L'hypothermie modérée induite chez un modèle murin : une solution thérapeutique au sepsis ?

Le sepsis, état pathologique lié à une réaction inflammatoire systémique suite à une infection, est lapremière cause de mortalité dans les unités de réanimation médicale et de soins intensifs hospitaliers.Parmi les pistes thérapeutiques envisagées, l’hypothermie est un bon candidat. En effet, l’hypothermiemodérée induite augmente la durée de survie de rats septiques. Ce travail avait pour objectifd’apporter des éléments permettant de comprendre et d’identifier les mécanismes responsables decet effet bénéfique. Pour cela, différentes fonctions couramment affectées lors du sepsis(inflammation, stress oxydant, défaillance rénale, capacités de transport de l’oxygène par le sang etéquilibre acide-base) ont été étudiées sur des rats septiques en hypothermie modérée (34°C). Lesrésultats obtenus révèlent que l’hypothermie modérée ralentit de manière significative la production decytokines pro-inflammatoires et tend à exercer une diminution de la production radicalaire systémiquechez les rats septiques. L’apparition de l’acidose métabolique et la défaillance rénale sont égalementretardées. Enfin, alors que le sepsis en normothermie conduit à une diminution de la coopérativité etde l’affinité de l’hémoglobine pour l’oxygène, synonymes d’une adaptation face à des modificationspotentiellement délétères, en hypothermie modérée, ces paramètres ne sont pas modifiés. Cesrésultats concourent à penser que l’hypothermie modérée en ralentissant l’évolution du sepsis permetd’augmenter la durée de survie des rats septiques. Ainsi, l’hypothermie pourrait constituer une pistepour traiter les patients atteints de sepsis sévère dans le but de temporiser l’inflammation et decontrôler l’agression retardant ainsi les défaillances d’organes.Despite numerous studies over the past twenty years, sepsis, a pathologic state related to a systemicinflammatory response following infection, remains the main cause of death in intensive care units.Among the therapeutic approaches proposed, hypothermia is a good candidate. Indeed, mild inducedhypothermia increased the survival duration of septic rats. This work aimed to provide elements tounderstand and identify the mechanisms responsible for this beneficial effect. Consequently, variousfunctions commonly affected during sepsis (inflammation, oxidative stress, renal failure, oxygen bloodcapacity and acid-base balance) were studied on septic rats maintained in mild induced hypothermia(34°C). The results showed that mild hypothermia significantly slows the cytokine proinflammatoryproduction and tends to exert a decrease in the radical systemic production of septic rats. Theappearance of metabolic acidosis and renal failure are also delayed. Finally, while in normothermiasepsis led to a decrease in the cooperativity and oxygen haemoglobin affinity, synonymous of anadaptation when faced with potential deleterious changes, in mild hypothermia, these parameters arenot modified. These results suggest that by reducing the development of sepsis, mild inducedhypothermia increases the survival duration of septic rats. Thus, hypothermia may be an option fortreating patients with severe sepsis by stalling inflammation and controlling aggression, therebydelaying organ failure

Effect of Induced Mild Hypothermia on Acid-Base Balance During Experimental Acute Sepsis in Rats

International audienceThe aim of this study was to determine the effect of induced mild hypothermia (34°C) on acid-base balance in septic rats. Twenty-eight male Sprague-Dawley rats median weight 306 g, range 251–333 g were used. After anesthesia and when the target temperature was reached (normothermia: 38°C or induced mild hypothermia: 34°C), sepsis was induced by cecal ligation and perforation. Measurements of cardiopulmonary parameters and blood samples were performed at T0h (occurring immediately after chirurgical procedures), T2h, T4h (at each temperature), and T6h (at 34°C only). Blood oxygen saturation, heart and respiratory rates, arterial blood pH, carbon dioxide partial pressure, sodium, potassium, chloride and calcium concentrations, hematocrit, blood lactate, tumor necrosis factor-α and interleukin-6 concentrations were measured on anesthetized rats. Other parameters such as bicarbonate concentration, hemoglobin concentration, base excess, and anion gap were estimated from measured parameters. Main results showed that an increase in both cytokines concentrations was observed in septic rats compared with sham rats. This increase was less marked at 34°C compared with 38°C. Moreover, sepsis induction led to a marked metabolic acidosis and hypothermia delayed this acidosis. Induced mild hypothermia delays the evolution of cytokines and metabolic acidosis during experimental sepsis

Effect of Induced Mild Hypothermia on Acid-Base Balance During Experimental Acute Sepsis in Rats

International audienceThe aim of this study was to determine the effect of induced mild hypothermia (34°C) on acid-base balance in septic rats. Twenty-eight male Sprague-Dawley rats median weight 306 g, range 251–333 g were used. After anesthesia and when the target temperature was reached (normothermia: 38°C or induced mild hypothermia: 34°C), sepsis was induced by cecal ligation and perforation. Measurements of cardiopulmonary parameters and blood samples were performed at T0h (occurring immediately after chirurgical procedures), T2h, T4h (at each temperature), and T6h (at 34°C only). Blood oxygen saturation, heart and respiratory rates, arterial blood pH, carbon dioxide partial pressure, sodium, potassium, chloride and calcium concentrations, hematocrit, blood lactate, tumor necrosis factor-α and interleukin-6 concentrations were measured on anesthetized rats. Other parameters such as bicarbonate concentration, hemoglobin concentration, base excess, and anion gap were estimated from measured parameters. Main results showed that an increase in both cytokines concentrations was observed in septic rats compared with sham rats. This increase was less marked at 34°C compared with 38°C. Moreover, sepsis induction led to a marked metabolic acidosis and hypothermia delayed this acidosis. Induced mild hypothermia delays the evolution of cytokines and metabolic acidosis during experimental sepsis

Effect of induced mild hypothermia on two pro-inflammatory cytokines and oxidative parameters during experimental acute sepsis.

International audienceThis study aimed to determine the effect of induced mild hypothermia (34°C) on the production of two cytokines (interleukin (IL-6) and tumor necrosis factor (TNF)alpha) and reactive nitrogen and oxygen species in plasma and the heart of acutely septic rats. After anesthesia and in conditions of normothermia (38°C) or mild hypothermia (34°C), acute sepsis was induced by cecal ligation and perforation. For each temperature three groups were formed: (1) baseline (blood sample collected at T0 hour), (2) sham (blood sample at T4 hours) and (3) septic (blood sample at T4 hours). At either temperature sepsis induced a significant increase in plasma IL-6, TNF-alpha and HO* concentration, compared with the sham groups (P≤0.016). Compared with the normothermic septic group, septic rats exposed to mild hypothermia showed a mild decrease in TNF-alpha concentration (104±50 pg/ml vs. 215±114 pg/ml; P>0.05) and a significant decrease in IL-6 (1131±402 pg/ml vs. 2494±691 pg/ml, P=0.038). At either temperature sepsis induced no enhancement within the heart of lipoperoxidation (malondialdehyde content) or antioxidant activities (superoxide dismutase and catalase). In conclusion, during acute sepsis, induced mild hypothermia appears to reduce some pro-inflammatory and oxidative responses. This may, in part, explain the beneficial effect of hypothermia on survival duration of septic rats

Does Induction Time of Mild Hypothermia Influence the Survival Duration of Septic Rats?

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Single Muscle Immobilization Decreases Single-Fibre Myosin Heavy Chain Polymorphism: Possible Involvement of p38 and JNK MAP Kinases

International audiencePurpose Muscle contractile phenotype is affected during immobilization. Myosin heavy chain (MHC) isoforms are the major determinant of the muscle contractile phenotype. We therefore sought to evaluate the effects of muscle immobilization on both the MHC composition at single-fibre level and the mitogen-activated protein kinases (MAPK), a family of intracellular signaling pathways involved in the stress-induced muscle plasticity. Methods The distal tendon of female Wistar rat Peroneus Longus (PL) was cut and fixed to the adjacent bone at neutral muscle length. Four weeks after the surgery, immobilized and contralateral PL were dissociated and the isolated fibres were sampled to determine MHC composition. Protein kinase 38 (p38), extracellular signal-regulated kinases (ERK1/2), and c-Jun-NH2-terminal kinase (JNK) phosphorylations were measured in 6-and 15-day immobilized and contralateral PL. Results MHC distribution in immobilized PL was as follows: I = 0%, IIa = 11.8 +/- 2.8%, IIx = 53.0 +/- 6.1%, IIb = 35.3 +/- 7.3% and I = 6.1 +/- 3.9%, IIa = 22.1 +/- 3.4%, IIx = 46.6 +/- 4.5%, IIb = 25.2 +/- 6.6% in contralateral muscle. The MHC composition in immobilized muscle is consistent with a faster contractile phenotype according to the Hill's model of the force-velocity relationship. Immobilized and contralateral muscles displayed a polymorphism index of 31.1% (95% CI 26.1-36.0) and 39.3% (95% CI 37.0-41.5), respectively. Significant increases in p38 and JNK phosphorylation were observed following 6 and 15 days of immobilization. Conclusions Single muscle immobilization at neutral length induces a shift of MHC composition toward a faster contractile phenotype and decreases the polymorphic profile of single fibres. Activation of p38 and JNK could be a potential mechanism involved in these contractile phenotype modifications during muscle immobilization

Comparison of Sodium Selenite and Selenium-Enriched Spirulina Supplementation Effects After Selenium Deficiency on Growth, Tissue Selenium Concentrations, Antioxidant Activities, and Selenoprotein Expression in Rats

Selenium contributes to physiological functions through its incorporation into selenoproteins. It is involved in oxidative stress defense. A selenium deficiency results in the onset or aggravation of pathologies. Following a deficiency, the repletion of selenium leads to a selenoprotein expression hierarchy misunderstood. Moreover, spirulina, a microalga, exhibits antioxidant properties and can be enriched in selenium.. Our objective was to determine the effects of a sodium selenite or selenium-enriched spirulina supplementation. Thirty-two female Wistar rats were fed for 12 weeks with a selenium-deficient diet. After 8 weeks, rats were divided into 4 groups and were fed with water, sodium selenite (20 μg Se/kg body weight), spirulina (3 g/kg bw), or selenium-enriched spirulina (20 μg Se/kg bw + 3 g spirulina/kg bw). Another group of 8 rats was fed with normal diet during 12 weeks. Selenium concentration and antioxidant enzyme activities were measured in plasma, urine, liver, brain, kidney, heart, and soleus. Expression of GPx (1, 3), Sel (P, S, T, W), SEPHS2, TrxR1, ApoER2, and megalin were quantified in liver, kidney, brain, and heart. We showed that a selenium deficiency leads to a growth delay, reversed by selenium supplementation despite a minor loss of weight in week 12 for SS rats. All tissues displayed a decrease in selenium concentration following deficiency. The brain seemed protected. We demonstrated a hierarchy in selenium distribution and selenoprotein expression. A supplementation of sodium selenite improved GPx activities and selenoprotein expression while a selenium-enriched spirulina was more effective to restore selenium concentration especially in the liver, kidney, and soleus

The diaphragm is better protected from oxidative stress than hindlimb skeletal muscle during CLP-induced sepsis

International audienceOBJECTIVES: The aim of this study was to determine whether non-lethal sepsis induced by cecal ligation and puncture (CLP) modulates oxidative damage and enzymatic antioxidant defenses in diaphragm and hindlimb skeletal muscles (soleus and Extensor Digitorus Longus (EDL)). METHODS: Female Wistar rats were divided into four experimental groups: (1) control animals, (2) animals sacrificed 2 hours or (3) 7 days after CLP, and (4) sham-operated animals. At the end of the experimental procedure, EDL, soleus, and diaphragm muscles were harvested and 4-hydroxynonenal (HNE)-protein adducts and protein carbonyl contents were examined in relation to superoxide dismutase and catalase expression and activities. RESULTS: We observed that both non-respiratory oxidative (i.e. soleus) and glycolytic skeletal muscles (i.e. EDL) are more susceptible to sepsis-induced oxidative stress than diaphragm, as attested by an increase in 4-HNE protein adducts and carbonylated proteins after 2 hours of CLP only in soleus and EDL. DISCUSSION: These differences could be explained by higher basal enzymatic antioxidant activities in diaphragm compared to hindlimb skeletal muscles. Together, these results demonstrate that diaphragm is better protected from oxidative stress than hindlimb skeletal muscles during CLP-induced sepsis