Biomedical subjects

Remi Neviere

Publications and source records attributed to Remi Neviere.

12 recordsLinked to original sources

PubMed2006

Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality.

OBJECTIVES: The purpose of this study was to test whether mitochondrial dysfunction is causative of sepsis sequelae, a mouse model of peritonitis sepsis induced by cecal ligation and perforation. Inhibition of mitochondrial permeability transition was achieved by means of pharmacological drugs and overexpression of the antiapoptotic protein B-cell leukemia (Bcl)-2. BACKGROUND: Sepsis is the leading cause of death in critically ill patients and the predominant cause of multiple organ failure. Although precise mechanisms by which sepsis leads to multiple organ dysfunction are unknown, growing evidence suggests that perturbations of key mitochondrial functions, including adenosine triphosphate production, Ca2+ homeostasis, oxygen-derived free radical production, and permeability transition, might be involved in sepsis pathophysiology. METHODS: Heart and lung functions were evaluated respectively by means of isolated heart preparation, bronchoalveolar lavage fluid protein concentration, lung wet/dry weight ratio, lung homogenate myeloperoxidase activity, and histopathologic grading. Respiratory fluxes, calcium uptake, and membrane potential were evaluated in isolated heart mitochondria. RESULTS: Peritonitis sepsis induced multiple organ dysfunction, mitochondrial abnormalities, and increased mortality rate, which were reduced by pharmacological inhibition of mitochondrial transition by cyclosporine derivatives and mitochondrial Bcl-2 overexpression. CONCLUSIONS: Our study provides strong evidence that mitochondrial permeability transition plays a critical role in septic organ dysfunction. These studies demonstrate that mitochondrial dysfunction in sepsis is causative rather than epiphenomenal and relevant in terms of vital organ function and outcome. Regarding the critical role of heart failure in the pathophysiology of septic shock, our study also indicates a potentially new therapeutic approach for treatment of sepsis syndrome.

Animals↗

PubMed2006

Sphingosine impairs mitochondrial function by opening permeability transition pore.

Growing evidence suggest that, in the heart, sphingosine participates to contractile dysfunction by altering calcium transients and mitochondria function. However, mechanisms underlying sphingosine-induced cardiac mitochondria dysfunction are poorly understood. Here, we studied the effects of sphingosine on isolated cardiac mitochondria of either wild-type or Bcl-2 overexpressing transgenic mice. Sphingosine induced reductions in ADP-coupled respiration, membrane potential, mitochondrial cytochrome c content and ATP production, which were partially prevented by cyclosporine A and mitochondrial Bcl-2 overexpression. These data suggest that sphingosine promotes mitochondrial permeability transition pore opening, which may result in uncoupled respiration and participate in cardiac contractile dysfunction.

Animals↗

PubMed2006

Cardiovascular protective role for activated protein C during endotoxemia in rats.

OBJECTIVE: We examined whether activated protein C (APC) treatment improves cardiovascular inflammation and dysfunction in endotoxemic rats. DESIGN AND SETTING: Randomized, controlled trial in an experimental laboratory of a university physiology department SUBJECTS: Male Sprague Dawley rats. INTERVENTIONS: Internal carotid artery and external jugular vein were catheterized under sterile conditions in rats. Instrumented rats infused or not with APC (240 microg/kg per hour) were challenged with E. coli endotoxin (10 mg/kg). Four hours after endotoxin challenge rats were prepared for cardiovascular functional studies and tissue and blood analyses. MEASUREMENTS AND RESULTS: Endotoxin administration induced systemic hypotension, depression of myocardial systolic performance and reduction in capillary density of the small intestine muscularis layer. Plasma levels of nitrite/nitrate, tumor necrosis factor alpha and macrophage migration inhibitory factor, mesentery venule leukocyte-endothelium interactions, heart and small intestine myeloperoxidase activities were increased in endotoxin-treated rats. APC largely prevented endotoxin-induced cardiovascular dysfunction with improved systemic hemodynamics, functional capillary density, and myocardial contractile performance. Beneficial cardiovascular effects of APC were associated with attenuation of entotoxin-induced inflammatory response in terms of plasma levels of nitrite/nitrate, tumor necrosis factor alpha, macrophage migration inhibitory factor, and endothelial cell-leukocyte activation. CONCLUSION: APC reduces systemic and tissue inflammation and preserves cardiovascular function during experimental endotoxemia.

Animals↗

PubMed2006

Significance and interpretation of elevated troponin in septic patients.

Because no bedside method is currently available to evaluate myocardial contractility independent of loading conditions, a biological marker that could detect myocardial dysfunction in the early stage of severe sepsis would be a helpful tool in the management of septic patients. Clinical and experimental studies have reported that plasma cardiac troponin levels are increased in sepsis and could indicate myocardial dysfunction and poor outcome. The high prevalence of elevated levels of cardiac troponins in sepsis raises the question of what mechanism results in their release into the circulation. Apart from focal ischemia, several factors may contribute to the microinjury and minimal myocardial cell damage in the setting of septic shock. A possible direct cardiac myocytotoxic effect of endotoxins, cytokines or reactive oxygen radicals induced by the infectious process and produced by activated neutrophils, macrophages and endothelial cells has been postulated. The presence of microvascular failure and regional wall motion abnormalities, which are frequently observed in positive-troponin patients, also suggest ventricular wall strain and cardiac cell necrosis. Altogether, the available studies support the contention that cardiac troponin release is a valuable marker of myocardial injury in patients with septic shock.

Humans↗

PubMed2005

Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction.

BACKGROUND: Although most of the deleterious effects of sepsis-induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular (LV) cardiomyocyte caspase activation is directly involved in sepsis-induced heart contractile dysfunction. METHODS AND RESULTS: LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection (10 mg/kg) displayed major reductions in contractile reserve and myofilament response to Ca2+. Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase-3, -8, and -9-like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD.fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum (10%) of endotoxin-treated rats induced contractile dysfunction, caspase-3-like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD.fmk- or zDEVD.cmk-treated rats or LV cardiomyocytes preincubated with zVAD.fmk or zDEVD.cmk. CONCLUSIONS: The results show an important relationship between endotoxin-induced caspase activation and reduced contractile reserve and sarcomere disarray at the level of single LV cardiomyocytes.

Actin Cytoskeleton↗

PubMed2005

Expression of apoptosis regulatory factors during myocardial dysfunction in endotoxemic rats.

OBJECTIVES: To document the time course of apoptosis pathway activation in sepsis and to determine whether Bcl-2 overexpression would improve endotoxin-induced myocardial dysfunction and mortality rate. DESIGN: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Male Sprague Dawley rats, wild-type C57BL/6 female mice, C57BL/6 female mice overexpressing Bcl-2. INTERVENTIONS: Hearts were isolated from rats treated with endotoxin (10 mg/kg, intravenously) to perform heart function, immunohistochemistry (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick 3'-end labeling, caspase 3), RNase protection assay, reverse transcriptase polymerase chain reaction, Western blotting (caspase 3), and radiolabeled annexin V studies. Twenty-four hours before endotoxin challenge (10 mg/kg, intravenously), rats were pretreated with saline or endotoxin (0.5 mg/kg, intraperitoneally), with or without parthenolide (1 mg/kg, intraperitoneally). Isolated hearts were used to test myocardial function. Mortality induced by endotoxin (10 mg/kg, intraperitoneally) was tested on wild-type or mice overexpressing Bcl-2. MEASUREMENTS AND MAIN RESULTS: Endotoxin-induced heart dysfunction was maximal at 4 and 8 hrs postinjection, started to improve, and was fully restored at 24 hrs after endotoxin treatment. Endotoxin also induced phosphatidylserine outer leaflet membrane exposure, caspase 3 activation, nuclear apoptosis, and changes in apoptosis gene expression. Bcl-2 overexpression induced by endotoxin pretreatment prevented endotoxin-induced myocardial dysfunction. Mice overexpressing Bcl-2 had dramatic improvement in survival rate compared with wild-type mice. CONCLUSIONS: These observations suggest that both death receptor and caspase-mediated apoptosis processes are activated in this sepsis model. Bcl-2 overexpression before endotoxin challenge prevents myocardial dysfunction in rats and improves survival rate in mice.

Animals↗

PubMed2004

Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats.

OBJECTIVES: The aim of this study was to test whether peroxynitrite neutralizers would reduce peroxynitrite accumulation and improve myocardial contractile dysfunction and inflammation in endotoxin-treated rats. BACKGROUND: Release of endogenous proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha in response to endotoxin is responsible for the production of large amounts of nitric oxide (NO), which may exert detrimental effects on the myocardium in animal models, isolated hearts, and isolated cardiac myocytes. Recent studies have indicated that many of the deleterious effects of NO are mediated by peroxynitrite, a powerful oxidant generated from a fast diffusion-limited reaction of NO and superoxide anion. METHODS: We studied the effects of peroxynitrite neutralizers, such as mercaptoethylguanidine (MEG) sodium succinate (10 mg/kg) and 5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrinato iron (III) (FeTPPS) (30 mg/kg) on peroxynitrite accumulation, in vivo endothelial cell-leukocyte activation on the mesenteric venule, and myocardial contractile dysfunction and inflammation in a model of sepsis induced by injection of endotoxin (10 mg/kg) in rats. RESULTS: Mercaptoethylguanidine sodium succinate and FeTPPS largely prevented the accumulation of peroxynitrite as measured by plasma rhodamine fluorescence and heart nitrotyrosine staining. Interestingly, MEG sodium succinate and FeTPPS improved endotoxin-induced myocardial contractile dysfunction, which was associated with reduced degradation of nuclear factor kappa B inhibitory protein I-kappa-B, plasma TNF-alpha levels, and microvascular endothelial cell-leukocyte activation. CONCLUSIONS: These observations suggest that the beneficial effects of MEG and FeTPPS on endotoxin-induced myocardial contractile dysfunction could be related to the unique effects of these compounds on cardiovascular inflammation processes.

Animals↗

PubMed2004

Calpain inhibitors improve myocardial dysfunction and inflammation induced by endotoxin in rats.

Excessive activation of calpains has been implicated in the pathophysiology of inflammation, trauma, and ischemia reperfusion injury. Here, we investigated the effects of calpain inhibition on myocardial dysfunction and inflammation induced by endotoxin in rats. Rats were treated i.v. with endotoxin (10 mg/kg) or endotoxin plus calpain inhibitors and were then prepared after 4 h for myocardial contractility assessment, detection of endothelium leukocyte interactions, and plasma TNF-alpha, nitrite/nitrate, and endocan levels. Compared with vehicle-treated rats, hearts from endotoxin-treated rats had reduced systolic performance that was partially prevented by calpain inhibitors, i.e., acetyl-leucyl-leucyl-arginal (leupeptin), carbobenzoxy-valyl-phenylalanial (calpain inhibitor III), and N-acetyl-leucinyl-leucinyl-norleucinal (ALLN). Leupeptin and calpain inhibitor III reduced plasma TNF-alpha levels in endotoxin-treated rats. ALLN reduced plasma TNF-alpha and nitrite/nitrate levels in endotoxin-treated rats. Endotoxin treatment increased mesenteric venule leukocyte rolling (10 +/- 3 leukocytes/min vs. 44 +/- 10 leukocytes/min; P < 0.01) and adhesion (2 +/- 2 leukocytes/min vs. 15 +/- 3 leukocytes/min; P < 0.01), which was reduced by calpain inhibitors. Attenuation of leukocyte endothelium interactions observed in calpain inhibitor-treated rats with sepsis was associated with increases in plasma anti-adhesion molecule endocan. In conclusion, calpain inhibitors improved endotoxin-induced cardiac dysfunction, which may be attributed to the modulation of endothelium leukocyte interactions in the inflamed vasculature.

Animals↗

PubMed2004

Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury.

In acute lung injury (ALI), a coagulation/fibrinolysis imbalance leads to fibrin deposition, persistence of which contributes to fibrotic evolution. Our study evaluated the effects of early inhibition of coagulation in Pseudomonas aeruginosa (Pa)-induced ALI through the use of recombinant human antithrombin (rhAT). The study was conducted in vivo on a murine model of Pa-induced ALI. Intravenous rhAT was administered simultaneously with intratracheal Pa. Four experimental groups were compared: CTR, intratracheal saline (0.5 mL/kg)/intravenous saline (1 mL); PNP, intratracheal Pa (0.5 mL/kg of 2 x 10(9) cfu)/intravenous saline; AT, intratracheal saline/intravenous rhAT (500 IU/kg); ATPNP, intratracheal Pa/intravenous rhAT. Epithelial and endothelial permeabilities were evaluated with radiolabeled albumin flux across the alveolar barrier (125I- and 131I-labeled albumin). Thrombin-antithrombin (TAT) complexes levels were used as markers of coagulation activation in blood samples and in BAL fluid. Epithelial and endothelial protein permeability were increased in Pa-induced ALI versus control. Intravenous rhAT administration led to further permeability disorders. Administration of rhAT in Pa ALI led to a rise in TAT complexes in ATPNP blood serum and BAL fluids compared with the other groups. In Pa-induced ALI the administration intravenous rhAT leads to major histologic damage, alveolar capillary barrier injury, and permeability increase. Such effects of the inhibition of thrombin activation by rhAT lead to the hypothesis of a probable beneficial role of early coagulation activation in ALI as a factor limiting both the extent of injury and permeability disorders. Our study suggests that inhibition of this initial procoagulative imbalance is potentially dangerous.

Animals↗

PubMed2004

Endotoxin-induced myocardial dysfunction: evidence for a role of sphingosine production.

OBJECTIVE: To determine whether sphingomyelinase pathway activation would participate in myocardial depression induced by endotoxin. DESIGN: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Male Sprague-Dawley rats, isolated rat heart, and cardiac myocytes. INTERVENTIONS: Cardiovascular function was evaluated in rats injected with saline, endotoxin (10 mg/kg, intravenously), and N-oleoylethanolamine (NOE; 10 mg/kg, intravenously). In ex vivo experiments, isolated rat hearts were perfused with endotoxin (5 microg/mL). For pharmacologic intervention, NOE (1 micromol/L) was admixed to the perfusate 20 mins before endotoxin. In in vitro experiments, ventricular myocytes were incubated with sphingosine (20 microM). Myocyte cell shortening and calcium transient were measured. Mitochondrial membrane potential was measured using the cationic dye tetramethylrhodamine methylester fluorescence technique. MEASUREMENTS AND MAIN RESULTS: Endotoxin treatment at 4 hrs did not alter mean arterial pressure and abdominal blood flow compared with control rats. Left ventricle developed pressure (LVDP) and its first derivatives (i.e., maximal and minimal change in pressure over time [dP/dtmax and dP/dtmin]) were decreased after 4 hrs in endotoxin-treated rats compared with control rats. NOE (10 mg/kg) treatment largely prevented left ventricular systolic function alterations of endotoxin-treated hearts (n = 6 in each group). In isolated rat heart, endotoxin (5 microg/mL) caused increases in tumor necrosis factor-alpha perfusate concentration and delayed depression of LVDP, dP/dtmax, and dP/dtmin after 60 mins, which was partially abrogated in the presence of the ceramidase inhibitor NOE (1 micromol/L). Sphingosine (20 microM) caused decreases in cell fractional shortening, calcium transient, and mitochondrial membrane potential of cardiac myocytes. CONCLUSION: These observations suggest that the sphingomyelinase pathway participates in endotoxin-induced myocardial depression.

Animals↗

PubMed2004

Clinical impact of inspiratory muscle impairment in sarcoidosis.

BACKGROUND AND AIM OF THE WORK: We evaluated the clinical consequences of inspiratory muscle impairment on exercise tolerance and quality of life in 34 sarcoid patients compared with 19 controls. METHODS: We measured pulmonary function tests, inspiratory muscle strength by maximal inspiratory pressure (PImax) and inspiratory muscle endurance (IME) by an incremental threshold loading test. IME was defined by the maximal sustainable pressure for 2 minutes (Plim2) and Plim2/PImax. Cycloergometer incremental exercise testing was performed in all patients. Health-related quality of life (HRQOL) was assessed by the SF-36 questionnaire in comparison with scores of 116 French controls. Dyspnea was assessed by the Modified Dyspnea Index (MDI). RESULTS: All SF-36 subscales were lower in sarcoid patients (p < 0.05). PImax% pred was similar in both groups whereas IME was markedly lower in sarcoid patients (p < 0.0001). Plim2 correlated with MDI (r = 0.44; p = 0.01) and SF-36 scales Physical Functioning (PF) (r = 0.42; p = 0.034) and Physical Role (PR) (r = 0.63; p = 0.0016). Plim2/PImax correlated with SF-36 subscales: PR (r = 0.62), vitality (VT) (r = 0.56) and social functioning (SF) (r = 0.39). Plim2 (r = 0.639; p = 0.0002) and Plim2/PImax (r = 0.36; p = 0.036) correlated with peak exercise tidal volume (V(T)max) but not with VO2max. CONCLUSIONS: Inspiratory muscle impairment was related to physical HRQOL scores but not to exercise tolerance, although it could impair exercising V(T) through an incipient inspiratory muscle fatigue.

Activities of Daily Living↗

PubMed2003

Ventilation-induced lung injury is associated with an increase in gut permeability.

Mechanical ventilation is associated with several harmful effects mainly related to high tidal volumes (Vt). Ventilator-induced lung injury can be responsible for an increased production of inflammatory mediators. We evaluated remote consequences on the gut of lung triggered inflammatory response, neutralizing anti-tumor necrosis factor (TNF) antibody was administered to assess the role of TNF in lung and gut permeability changes. Rats were anesthetized and ventilated for 2 h. A control group (Con: Vt = 10 mL/kg) was compared with a high Vt group (HV: Vt = 30 ml/kg). One microCi of I125-labeled human serum albumin was injected to measure extravascular albumin space. Gut permeability was evaluated by plasma-to-lumen ratio leakage of I125 human serum albumin. Extravascular albumin space increased in the HV group from 446 +/- 50 microL to 2783 +/- 887 microL. Gut index of permeability increased from 5.1 +/- 1.2 to 14.2 +/- 4.9. Anti-TNF antibody prevented both lung and gut increase in permeability. High tidal volume ventilation resulted in an increase in lung edema and gut permeability, antagonism of TNF with neutralizing antibodies abrogated the increase in gut permeability as well as lung edema.

Animals↗