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Interface INSERM-SFAR-SRLF « Predisposition de la réponse à l’agression » D Payen, MD, Ph D [email protected] Inflammation et métabolisme sont étroitement intriqués… Argument phylogénique et « anatomique » the Drosophila fat body incorporates the mammalian homologues of the liver and the haematopoietic and immune Systems. Function: sensing energy and nutrient availability, coordinates the appropriate metabolic and survival responses site of coordination of pathogen responses with metabolic status. Therapeutic targets at the interface between metabolic and inflammatory pathways Argument génétique constitutif The constitutive view Topic: Studies on SNP’s associations with innate immune response. 3 examples of leading pathways: – TNF- promoter variants – TLR4 haplotypes – HLA-DB variants Strategy: known prot gene SNPs association Genetic Polymorphisms and Severe Sepsis Gene Susceptibility and/or Outcome Mannose Binding Lectin IL-18 IL-10 IL-6 IL-1 locus IL-4 Meningococcemia, Pneumococcemia Gram Septic Severenegative/positive sepsis Shock Legionnaire’s Disease Septic Shock Meningococcemia; Pneumococcemia Meningococcemia Septic Shock; Cerebral Malaria Severe Sepsis Severe Sepsis, Meningococcemia Severe sepsis Severe Sepsis Viral Pneumonia PAI-1 FactorV Leiden Meningococcemia; Severe sepsis Meningococcemia; Severe sepsis Toll-Like Receptor 4/2 Toll-Like Receptor 5 CD14 FCgRII Receptor TNF locus Limitations of gene by gene approach Clark et al. Intensive Care Med 2006 32:1706-1712 Hope in development of genome wide association methods (600 000 variants studied in one shot!) Argument génomique • Gene expression in whole blood leukocytes determined before and at 2, 4, 6, 9 and 24 h after the i.v LPS to 4 HV, compared to 4 additional subjects without LPS. • Only 3% of the genes modified their expression • Essentially under-expression human blood leukocyte response to acute systemic inflammation the transient dysregulation of leukocyte bioenergetics &modulation of translational machinery Argument neuro-hormonal Insulin-receptor signalling interfaces with inflammatory signalling at the level of insulin-receptor substrates through activation of serine kinases. Figure 2 - Kaplan Meier Curves for 28 day all-cause mortality in (a) ACTH nonresponders (b) ACTH responders and (c) all patients (b) ACTH responders (a) ACTH non-responders 1.00 1.00 0.75 0.75 0.50 0.50 0.25 steroid 0.25 placebo 0 5 placebo P value for log rank test: 0.937 0 10 15 20 25 steroid P value for log rank test: 0.850 0 30 0 5 10 15 20 (c) All patients 1.00 0.75 P value for log rank test: 0.813 0.50 0.25 steroid placebo 0 0 5 10 15 20 25 30 25 30 Figure 3 - Kaplan Meier Curves for time to reversal of shock in (a) ACTH nonresponders (b) ACTH responders and (c) all patients (b) ACTH responders 1.00 (a) ACTH non-responders 1.00 steroid placebo 0.75 0.75 0.50 0.50 0.25 0.25 0 P value for log rank test: <0.001 0 5 10 15 20 25 steroid placebo 30 0 P value for log rank test: 0.038 0 5 10 15 (c) All patients 1.00 steroid placebo 0.75 P value for log rank test: <0.001 0.50 0.25 0 0 5 10 15 day 20 25 30 20 25 3 0 Sub-paper from Corticus data base Our article: shock reversal & outcome QS: Why success in shock reversal did not improve outcome? Within the first five days 1.0 Incidence of shock reversal according to treatment arm incidence Cumulative 0.2 0.4 0.6 0.8 Hydrocortisone Placebo 0.0 P<0.0001 0 1 2 3 4 5 Days after randomization 6 Within the first five days 0.4 0.6 Hydrocortisone Placebo 0.2 P= 0.28 0.0 Cumulative incidence 0.8 1.0 Incidence of death prior to shock reversal according to treatment arm 0 1 2 3 Days after randomization 4 5 6 Argument biochimique Free energy used by cells respiration or glycolysis Alternatively, reactions can be centred around ATP. • ATP-producers include glycolysis & oxidative phosphorylation • ATP-consumers: transport of cations & synthesis of macromolecules energy consuming functions of immune cells • Synthesis of macromolecule & ion transport; O2 is mainly used by mitochondria, non-mitochondrial O2 consumption is negligible O2 is used for what type of functions? Antimycine A ATP synthase Respiratoire Chain H+ ADP+Pi NADPH oxydase O2 protein Synthesis Ouabaïne ATP ADN/ARN synthesis Na+, K+ ATPase Ca2+ ATPase DPI Inhibition Cycloheximide Chlorure de lanthanum Actinomycine D Buttgereit, Biochem J, 1995. Global VO2: the different fractions % O2 Cellules 100 95 DPI Cycloheximide 90 Ouabaïne ActinomycineD Chlorure de lanthanum Antimycine A 78 ngatomes O2 85 80 Sec 75 0 500 1000 1500 2000 2500 3000 Effects septic plasma septique on baseline (V0) & stimulated reponse Septic plasma modifications similar to those observed in septic cells Plasmatic factors +++ Mitochondrial VO2 becomes more decoupled after incubation in septic plasma. It cannot result from tissue hypoxia!!!! M Integration of stress-signalling mechanisms. Le sucre et inflammation… Exogenous glucose (NUTRITION) J Appl Physiol 1997 Fed Fasted Fasted+iP G Exogenous glucose (NUTRITION) J Appl Physiol 1997 In conclusion, glucose metabolism interferes with hemodynamic, metabolic, and inflammatory responses to LPS. MAJOR ROLE OF EXOGENOUS GLUCOSE O2 consumption rate, ngatoms O2/min/107 cells 16 Vo Vstim ionomycin Vstim PMA p=0.003 12 8 4 0 NG HG Delta increase in O2 consumption, % B A 200 Delta ionomycin Delta PMA p=0.004 150 100 50 0 NG Fig. 4 HG Vo, ngatoms O2/min/107 cells A 10 HV sepsis 8 6 4 2 r=0.44 p=0.009 0 0 Delta increase in O2 consumption, % B 10000 20000 30000 40000 50000 HLA-DR, site number 200 150 100 Iono+PMA r=0.57 p=0.0014 50 HV sepsis 0 0 Delta increase in O2 consumption, % C Fig. 5 10000 20000 30000 40000 50000 HLA-DR, site number 225 175 125 ADP 75 r=0.58 p=0.049 25 HV s eps is -25 0 10000 20000 30000 HLA-DR, site number 40000 50000 Un example of acute inflammation aigue in human beings: hepatic transplantation Day 4 after OLT Argument inflammatoire Immunity triggers inflammation Pathogen pathway PAMPs or MAMPs “stranger model” Infection and sepsis Cell and tissue lesions DAMPs “danger model” infection, trauma, postop, burns Kono et coll. Nat Rev Imm 2008 Cell death and inflammation. - Necrotic cell death DAMPs receptors on leukocytes + prod of pro-inflam cytokines (IL-1). - Other molecules proteases; hydrolases act on EC components + mediators (complement fragments) or DAMPs prod of pro-inflam cytokines by host cells. - Pro-inflam mediators local vascular endothelium ‘leaky’, attracts neutrophils and monocytes/macrophages soluble (antibody) and cellular defences in the tissue Donc, les facteurs de prédisposition Constitutive Acquired Polymorphisms? Epigenetic… Polymorphisms SNPs… Chronic disease Pharmacogenomic Drug induced gene Expression changes Chronic treatment Poor or good Quality of feeding Reversing shock ≠ Improve outcome Surviving shock increases the risks of disease Proteins released Are changed by Environment (nitrosylated…) Metabolic failure Not related to perfusion Need for Markers Outcome D Payen 2010 Shock severity is characterized by scores… Outcome may then depend on injury but also on acquired negative factors… Severity Score Difficult to reverse but good reserve INJURY TISSUE RESERVE = Co-morbidity AGE Co-morbidity Easy to reverse But high co-morbidity in elderly… Severe Injury + good tissue reserve Moderate injury + high Co-morbidity Similar severity score Survivors of hospitalization for community-acquired pneumonia are at increased risk of cardiovascular events, repeated infections, and death in the following months. But the cause is unknown…Early and long-lasting mechanisms? Viral co-infections and tissue damage Crit Care Med 2009; 37:1850-1857 242 ICU patients, 39 CMV infections ICU mortality: 54% in CMV patients vs 37% in others (p=0.082) In-hospital mortality: 59% vs 41% (p=0.058) ICU LOS: 32d vs 12d (p<0.001) Length of MV: 27d vs 10d At least one bacterial nosoc inf: 69% vs 33% (p<0.001) En conclusion • Métabolisme et inflammation sont intriqués • Les raisons et les preuves sont multiples • Les facteurs enzymatiques, les substrats, les organelles, les facteurs nucléaires interférent pour assurer et moduler la réponse inflammatoire • Le traitement et les biomarqueurs métaboliques et inflammatoires constituent un espoir diagnostique et thérapeutique Attendons les données futures…. ENERGY CONSUMING FUNCTIONS OF IMMUNE CELLS Specific immune functions General housekeeping functions Migration Active transport of molecules and ions Cytokinesis Mitochondrial oxygen consumption oxidative phosphorilation (> 90 %). Phagocytosis ATP Antigen processing Antigen presentation Activation Synthesis of macromolecules (RNA/DNA/protein synthesis) Electron transport chain Saraste M. Science, 1999. Effector functions Buttgereit F. Immunology Today, 2000. LPS injection: an example of ACUTE INFLAMMATION … Calgranulines: an example of DAMPs molecule May be a prognostic marker… alive dead Gobal population n = 111 n=61 n=50 25 20 S100A8/A9 pg/ml 18 16 14 12 10 8 20 15 10 5 6 4 0 2 Plasma S100 A8/A9 complex D0 SOFA D0 NS (p<0,09) p<0,0001 Payen D, Lukazsewicz AC et al. (in review) (Patented in December 2008) * 30 * Plasma S100A8/A9 (g/ml) 28 26 * 24 * 22 20 18 alive 16 (41) 14 dead (15) (50) 12 (8) 10 8 6 4 (60) (59) (59) (43) 2 (46) 0 D0 D1 D7 D14 D28 Figure: trend over time of S100A8/A9 complex, according to outcome, in plasma. Results expressed in g/ml. Effectives in brackets. *p=<0.0001, test de Mann Whitney Cinétique des “alive”: D0-D28, p<0.0001, test de Friedman, n=34 D0-D14, p<0.0001, test de Friedman, n=41 D0-D7, p=0.0005, test de Friedman, n=57 Cinétique des “dead”: D0-D14,NS, test de Friedman, n=8 D0-D7, p=0.0010, test de Friedman, n=15 S100A8/A9 in patients without shock at D0 N=8 survivors N=8 non survivors 28 24 p=0.0008 Plasma S100A8/A9 (g/ml) 20 alive 16 dead 12 8 4 0 D0 Mann whitney test, p=0.0008 Metabolic failure and cell recovery Levine et al. Cell 2008 132:27-42 Signals for heterophagic removal of apoptotic cells Degradation of misfolded proteins Removal of surplus or damage organelles Genomic stability Singer et al. Lancet 2004, Belikova et al. CCM 2007 Impairment of capacity of repair? Exple: autophagy STRESS ADAPTATION Generation of ATP in stressed cells Metabolic alterations: HOMEOSTASIS Provision of nutrients during catabolism – to sustain metabolism during nutrient deprivation – to prevent the accumulation of damaged, toxic proteins and organelles during stress – Implicated in anti-microbial defense inhibits cell death by necrosis Autophagy in innate and adaptive immunity Autophagy is impaired in: degenerative disease, heart disease, aging, cancer, dysimmunity… Levine et al. Cell 2008 132:27-42