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Chemistry and Biochemistry of Oxygen Therapeutics From Transfusion to Artificial Blood

by: Mozzarelli, Andrea; Bettati, Stefano

Chemistry and Biochemistry of Oxygen Therapeutics From Transfusion to Artificial Blood

by: Mozzarelli, Andrea; Bettati, Stefano

ISBN 13:
9780470686683
ISBN 10:
0470686685
Edition: 1st
Format: Hardcover
Copyright: 09/13/2011
Publisher: Wiley

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Chemistry and Biochemistry of Oxygen Therapeutics From Transfusion to Artificial Blood > ISBN13: 9780470686683

Summary

Scientists are developing oxygen therapeutics, or "blood substitutes," with the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. This book links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development, starting with the observation that an oxygen therapeutic agent can be developed only upon a deep understanding of oxygen and nitric oxide, homeostasis and regulation, and the well-documented correlations between adverse effects of a specific product and its biochemical-physiological properties.

Author Biography

Professor Andrea Mozzarelli, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Parma, Italy
Andrea Mozzarelli is Full Professor of Biochemistry in the Pharmacy Faculty at the University of Parma, teaching general and applied Biochemistry. He is Member of the International Advisory Board for Vitamin B6, PQQ, Carbonyl Catalysis and Quinoproteins Meetings, and was scientific organizer of the international courses on "From Structural Genomics to Drug Discovery" held at the University of Parma in 2000, 2002 and 2004. Between 2004 and 2006 Professor Mozzarrelli was head of a research unit of a EU funded project on "EuroBlood substitutes". He is President of the XII International Symposium on Blood Substitutes, to be held in Parma, Italy, on August 25-28, 2009 (http://alice.bio.unipr.it/blood2009/).

Professor Stefano Bettati, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Parma, Italy.

List of Contributors xvii

Preface xxiii

1. Introduction 1
Richard B. Weiskopf

References 5

Part I. Oxygen: Chemistry, Biochemistry, Physiology and Toxicity 9

2. Hemoglobin Reactivity and Regulation 11
Stefano Bettati and Andrea Mozzarelli

2.1 Introduction 11

2.2 Oxygen Loading and Transport 11

2.3 NO Reactivity with Hb 15

2.4 Hb Oxidation 16

2.5 Nitrite Reactivity with Hb 16

2.6 Amino-acid Determinants of Hb Reactivity:

Natural and Engineered Hbs 17

2.6.1 Modulation of Oxygen Affinity and Cooperativity 17

2.6.2 NO Reactivity and Oxidation 18

2.7 Conclusion 18

Acknowledgments 19

References 19

3. The Major Physiological Control Mechanisms of Blood Flow and Oxygen Delivery 23
Raymond C. Koehler

3.1 Introduction 23

3.2 Autoregulation of Blood Flow to Changes in Perfusion Pressure 23

3.3 Metabolic Regulation of Blood Flow 26

3.4 O2 Transport 27

3.5 O2 Delivery 27

3.6 Endothelial Control of Vasomotor Tone 29

3.7 Effect of Cell-free Hb on Endothelial Function 31

3.8 Hypoxic Hypoxia 33

3.9 Carbon Monoxide Hypoxia 36

3.10 Anemia 36

3.11 Conclusion 39

References 39

4. The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen 47
Tim J. McMahon and Joseph Bonaventura

4.1 Introduction 47

4.2 Role of Mammalian Mb in O2 Homeostasis 47

4.3 What’s Missing in the Mb Knockout Mouse 48

4.4 Evolutionary Origins of Mb and the Nitrogen Cycle 49

4.5 Human Hb: Evolved Sensor of pO2 and Redox 49

4.6 Broad Reactivity and Influence of NO: Lessons from the Microcosm Hb 49

4.7 Some Fish Demonstrate a Fundamental “Need” for Hb-dependent NO Cycling, as in Humans 50

4.8 Reactions of NO with Hb that Preserve NO Bioactivity 52

4.9 Mammalian RBC/Hb–NO Interactions 52

4.10 A Mutant Mouse Challenges the SNO-Hb Hypothesis, but does not Overthrow it 54

4.11 Signaling by Hb-derived SNO: A Metabolically Responsive, Regulated Pathway 54

4.12 Signaling by Hb-derived SNO: Pathway Complexity Revealed by Multiple Defects in Disease States 55

4.13 Therapeutic Implications of the Hb–NO Signaling System 56

4.14 HBOCs, NO, and SNO 56

4.15 Other Gaseous Hb Ligands of Potential Therapeutic Significance 57

4.16 NO-related Enzymatic Activities of Hb: Reconciling Nitrite Reductase and SNO Synthase Functions 57

4.17 Measuring Biologically Relevant Hb–NO Adducts 58

4.18 Conclusion 58

Acknowledgments 58

References 59

5. The Role of Reactive Oxygen and Nitrogen Species in Ischemia/Reperfusion Injury 63
Ester Spagnolli and Warren M. Zapol

5.1 Introduction 63

5.2 Redox System and Free Radicals in Biological Systems 64

5.3 Pathophysiology of Ischemia/Reperfusion Injury 65

5.3.1 Cell Death 65

5.3.2 The Inflammatory Response 67

5.4 Protection Against I/R Injury 67

5.4.1 Ischemic Pre- and Post-conditioning 67

5.4.2 Pharmacological Conditioning 68

5.4.2.1 The Protective Role of ROS and Antioxidants 68

5.4.2.2 The Protective Role of NO 69

5.4.2.3 NO-based Therapies for I/R Injury 70

5.5 Conclusion 72

Acknowledgments 72

References 72

Part II. Medical Needs for Oxygen Supply 79

6. Acute Traumatic Hemorrhage and Anemia 81
Lena M. Napolitano

6.1 Introduction 81

6.2 Blood Transfusion in Trauma 83

6.2.1 Massive Transfusion 83

6.2.2 Massive Transfusion and Coagulopathy 83

6.2.3 Hypotensive or Delayed Resuscitation 84

6.2.4 Hemostatic Resuscitation 84

6.2.5 Massive Transfusion Protocols 86

6.2.6 Transfusion after Hemorrhage Control 86

6.2.7 Efficacy of RBC Transfusion in Trauma and Associated Risks 86

6.3 Oxygen Therapeutics in Trauma 88

6.3.1 Diaspirin Crosslinked Hb 90

6.3.2 Hemopure 90

6.3.3 PolyHeme 91

6.3.4 MP4OX 93

6.3.5 Recombinant Human Hb 95

6.3.6 Adverse Effects of HBOCs 95

6.3.7 HBOCs in Trauma: A Way Forward? 96

6.4 Conclusion 97

References 97

7. Diagnosis and Treatment of Haemorrhages in ‘Nonsurgical’ Patients 107
Umberto Rossi and Rosa Chianese

7.1 Introduction 107

7.1.1 Aetiopathogenetic Classification 107

7.1.2 Multifactorial Pathogenesis 108

7.1.3 Haemorrhagic Syndromes from Antithrombotic Treatment or Prophylaxis 108

7.2 Clinical Assessment 111

7.2.1 Medical History 111

7.2.2 Physical Examination 112

7.3 Laboratory Tests 113

7.3.1 Screening Tests 113

7.3.2 Second-level Laboratory Tests 113

7.3.3 Other Tests 114

7.4 Haemorrhagic Syndromes Clinically Indicative of Systemic Defects with Normal Screening Tests 117

7.5 Blood and Blood Components in the Treatment of Haemorrhagic Syndromes 118

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