that human monocytes produced TNF-alpha in response to zymosan, a particulate agonist. Protein kinase C (PKC) seems to play a regulatory role in zymosan-induced TNF-alpha secretion. The pretreatment of monocytes with PMA induced a dose-dependent inhibition of zymosan-stimulated TNF production. This inhibition was likely due to an activation of PKC because it was prevented by inhibitors of PKC, sphingosine, and staurosporine. Moreover, PMA elicited a profound down-modulation of zymosan binding to monocytes. The inhibition of zymosan binding and TNF production displayed similar dose-dependence, suggesting that both events were closely related. In addition, PMA did not modify the expression of CD11b/CD18 receptor that is involved in zymosan recognition. In view of these findings, qualitative changes of CD11b/CD18 molecules might account for the inhibition of zymosan binding and TNF production. Thus, PMA specifically increased the association of CD11b/CD18 with the detergent-insoluble cytoskeleton. Cytochalasin B but not microtubule disrupters, nocodazole and colchicine, partially prevented the inhibition of zymosan binding. Hence, the inhibitory action of PMA on zymosan binding seems to be mediated by an increase in attachment of zymosan receptor to cytoskeleton and more likely to microfilaments. The regulatory activity of PKC might represent a first way of limiting cytokine over-production in response to pathogens which interact with monocytes via CD11/CD18 molecules.

Antigens, CD↗
PubMed1992

Chronic and intradialytic effects of high-flux hemodialysis on tumor necrosis factor-alpha production: relationship to endotoxins.

Tumor necrosis factor-alpha (TNF alpha) likely plays a role in hemodialysis-associated complications. As TNF alpha is mainly produced by monocytes in response to endotoxins, we studied its production and the presence of circulating endotoxins in patients dialyzed on polyacrylonitrile (PAN) membrane. Spontaneous production of TNF alpha was observed in patients before the dialysis session and increased during the session. Endotoxins were present in serum from patients chronically dialyzed with PAN and increased during hemodialysis session. In addition, intradialytic decrease in CD14 antigen expression on circulating monocytes, which could be caused by endotoxins, was found. The continuous presence of low amounts of circulating endotoxins between sessions may explain the chronic increase in TNF alpha secretion, while high amounts of circulating endotoxins may account for intradialytic oversecretion of TNF alpha and downmodulation of CD14. We suggest that endotoxin-free dialysates should be a prerequisite for the use of high-flux membranes.

Acrylic Resins↗
PubMed1992

Double localization of F-actin in chemoattractant-stimulated polymorphonuclear leucocytes.

Uniform concentrations of chemoattractants such as formylpeptides induced a morphological polarization of human polymorphonuclear leucocytes (PMNs) and a concentration of F-actin at the cell front. They also induced a transient increase in filamentous actin (F-actin) which preceded the cell shape change. We combined fluorescence microscopy and image analysis to study the localization of F-actin, as revealed by a specific probe (bodipyTM phallacidin) in suspended PMNs stimulated by chemoattractants. F-actin exhibited remarkable concentration in focal points after a 30 s exposure to 10(-8) M formylmethionyl-leucyl-phenylalanine (fMet-Leu-Phe), although no shape change of PMNs was detectable. A 10-min incubation with formylpeptide (10(-6) to 10(-9) M) induced the morphological polarization of PMNs and the appearance of a principal focus of F-actin in the cell head region and a secondary focus in the cell posterior end. The distribution of F-actin-associated fluorescence in 2D images of polarized PMNs might be due to an actual concentration of F-actin in privileged areas, to a local concentration of plasma membrane drawing filamentous actin or to variations in the cell volume. Then, we studied the distribution of a cytoplasmic marker, fluorescein diacetate and a membrane probe, TMA-DPH, in unstimulated rounded PMNs and in spherical and morphologically polarized PMNs stimulated by formylpeptide. The distribution of neither of these probes was correlated with F-actin distribution, especially in rounded PMNs stimulated 30 s with 10(-8) M fMet-Leu-Phe, suggesting that F-actin was concentrated in two foci located in the cell head region and in the cell posterior end. In addition, zymosan-activated serum induced the morphological polarization of PMNs and the appearance of two foci of filamentous actin, demonstrating that binding of formylpeptide to its specific receptor was not required for F-actin reorganization. We conclude that the accumulation of F-actin probably resulted from local filament assembly and put forward the hypothesis that microfilament reorganization in two centres drives the morphological polarization of PMNs.

Actin Cytoskeleton↗
PubMed1991

Role of tumor necrosis factor-alpha in Sneddon-Wilkinson subcorneal pustular dermatosis. A model of neutrophil priming in vivo.

A patient with IgG-kappa-associated subcorneal pustular dermatosis (Sneddon-Wilkinson disease) refractory to dapsone, etretinate, and plasma exchange was successfully treated with corticosteroids. A study of neutrophils from both blood and pustules was carried out before and during treatment. Levels of tumor necrosis factor-alpha were measured in serum, pustules, content, and supernatant of monocytes. The results suggest that a hyperactivation of neutrophils in the skin is due at least partly to excessive production of tumor necrosis factor-alpha.

Aged↗
PubMed1991

Haemodialysis membranes modulate chronically the production of TNF alpha, IL1 beta and IL6.

As cytokines may play a role in the adverse effects of haemodialysis, TNF alpha, IL1 beta and IL6 were investigated before the haemodialysis session (chronic effect) and after 30 and 60 min (session effect). We found that haemodialysis exerts a chronic effect on cytokines but the type of haemodialysis membrane, Cuprophan or Hemophan, specifically influences each cytokine. Circulating levels of TNF and unstimulated production of TNF and IL1 by monocytes were increased in patients dialysed with Hemophan, whereas a greater LPS-stimulated production of TNF was observed in patients dialysed with Cuprophan. Both types of membrane induced a higher production of IL6 as compared to controls. The alternate use of Cuprophan and Hemophan demonstrated that the production of TNF and IL1 was dependent on the type of haemodialysis membrane. We also found that Cuprophan induced a reversible decrease of spontaneous and LPS-stimulated production of TNF, IL1 and IL6 during the haemodialysis session. Taken together, these results suggest that Hemophan induced a sustained production of cytokines whereas Cuprophan primed monocytes, probably through the activation of the complement pathway.

Aged↗
PubMed1990

Skin necrosis after injection of aminosides. Arthus reaction, local toxicity, thrombotic process or pathergy?

A case of extensive skin necrosis following intramuscular injections of sisomycin is described. Eight cases of necrosis following subcutaneous injections of aminoside antibiotics have been reported in elderly females under anticoagulant theray, but the pathogenic mechanisms of these lesions have not been investigated. Defective fibrinolysis and abnormalities of oxidative metabolism of neutrophils were noted in our patient. Four major mechanisms are discussed: an Arthus reaction, a thrombotic process, a direct toxicity of aminosides for subcutaneous tissue, or a pyoderma-like neutrophilic reaction. Subjects with a tendency to thrombosis and/or abnormalities of neutrophil functions may be predisposed to these skin necroses.

Arthus Reaction↗