Mechanisms of Sepsis-Induced Organ Dysfunction and Recovery (eBook)

Table of Contents 5
Contributors 8
Common Abbreviations 13
.B 13
Setting the Scene 14
Introduction - What is the Cause of Death in Multiple Organ Failure? 14
The Role of Tissue Hypoxia 14
a 15
The Role of Cellular Alterations 15
The Role of the Mitochondrion 15
The Role of Necrosis and Apoptosis 16
.. 16
The Role of pH 16
Role of Oxygen Free Radicals 17
The Role of Nitric Oxide 18
The Role of Carbon Monoxide 18
Other Pathways 19
Immune Dysregulation 19
ß 19
The Role of Fever 19
Influence of Organ Systems The Role of the Endothelium 20
The Role of Coagulation Abnormalities 20
The Role of the Epithelium 21
The Role of the Gut 21
The Role of the Brain 21
The Role of the Endocrine System 21
.B) 22
.B) 22
Interorgan Interplay 22
Therapeutic Interventions – the Iatrogenic Component 22
Conclusion 23
References 23
Genetics and Severe Sepsis 29
Introduction 29
Rationale for Genetics in Sepsis and Infectious Diseases 29
Genetic Predisposition to Severe Sepsis: Mendelian or Non- Mendelian Genetics? 30
Single Gene Defects 30
.) 31
. 31
Complex Multifactorial Disorders 31
Genetic Polymorphisms in Severe Sepsis and Septic Shock 32
Gene Polymorphisms Altering Pathogen Recognition ( Table 2) 33
Mannose Binding Lectin 33
Fc. Receptor Polymorphism and Encapsulated Bacteria Infections 35
LPS Complex Receptor 35
.B) 35
Gene Polymorphisms Modifying the Inflammatory Immune Response 36
a, 36
Pro-inflammatory Cytokines: TNF- 36
a 36
a 36
a 37
a 37
a 37
a 37
a 37
a 37
a 37
Anti-inflammatory Cytokine SNPs: IL-10 38
. 38
= 38
Hemostatic Gene Polymorphisms and Severe Sepsis 39
a 39
Perspectives and Conclusions 40
References 41
Cell Signaling Pathways of the Innate Immune System During Acute Inflammation 46
Introduction 46
A Survey of the Currently Recognized Pattern Recognition Receptors 47
.B 47
.B), 47
.B 47
.B 49
The TLR2 Complex 50
TLR3 51
ß) 51
.B 51
TLR4 51
ß 51
TLR5 52
TLR7 and TLR8 53
.- 53
TLR9 53
a, 53
. 53
TLR10 54
TLR11 54
The NOD Proteins 54
.B 55
Coordination of TLR Signals in Response to Bacterial Pathogens 55
Coordination of TLR Signals in Response to Viral Pathogens 55
Coordination of TLR Signals in Response to Fungal Pathogens 59
Coordination of TLR Signals in Response to Parasitic Pathogens 59
The Contribution of the TLRs to Phagocytosis by Immune Effector Cells 60
Conclusion 62
References 62
Early-Onset Pro-inflammatory Cytokines 65
Introduction 65
Tumor Necrosis Factor 65
a 65
ß, 65
Experimental Animal Models ( Table 1) 66
Clinical Studies 67
Interleukin-1 68
Experimental Animal Models ( Table 1) 69
Clinical Studies 69
Interleukin-6 70
Experimental Animal Models ( Table 1) 70
Clinical Studies 70
Interferon Gamma, Interleukin-12, and Interleukin 18 70
Experimental Animal Models ( Table 2) 71
Clinical Studies 71
Macrophage Migration Inhibitory Factor (MIF) 72
Experimental Animal Models ( Table 2) 73
Clinical Studies 73
Conclusion 74
References 74
The Significance of HMGB1, a Late-Acting Pro- inflammatory Cytokine 77
Introduction 77
a 77
a 77
a 78
a 78
a, 78
a 78
a, 78
a, 78
a 78
a 78
a 78
a, 78
a 78
HMGB1 and Sepsis 79
a 79
a, 79
HMGB1, Hemorrhage, and Burns 79
µg/ 80
aandIL- 80
a, 80
HMGB1 and Acute Lung Injury 80
a, 80
a 80
Receptors for HMGB1 Include RAGE, TLR2, and TLR4 80
a 80
Cellular Activation Pathways Induced by HMGB1 81
.B), 81
ß 81
.B 81
.B 81
Release of HMGB1 from Necrotic Cells Triggers Inflammation 81
Conclusion 82
a 82
References 83
Nitric Oxide 86
Introduction 86
Reactivity and Cellular Targets of NO and its Derivatives Direct Effects of NO 87
NO Derivatives and Their Molecular Targets 87
µM), 87
Generation of Nitric Oxide: The Nitric Oxide Synthases 87
µM). 89
Cellular Effects of NO Vasorelaxant Effect 90
NO and the Immune Response 90
. 90
a 90
.B)- 90
.B 90
Effects of NO onMitochondria 90
µM) 91
Apoptosis and Necrosis 92
Mitochondrial Biogenesis 93
. 93
Measurement of NO Production 93
NO Production in Sepsis Overproduction of NO 93
µM 93
Sources of NO in Sepsis: Involvement of the Different NOS Isoforms 94
Effects of NO in Sepsis-induced MOF NO and the Circulatory System 95
a, 95
NO and Metabolism 96
Pharmacological Modulation of NO Levels in Sepsis 97
Modulation of NOS Protein Expression 97
a, 97
Inhibition of NOS Isoforms 97
Conclusion 100
References 100
Involvement of Reactive Oxygen and Nitrogen Species in the Pathogenesis of Acute Lung Injury 105
Introduction 105
Formation of Oxidative and Nitrosative Species Reactive Oxygen Species 105
Production of Nitric Oxide and Reactive Nitrogen Species 106
Reactive Oxygen/Nitrogen Species as Signaling Molecules 109
Thiols 109
Activation of Protein Kinases 110
Activation of Nuclear Factor-kappa B (NF- 110
.B, 110
.B 110
.B 110
Intracellular 110
Ca+ 110
PKC andMAPK 110
Adhesion Molecules 111
Functional Consequences of Protein Nitration In Vitro Surfactant Protein- A ( SP- A) 112
Current In Vivo Evidence Implicating RNS and ROS as Contributors to Lung Injury 112
a- 112
a- 112
a1- 112
The ‘Good’ Side of NO 114
.B 114
Inhaled NO and ARDS: An ongoing debate 114
Hypercapnia: An Example of a Radical Quandary? 115
Therapies to Attenuate RNS/ROS-Mediated Lung Injury 115
a- 115
a- 115
a- 116
ß- 116
.- 116
a- 116
ß- 116
Conclusion 117
References 117
Heat Shock Proteins in Inflammation 120
Introduction 120
Heat Shock Proteins as ‘Disease Regulators’: Sepsis and Acute Respiratory Distress Syndrome (Fig. 1) 122
a), 123
ß- 123
HSP70 Inhibits Pro-inflammatory Cell Signaling Pathways in ARDS 124
a 124
a 124
.B( 124
.B) 124
.B 124
.B 124
.B 124
.B 124
.B 124
.B 124
.B 124
.B- 124
.B 124
.B, 124
.B 124
Conclusion 125
References 125
Fibrosis in the Acute Respiratory Distress Syndrome 129
Introduction 129
Pathogenesis of ALI/ARDS 129
What Drives the Fibrotic Response in ALI/ARDS? 131
a 131
a) 131
a 131
a) 131
ß 131
ß1 131
Evidence for the Role of the Coagulation Cascade in ALI/ARDS 131
Thrombin and Proteinase Activated Receptors (PARs) 133
PAR-Mediated Cellular Effects of Thrombin Pertinent to Fibrosis in ALI/ ARDS 133
a1( 134
ß 134
a1( 134
a1( 134
ß 134
Emerging Concepts Regarding PARs and Fibrosis 135
Clinical Implications and Conclusion 136
a, 137
ß 137
a, 137
References 138
Resolution of Inflammation 142
Introduction 142
The Course of Inflammation 142
Normal Inflammatory Resolution 143
Endogenous Anti-inflammatory Processes Anti- inflammatory Cytokines 143
a), 143
.) 144
., 144
a 144
a. 145
., 145
. 145
a 145
. 145
a 145
a 145
. 145
Cytokine Receptors and Anti-inflammatory Signals 145
ß 146
Balance of Pro- and Anti-inflammatory Mediators 146
Other Endogenous Immunomodulatory Agents Adenosine 147
.B 147
.B) 147
Lipoxins, Epilipoxins, and Resolvins 147
Galectin-3 148
Leptin 148
Regulation of Inflammation by Local Inflammatory Cell Subpopulations T Helper Cells: Th1 and Th2 Cytokines and T Cell Switching 149
ß1. 151
Macrophage Switching 152
ß 152
ß 152
Apoptosis What Is Apoptosis? 152
a 153
ß, 153
Apoptosis and Normal Inflammatory Resolution 154
a, 154
a, 155
., 155
Emigration 155
Fibrosis 157
a 157
ß, 157
a, 157
Conclusion 157
References 157
Compartmentalized Activation of Immune Cells During Sepsis and Organ Dysfunction 164
Introduction 164
Activating Stimuli Immune Cell Activation by Bacteria 164
Role of Endotoxin and Other Pathogen-associated Microbial Products 165
., 166
Nature of Immune Cells ActivatedWithin Tissues Macrophages 166
a 166
.B) 171
.Bdimers 171
a, 171
ß 171
ß), 171
Neutrophils 171
.B, 171
a 171
Lymphocytes 172
Natural Killer Cells 172
Mast Cells 172
Differences between Compartments 172
.Bactivation 173
.B 173
a 173
Local Detection of an On-going Process of Inflammation 174
Lungs 174
.B 174
Liver 175
Spleen 175
.B 175
Gut 175
.B 176
Peritoneum 176
Brain 176
Heart 176
Bone Marrow 176
Muscle 176
.B 176
Other Tissues 177
The Blood Compartment 177
.B 178
Leukocyte Recruitment as a Key Factor of Local Inflammation 178
The Cross-talk Between Compartments How Does the Inflammatory Response Spread from Organ to Organ? 179
ß 179
.B 180
The Peripheral Nervous System as a Link Between Compartments 180
ß2- 180
a7 180
Conclusion 181
References 181
The Neutrophil in the Pathogenesis of Multiple Organ Dysfunction Syndrome 186
Introduction 186
Antimicrobial Defenses of the Neutrophil Neutrophil Localization at an Inflammatory Focus 186
a, 186
ß2 187
ß2- 188
a- 188
Pathogen Recognition and Uptake 189
Pathogen Killing 190
a, 192
. 192
Apoptosis and the Termination of Neutrophil-Mediated Inflammation 192
Cellular Mechanisms of Neutrophil Apoptosis 192
a 192
.B) 193
.B 193
a 193
Inhibition of Neutrophil Apoptosis During Inflammation 193
a, 193
.B 194
.B 194
.B 194
.B 194
d 195
.B 195
a 195
a 195
a 195
Activation of Neutrophil Apoptosis by Microbial Phagocytosis 195
ß2- 196
ß2- 196
ß2- 196
ß2- 196
The Role of the Neutrophil in Clinical Inflammation 197
Conclusion 199
.B 199
References 199
The Role of the Macrophage 205
Introduction 205
Origin of Tissue Macrophages 205
. 206
Macrophages Express an Armada of Receptors 206

Macrophages Play a Central Role in the Pathogenesis of Sepsis 208
a7- 210
Macrophage Products and Receptors: Therapeutic Targets? 210
a7 210
References 210
The Role of the Endothelium 213
Introduction 213
A Primer in Endothelial Biology 213
The Endothelium is a Spatially Distributed Organization 213
The Endothelium is Derived from Lateral Plate Mesoderm 213
The Endothelium Evolved in Concert with the Closed Circulation 214
The Endothelium is a Multifunctional Organ 214
Endothelial Cell Heterogeneity 214
Mechanisms of Endothelial Cell Heterogeneity 215
Endothelium in Disease 216
Endothelial Diagnostics and Therapeutics 216
Endothelium in Critical Care 217
Input 217
.B) 217
.B 217
.B, 217
.B- 217
.B 217
a) 218
a). 218
Output 219
Conclusion 224
References 225
Differential Effects of Pro-Inflammatory Mediators on Alveolar Epithelial Barrier Function 230
Introduction 230
a, 230
ß) 230
Normal Alveolar Epithelial Barrier 230
The Alveolar Epithelial Barrier to Pathologic Stimuli 231
Pro-inflammatory Molecules and Alveolar Epithelial Fluid Transport 232
a 232
a 232
a 232
a 233
ß1. 233
a- 233
a- 233
aENaC) 233
aENaC 233
ß1. 233
ß1 233
ß1 233
ß1 233
aENaC 233
aENaC 233
ß1 234
ß1 234
Gene Expression of Inflammatory and Transport Molecules in Human Alveolar Type II Cells 234
a, 234
. 234
Conclusions 234
a 234
References 235
Macrocirculatory Disturbances 238
Introduction 238
Global Hemodynamic Alterations 238
Decreased Vascular Tone 238
Decreased Venous Return 239
Myocardial Depression 240
Altered Oxygen Extraction and VO2/DO2 Dependency 240
Consequences of Global Hemodynamic Alterations 240
Regional Blood Flow Alterations 241
Hepatosplanchnic Hemodynamics 241
Renal Perfusion 243
Cerebral Perfusion 243
Conclusion 243
References 244
TheMicrocirculation Is a Vulnerable Organ in Sepsis 247
Introduction: The Microcirculation as a Key Organ in Septic Shock 247
The Microcirculation as a Functional System 247
Scientific Importance of the Microcirculation 249
The Septic Microcirculation 249
Dysfunction of Individual Microcirculatory Components 250
a, 251
Dysoxia and the Oxygen Extraction Paradox 251
Microcirculatory and Mitochondrial Distress Syndrome (MMDS) 252
Monitoring the Microcirculation 253
Resuscitating the Microcirculation 254
Conclusion 256
References 256
The Cholinergic Anti-inflammatory Pathway: Connecting the Mind and Body 261
Introduction 261
a7 261
Identification of the Cholinergic Anti-inflammatory Pathway 262
a7 262
.B), 262
a7 262
a7 262
Functional Anatomy of the Vagus Nerve 263
Clinically Approved Vagus Nerve Stimulators 263
Vagus Nerve Stimulators as Anti-inflammatory Devices 264
Inflammatory Bowel Disease 264
Rheumatoid Arthritis 265
Diabetes 265
Atherosclerosis 266
Biofeedback and Inflammation 266
ß- 267
Conclusion 268
References 268
Coagulation in Sepsis 271
Introduction 271
Coagulation and Tissue Factor 271
Anticoagulant Mechanisms 273
Interaction Between Coagulation and Inflammation 275
a, 275
a 275
a 275
a 276
ß2 277
.B 277
a, 277
.B 277
a 277
Coagulation Activation and Organ Failure 278
Clinical Trials with Anticoagulants in Sepsis 279
Conclusion 281
References 281
The Role of Insulin and Blood Glucose Control 284
Introduction 284
Hyperglycemia and Outcome in Critical Illness 284
Blood Glucose Control with Intensive Insulin Therapy 285
Insulin Resistance and Hyperglycemia 287
Preventing Glucose Toxicity with Intensive Insulin Therapy 288
ß 288
Metabolic and Non-Metabolic Effects of Blood Glucose Control with Intensive Insulin Therapy 289
Glucose Control or Insulin? 290
Conclusion 290
References 291
Dysfunction of the Bioenergetic Pathway 295
Introduction 295
How Does Inflammation Lead to Organ Failure? 295
Mitochondria in Health 297
Mitochondria in Sepsis 298
Nitric Oxide: AMechanism forMitochondrial Inhibition 298
. 299
Influence of Hormones on Mitochondrial Activity in Health and Sepsis 299
The Role of Mitochondria in Sepsis-induced Cell Death 300
Changes in Mitochondrial Phenotype 301
Mitochondrial Recovery 301
Mitochondrial Protection 302
Conclusion 303
References 304
Metabolic Pathways 307
Introduction 307
Protein Metabolism 307
Glutamine Metabolism 310
a- 310
Glutathione Metabolism 311
Mitochondrial Metabolism 313
Conclusion 313
References 314
Cell Death and Acute Lung Injury 317
Introduction 317
Epithelial Function in the Lungs 317
Alveolar Membrane Damage in Acute Lung Injury 318
Apoptosis and Inflammation in ALI. 319
.B) 321
a 321
Experimental Links between Pro-Apoptotic Pathways and Fibrosis 322
a 323
ß, 323
ß 323
ß 323
Endothelial Cell Apoptosis 323
a 323
.B 324
Should Epithelial and Endothelial Apoptosis be Inhibited? 324
Conclusion 325
References 326
Mechanisms of Immunodepression after Central Nervous System Injury 331
Introduction 331
Infections after CNS Injury 331
Impaired Cell-mediated Immune Responses after CNS Injury 332
Communication Between the CNS and Immune System 333
Sensing of Inflammation by the CNS 333
a), 334
Modulation of Immune Responses by the CNS 334
a), 335
ß2- 335
a. 335
a- 335
a- 335
Immunodepression as a Result of CNS Injury 335
. 336
a 336
Induction of CNS Injury-induced Immunodepression by Humoral Signaling? 338
a, 338
ß2- 338
Induction of CNS Injury-induced Immunodepression by ‘ Neurogenic’ Mechanisms? 339
How to Measure Immunodepression? 340
Conclusion 342
References 342
Pulmonary Dysfunction 348
Introduction Definitions 348
SIRS, Sepsis, and Severe Sepsis: Precipitating Factors 348
Incidence, Morbidity, and Mortality of Sepsis Incidence and Characteristics of Sepsis 348
Organ Failure in Sepsis 349
Lung Failure in Sepsis 349
Pathophysiology of Sepsis The Dysfunctional Inflammatory Response 350
Reactive Oxygen Species and the Inflammatory Response 351
Role of ROS, Cytotoxicity, Iron, and Cell Signaling in the Pathophysiology of the Sepsis Syndromes and Lung Failure 351
Trials of Anti Oxidants in Patients with ALI/ARDS 354
Direct and Indirect Iron-Regulated Cell Signaling Mechanisms: Role of Iron Regulatory Proteins and Hemoxygenases 354
.B) 356
Endothelial and Epithelial Dysfunction Loss of Barrier Function 357
Loss of Pulmonary Vascular Control 358
Repair and Fibrosis 359
ß 359
ß) 359
ß1 359
ß1 359
a 359
ß 359
Conclusion 359
References 359
The Gut 364
Introduction 364
Intestinal Epithelial Permeability is Increased in Critically Ill Patients 364
Alterations in Intestinal Epithelial Permeability 365
Multiple Proteins are Necessary for the Assembly and Function of Tight Junctions 365
Nitric Oxide (NO) and/or Peroxynitrite ( ONOO-) Are Involved in the Regulation of Tight Junction Protein Expression and Function 366
., 366
. 366
. 366
NO-dependent Changes in Na+,K+-ATPase Activity can Affect Tight Junction Assembly and Function 367
Functional iNOS Expression is Essential for LPS-induced Alterations in Intestinal Permeability in Mice 367
Endotoxemia is Associated with Derangements in Ileal Mucosal Tight Junction Protein Localization 368
Surgical Stress Leads to Systemic Absorption of Gut-derived Toxins 369
Release of Toxic Materials into the Lymphatic Drainage from the Gut 370
Release from Enterocytes of Pro-inflammatory Cytokines 371
References 372
Endogenous Danger Signals in Liver Injury: Role of High Mobility Group Box Protein- 1 377
Introduction 377
Endogenous Proteins and Toll-like Receptors 377
High Mobility Group Box Protein-1: Mediator of Inflammation in Liver Ischemia/Reperfusion 379
Sensing the Danger in the Liver 381
Conclusion 382
References 384
Sepsis-induced Acute Renal Failure and Recovery 386
Introduction 386
Epidemiology of Sepsis-induced Acute Renal Failure in the ICU 386
Pathophysiology of Sepsis-induced Acute Renal failure: ‘ Time for a Paradigm Shift’ 387
Renal Perfusion 387
Inflammation 388
Cellular Mechanisms 392
a/ 394
Coagulation 394
Renal Recovery following Acute Renal Failure 395
Conclusion 395
References 396
Sepsis-Induced Brain Dysfunction 399
Introduction 399
Definition 399
Cerebral Mechanisms Involved During Sepsis Brain Structures 399
Neuroendocrine Mechanisms 401
The Immune System 401
Blood-brain Barrier 402
a/ 402
.B 402
.B) 402
a 402
a, 402
Apoptosis 402
a 402
Neuropathology 403
Clinical Features: Sepsis-associated Encephalopathy Introduction 403
Definition 404
Clinical Features 404
Evaluation 404
Investigations Electroencephalogram and Somatosensory Evoked Potentials 404
= 405
= 405
= 405
= 405
= 405
Magnetic Resonance Imaging (MRI) 405
Biological Investigations 405
Conclusion 405
References 406
Myocardial Depression in Sepsis and Septic Shock 407
Introduction 407
a 407
a), 407
.) 407
ß 407
Clinical Manifestations of Cardiovascular Dysfunction Historical Perspectives 408
Ventricular Function 409
Left Ventricular Function 410
Right Ventricular Function 412
Cardiovascular Prognostic Factors in Septic Shock 413
Etiology of Myocardial Depression in Sepsis and Septic Shock 415
Organ Level 415
a 417
a 417
a 417
a 417
aadministered 417
a 417
a 417
a 419
a. 419
a 419
a 419
a 420
Cellular Level 421
a, 421
a 421
a 421
a, 421
ß- 421
a- 422
a 422
a, 422
a 422
.B) 422
.B 422
Conclusion 423
a, 423
a, 423
.B 423
References 423
Skeletal Muscle 428
Introduction 428
Contractile Dysfunction 428
Impairment of Muscle Metabolism in Sepsis 429
Neuropathy and Myopathy 430
Muscle Loss 431
.B) 431
Pathogenetic Factors in Myopathy of Critical Illness 431
a, 431
a 432
Failed Protective Responses in Skeletal Muscle During Sepsis: A Role for Heat Shock Proteins and Glutamine in Mediating Muscle Function 432
.B, 433
aB- 434
a, 434
Conclusion 435
References 435
Subject Index 439