1;Table of Contents;5 2;Contributors;8 3;Common Abbreviations;13 3.1;.B;13 4;Setting the Scene;14 4.1;Introduction - What is the Cause of Death in Multiple Organ Failure?;14 4.2;The Role of Tissue Hypoxia;14 4.3;a;15 4.4;The Role of Cellular Alterations;15 4.5;The Role of the Mitochondrion;15 4.6;The Role of Necrosis and Apoptosis;16 4.7;..;16 4.8;The Role of pH;16 4.9;Role of Oxygen Free Radicals;17 4.10;The Role of Nitric Oxide;18 4.11;The Role of Carbon Monoxide;18 4.12;Other Pathways;19 4.13;Immune Dysregulation;19 4.14;ß;19 4.15;The Role of Fever;19 4.16;Influence of Organ Systems The Role of the Endothelium;20 4.17;The Role of Coagulation Abnormalities;20 4.18;The Role of the Epithelium;21 4.19;The Role of the Gut;21 4.20;The Role of the Brain;21 4.21;The Role of the Endocrine System;21 4.22;.B);22 4.23;.B);22 4.24;Interorgan Interplay;22 4.25;Therapeutic Interventions - the Iatrogenic Component;22 4.26;Conclusion;23 4.27;References;23 5;Genetics and Severe Sepsis;29 5.1;Introduction;29 5.2;Rationale for Genetics in Sepsis and Infectious Diseases;29 5.3;Genetic Predisposition to Severe Sepsis: Mendelian or Non- Mendelian Genetics?;30 5.4;Single Gene Defects;30 5.5;.);31 5.6;.;31 5.7;Complex Multifactorial Disorders;31 5.8;Genetic Polymorphisms in Severe Sepsis and Septic Shock;32 5.9;Gene Polymorphisms Altering Pathogen Recognition ( Table 2);33 5.10;Mannose Binding Lectin;33 5.11;Fc. Receptor Polymorphism and Encapsulated Bacteria Infections;35 5.12;LPS Complex Receptor;35 5.13;.B);35 5.14;Gene Polymorphisms Modifying the Inflammatory Immune Response;36 5.15;a,;36 5.16;Pro-inflammatory Cytokines: TNF-;36 5.17;a;36 5.18;a;36 5.19;a;37 5.20;a;37 5.21;a;37 5.22;a;37 5.23;a;37 5.24;a;37 5.25;a;37 5.26;Anti-inflammatory Cytokine SNPs: IL-10;38 5.27;.;38 5.28;=;38 5.29;Hemostatic Gene Polymorphisms and Severe Sepsis;39 5.30;a;39 5.31;Perspectives and Conclusions;40 5.32;References;41 6;Cell Signaling Pathways of the Innate Immune System During Acute Inflammation;46 6.1;Introduction;46 6.2;A Survey of the Currently Recognized Pattern Recognition Receptors;47 6.3;.B;47 6.4;.B),;47 6.5;.B;47 6.6;.B;49 6.7;The TLR2 Complex;50 6.8;TLR3;51 6.9;ß);51 6.10;.B;51 6.11;TLR4;51 6.12;ß;51 6.13;TLR5;52 6.14;TLR7 and TLR8;53 6.15;.-;53 6.16;TLR9;53 6.17;a,;53 6.18;.;53 6.19;TLR10;54 6.20;TLR11;54 6.21;The NOD Proteins;54 6.22;.B;55 6.23;Coordination of TLR Signals in Response to Bacterial Pathogens;55 6.24;Coordination of TLR Signals in Response to Viral Pathogens;55 6.25;Coordination of TLR Signals in Response to Fungal Pathogens;59 6.26;Coordination of TLR Signals in Response to Parasitic Pathogens;59 6.27;The Contribution of the TLRs to Phagocytosis by Immune Effector Cells;60 6.28;Conclusion;62 6.29;References;62 7;Early-Onset Pro-inflammatory Cytokines;65 7.1;Introduction;65 7.2;Tumor Necrosis Factor;65 7.3;a;65 7.4;ß,;65 7.5;Experimental Animal Models ( Table 1);66 7.6;Clinical Studies;67 7.7;Interleukin-1;68 7.8;Experimental Animal Models ( Table 1);69 7.9;Clinical Studies;69 7.10;Interleukin-6;70 7.11;Experimental Animal Models ( Table 1);70 7.12;Clinical Studies;70 7.13;Interferon Gamma, Interleukin-12, and Interleukin 18;70 7.14;Experimental Animal Models ( Table 2);71 7.15;Clinical Studies;71 7.16;Macrophage Migration Inhibitory Factor (MIF);72 7.17;Experimental Animal Models ( Table 2);73 7.18;Clinical Studies;73 7.19;Conclusion;74 7.20;References;74 8;The Significance of HMGB1, a Late-Acting Pro- inflammatory Cytokine;77 8.1;Introduction;77 8.2;a;77 8.3;a;77 8.4;a;78 8.5;a;78 8.6;a,;78 8.7;a;78 8.8;a,;78 8.9;a,;78 8.10;a;78 8.11;a;78 8.12;a;78 8.13;a,;78 8.14;a;78 8.15;HMGB1 and Sepsis;79 8.16;a;79 8.17;a,;79 8.18;HMGB1, Hemorrhage, and Burns;79 8.19;µg/;80 8.20;aandIL-;80 8.21;a,;80 8.22;HMGB1 and Acute Lung Injury;80 8.23;a,;80 8.24;a;80 8.25;Receptors for HMGB1 Include RAGE, TLR2, and TLR4;80 8.26;a;80 8.27;Cellular Activation Pathways Induced by HMGB1;81 8.28;.B),;81 8.29;ß;81 8.30;.B;81 8.31;.B;81 8.32;Release of HMGB1 fr