Binghe Wang, PhD, is Regents’ Professor of Chemistry, Georgia Research Alliance Eminent Scholar, and Director for the Center for Diagnostics and Therapeutics at Georgia State University.Leo E. Otterbein, PhD, is Professor of Surgery at Harvard Medical School.

• List of Contributors viiiPreface: Carbon Monoxide: Promises and Challenges in Its Pharmaceutical Development xiiSection I General Background and Physiological Actions 11 Endogenous CO Production in Sickness and in Health 3Ladie Kimberly De La Cruz and Binghe Wang2 Molecular Mechanisms of Actions for CO: An Overview 27Rodrigo W. Alves de Souza, Leo E. Otterbein, and Nils Schallner3 Pharmacokinetic Characteristics of Carbon Monoxide 44Xiaoxiao Yang, Mingjia Wang, Chalet Tan, Wen Lu, and Binghe Wang4 Carbon Monoxide and Energy Metabolism 88Daniela Dias-Pedroso, Nuno Soares, and Helena L.A. Vieira5 Role of CO in Circadian Clock 97Hiroaki Kitagishi and Ikuko Sagami6 Carbon Monoxide and Mitochondria 108Claude A. Piantadosi7 Carbon Monoxide, Oxygen, and Pseudohypoxia 118Grace E. Otterbein, Michael S. Tift, and Ghee Rye Lee8 Nitric Oxide in Human Physiology: Production, Regulation, and Interactionwith Carbon Monoxide Signaling 136Maryam K. Mohammed and Brian S. Zuckerbraun9 When Carbon Monoxide Meets Hydrogen Sulfide 160Rui Wang Copyrighted Material10 Biliverdin and Bilirubin as Parallel Products of CO Formation: Not Just Bystanders 175Libor VitekSection II Delivery Forms 19511 Delivery Systems and Noncarrier Formulations 197James Byrne, Christoph Steiger, Jakob Wollborn, and Giovanni Traverso12 Metal-Based Carbon Monoxide-Releasing Molecules (CO-RMs) as Pharmacologically Active Therapeutics 203Roberta Foresti, Djamal Eddine Benrahla, Shruti Mohan, and Roberto Motterlini13 Organic CO Donors that Rely on Photolysis for CO Release 223Yi Liao14 Organic Carbon Monoxide Prodrugs that Release CO Under Physiological Conditions 232Zhengnan Yuan and Binghe Wang15 Targeted Delivery of Carbon Monoxide 259Lisa M. Berreau16 Anesthesia-Related Carbon Monoxide Exposure 286Richard J. Levy17 Natural Products that Generate Carbon Monoxide: Chemistry and Nutritional Implications 302Ladie Kimberly De La Cruz and Binghe WangSection III Carbon Monoxide Sensing and Scavenging 31918 Fluorescent Probes for Intracellular Carbon Monoxide Detection 321Ryan R. Walvoord, Morgan R. Schneider, and Brian W. MichelSection IV Therapeutic Applications 34519 CO in Solid Organ Transplantation 347Roberta Foresti, Roberto Motterlini, and Stephan Immenschuh20 Carbon Monoxide in Lung Injury and Disease 360Stefan W. Ryter21 Carbon Monoxide in Acute Brain Injury and Brain Protection 377Alexandra Mazur, Madison Fangman, Rani Ashouri, Hannah Pamplin, Shruti Patel, and Sylvain Doré22 CO as a Protective Mediator of Liver Injury: The Role of PERK in HO-1/ CO-Mediated Maintenance of Cellular Homeostasis in the Liver 385Yeonsoo Joe, Jeongmin Park, Mihyang Do, Stefan W. Ryter, Young-Joon Surh, Uh-Hyun Kim, and Hun Taeg Chung23 CO and Cancer 401James N. Arnold and Joanne E. Anstee24 CO and Diabetes 423Rebecca P. Chow and Hongjun Wang25 Carbon Monoxide and Acute Kidney Injury 434Mark de Caestecker26 CO as an Antiplatelet Agent: An Energy Metabolism Perspective 453Patrycja Kaczara, Kamil Przyborowski, Roberto Motterlini, and Stefan Chlopicki27 CO in Gastrointestinal Physiology and Protection 466Katarzyna Magierowska and Marcin Magierowski28 Carbon Monoxide and Sickle Cell Disease 482Edward Gomperts, John Belcher, Howard Levy, and Greg Vercellotti29 CO and Pain Management 497Olga Pol30 Clinical Trials of Low-Dose Carbon Monoxide 511Edward Gomperts, Andrew Gomperts, and Howard LevyIndex 528

Binghe Wang, PhD, is Regents’ Professor of Chemistry, Georgia Research Alliance Eminent Scholar, and Director for the Center for Diagnostics and Therapeutics at Georgia State University.Leo E. Otterbein, PhD, is Professor of Surgery at Harvard Medical School.

• List of Contributors viiiPreface: Carbon Monoxide: Promises and Challenges in Its Pharmaceutical Development xiiSection I General Background and Physiological Actions 11 Endogenous CO Production in Sickness and in Health 3Ladie Kimberly De La Cruz and Binghe Wang2 Molecular Mechanisms of Actions for CO: An Overview 27Rodrigo W. Alves de Souza, Leo E. Otterbein, and Nils Schallner3 Pharmacokinetic Characteristics of Carbon Monoxide 44Xiaoxiao Yang, Mingjia Wang, Chalet Tan, Wen Lu, and Binghe Wang4 Carbon Monoxide and Energy Metabolism 88Daniela Dias-Pedroso, Nuno Soares, and Helena L.A. Vieira5 Role of CO in Circadian Clock 97Hiroaki Kitagishi and Ikuko Sagami6 Carbon Monoxide and Mitochondria 108Claude A. Piantadosi7 Carbon Monoxide, Oxygen, and Pseudohypoxia 118Grace E. Otterbein, Michael S. Tift, and Ghee Rye Lee8 Nitric Oxide in Human Physiology: Production, Regulation, and Interactionwith Carbon Monoxide Signaling 136Maryam K. Mohammed and Brian S. Zuckerbraun9 When Carbon Monoxide Meets Hydrogen Sulfide 160Rui Wang Copyrighted Material10 Biliverdin and Bilirubin as Parallel Products of CO Formation: Not Just Bystanders 175Libor VitekSection II Delivery Forms 19511 Delivery Systems and Noncarrier Formulations 197James Byrne, Christoph Steiger, Jakob Wollborn, and Giovanni Traverso12 Metal-Based Carbon Monoxide-Releasing Molecules (CO-RMs) as Pharmacologically Active Therapeutics 203Roberta Foresti, Djamal Eddine Benrahla, Shruti Mohan, and Roberto Motterlini13 Organic CO Donors that Rely on Photolysis for CO Release 223Yi Liao14 Organic Carbon Monoxide Prodrugs that Release CO Under Physiological Conditions 232Zhengnan Yuan and Binghe Wang15 Targeted Delivery of Carbon Monoxide 259Lisa M. Berreau16 Anesthesia-Related Carbon Monoxide Exposure 286Richard J. Levy17 Natural Products that Generate Carbon Monoxide: Chemistry and Nutritional Implications 302Ladie Kimberly De La Cruz and Binghe WangSection III Carbon Monoxide Sensing and Scavenging 31918 Fluorescent Probes for Intracellular Carbon Monoxide Detection 321Ryan R. Walvoord, Morgan R. Schneider, and Brian W. MichelSection IV Therapeutic Applications 34519 CO in Solid Organ Transplantation 347Roberta Foresti, Roberto Motterlini, and Stephan Immenschuh20 Carbon Monoxide in Lung Injury and Disease 360Stefan W. Ryter21 Carbon Monoxide in Acute Brain Injury and Brain Protection 377Alexandra Mazur, Madison Fangman, Rani Ashouri, Hannah Pamplin, Shruti Patel, and Sylvain Doré22 CO as a Protective Mediator of Liver Injury: The Role of PERK in HO-1/ CO-Mediated Maintenance of Cellular Homeostasis in the Liver 385Yeonsoo Joe, Jeongmin Park, Mihyang Do, Stefan W. Ryter, Young-Joon Surh, Uh-Hyun Kim, and Hun Taeg Chung23 CO and Cancer 401James N. Arnold and Joanne E. Anstee24 CO and Diabetes 423Rebecca P. Chow and Hongjun Wang25 Carbon Monoxide and Acute Kidney Injury 434Mark de Caestecker26 CO as an Antiplatelet Agent: An Energy Metabolism Perspective 453Patrycja Kaczara, Kamil Przyborowski, Roberto Motterlini, and Stefan Chlopicki27 CO in Gastrointestinal Physiology and Protection 466Katarzyna Magierowska and Marcin Magierowski28 Carbon Monoxide and Sickle Cell Disease 482Edward Gomperts, John Belcher, Howard Levy, and Greg Vercellotti29 CO and Pain Management 497Olga Pol30 Clinical Trials of Low-Dose Carbon Monoxide 511Edward Gomperts, Andrew Gomperts, and Howard LevyIndex 528

Binghe Wang, PhD, is Regents’ Professor of Chemistry, Georgia Research Alliance Eminent Scholar, and Director for the Center for Diagnostics and Therapeutics at Georgia State University.Leo E. Otterbein, PhD, is Professor of Surgery at Harvard Medical School.

• List of Contributors viiiPreface: Carbon Monoxide: Promises and Challenges in Its Pharmaceutical Development xiiSection I General Background and Physiological Actions 11 Endogenous CO Production in Sickness and in Health 3Ladie Kimberly De La Cruz and Binghe Wang2 Molecular Mechanisms of Actions for CO: An Overview 27Rodrigo W. Alves de Souza, Leo E. Otterbein, and Nils Schallner3 Pharmacokinetic Characteristics of Carbon Monoxide 44Xiaoxiao Yang, Mingjia Wang, Chalet Tan, Wen Lu, and Binghe Wang4 Carbon Monoxide and Energy Metabolism 88Daniela Dias-Pedroso, Nuno Soares, and Helena L.A. Vieira5 Role of CO in Circadian Clock 97Hiroaki Kitagishi and Ikuko Sagami6 Carbon Monoxide and Mitochondria 108Claude A. Piantadosi7 Carbon Monoxide, Oxygen, and Pseudohypoxia 118Grace E. Otterbein, Michael S. Tift, and Ghee Rye Lee8 Nitric Oxide in Human Physiology: Production, Regulation, and Interactionwith Carbon Monoxide Signaling 136Maryam K. Mohammed and Brian S. Zuckerbraun9 When Carbon Monoxide Meets Hydrogen Sulfide 160Rui Wang Copyrighted Material10 Biliverdin and Bilirubin as Parallel Products of CO Formation: Not Just Bystanders 175Libor VitekSection II Delivery Forms 19511 Delivery Systems and Noncarrier Formulations 197James Byrne, Christoph Steiger, Jakob Wollborn, and Giovanni Traverso12 Metal-Based Carbon Monoxide-Releasing Molecules (CO-RMs) as Pharmacologically Active Therapeutics 203Roberta Foresti, Djamal Eddine Benrahla, Shruti Mohan, and Roberto Motterlini13 Organic CO Donors that Rely on Photolysis for CO Release 223Yi Liao14 Organic Carbon Monoxide Prodrugs that Release CO Under Physiological Conditions 232Zhengnan Yuan and Binghe Wang15 Targeted Delivery of Carbon Monoxide 259Lisa M. Berreau16 Anesthesia-Related Carbon Monoxide Exposure 286Richard J. Levy17 Natural Products that Generate Carbon Monoxide: Chemistry and Nutritional Implications 302Ladie Kimberly De La Cruz and Binghe WangSection III Carbon Monoxide Sensing and Scavenging 31918 Fluorescent Probes for Intracellular Carbon Monoxide Detection 321Ryan R. Walvoord, Morgan R. Schneider, and Brian W. MichelSection IV Therapeutic Applications 34519 CO in Solid Organ Transplantation 347Roberta Foresti, Roberto Motterlini, and Stephan Immenschuh20 Carbon Monoxide in Lung Injury and Disease 360Stefan W. Ryter21 Carbon Monoxide in Acute Brain Injury and Brain Protection 377Alexandra Mazur, Madison Fangman, Rani Ashouri, Hannah Pamplin, Shruti Patel, and Sylvain Doré22 CO as a Protective Mediator of Liver Injury: The Role of PERK in HO-1/ CO-Mediated Maintenance of Cellular Homeostasis in the Liver 385Yeonsoo Joe, Jeongmin Park, Mihyang Do, Stefan W. Ryter, Young-Joon Surh, Uh-Hyun Kim, and Hun Taeg Chung23 CO and Cancer 401James N. Arnold and Joanne E. Anstee24 CO and Diabetes 423Rebecca P. Chow and Hongjun Wang25 Carbon Monoxide and Acute Kidney Injury 434Mark de Caestecker26 CO as an Antiplatelet Agent: An Energy Metabolism Perspective 453Patrycja Kaczara, Kamil Przyborowski, Roberto Motterlini, and Stefan Chlopicki27 CO in Gastrointestinal Physiology and Protection 466Katarzyna Magierowska and Marcin Magierowski28 Carbon Monoxide and Sickle Cell Disease 482Edward Gomperts, John Belcher, Howard Levy, and Greg Vercellotti29 CO and Pain Management 497Olga Pol30 Clinical Trials of Low-Dose Carbon Monoxide 511Edward Gomperts, Andrew Gomperts, and Howard LevyIndex 528