Tài liệu SLEEP-RELATED BREATHING DISORDERS EXPERIMENTAL MODELS AND THERAPEUTIC POTENTIAL docx

But, many otherfunctions, such as behavior, are also affected by sleep disorders.This Lung Biology in Health and Disease series recognized very earlythe importance of research on sleep,

SLEEP-RELATED BREATHING DISORDERS

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ISBN: 0-8247-0877-6

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Executive Editor

Claude Lenfant

Director, National Heart, Lung, and Blood Institute

National Institutes of Health Bethesda, Maryland

1 Immunologic and Infectious Reactions in the Lung, edited by C H.

Kirkpatrick and H Y Reynolds

2 The Biochemical Basis of Pulmonary Function, edited by R G Crystal

3 Bioengineering Aspects of the Lung, edited by J B West

4 Metabolic Functions of the Lung, edited by Y S Bakhle and J R Vane

5 Respiratory Defense Mechanisms (in two parts), edited by J D Brain,

D F Proctor, and L M Reid

6 Development of the Lung, edited by W A Hodson

7 Lung Water and Solute Exchange, edited by N C Staub

8 Extrapulmonary Manifestations of Respiratory Disease, edited by E D.

Robin

9 Chronic Obstructive Pulmonary Disease, edited by T L Petty

10 Pathogenesis and Therapy of Lung Cancer, edited by C C Harris

11 Genetic Determinants of Pulmonary Disease, edited by S D Litwin

12 The Lung in the Transition Between Health and Disease, edited by P T.

Macklem and S Permutt

13 Evolution of Respiratory Processes: A Comparative Approach, edited

by S C Wood and C Lenfant

14 Pulmonary Vascular Diseases, edited by K M Moser

15 Physiology and Pharmacology of the Airways, edited by J A Nadel

16 Diagnostic Techniques in Pulmonary Disease (in two parts), edited by

M A Sackner

17 Regulation of Breathing (in two parts), edited by T F Hornbein

18 Occupational Lung Diseases: Research Approaches and Methods,

edited by H Weill and M Turner-Warwick

19 Immunopharmacology of the Lung, edited by H H Newball

20 Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by

B L Fanburg

21 Sleep and Breathing, edited by N A Saunders and C E Sullivan

22 Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and ment, edited by L S Young

Treat-23 Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung

Dis-ease, edited by H L Atkins

24 Acute Respiratory Failure, edited by W M Zapol and K J Falke

25 Gas Mixing and Distribution in the Lung, edited by L A Engel and M.

Paiva

edited by G Carlon and W S Howland

27 Pulmonary Development: Transition from Intrauterine to Extrauterine

Life, edited by G H Nelson

28 Chronic Obstructive Pulmonary Disease: Second Edition, edited by T L.

Petty

29 The Thorax (in two parts), edited by C Roussos and P T Macklem

30 The Pleura in Health and Disease, edited by J Chr é tien, J Bignon, and

A Hirsch

31 Drug Therapy for Asthma: Research and Clinical Practice, edited by J.

W Jenne and S Murphy

32 Pulmonary Endothelium in Health and Disease, edited by U S Ryan

33 The Airways: Neural Control in Health and Disease, edited by M A.

Kaliner and P J Barnes

34 Pathophysiology and Treatment of Inhalation Injuries, edited by J Loke

35 Respiratory Function of the Upper Airway, edited by O P Mathew and

G Sant'Ambrogio

36 Chronic Obstructive Pulmonary Disease: A Behavioral Perspective,

edited by A J McSweeny and I Grant

37 Biology of Lung Cancer: Diagnosis and Treatment, edited by S T.

Rosen, J L Mulshine, F Cuttitta, and P G Abrams

38 Pulmonary Vascular Physiology and Pathophysiology, edited by E K.

Weir and J T Reeves

39 Comparative Pulmonary Physiology: Current Concepts, edited by S C.

Wood

40 Respiratory Physiology: An Analytical Approach, edited by H K Chang

and M Paiva

41 Lung Cell Biology, edited by D Massaro

42 Heart–Lung Interactions in Health and Disease, edited by S M Scharf

and S S Cassidy

43 Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited

by M J Hensley and N A Saunders

44 Surgical Pathology of Lung Neoplasms, edited by A M Marchevsky

45 The Lung in Rheumatic Diseases, edited by G W Cannon and G A.

Zimmerman

46 Diagnostic Imaging of the Lung, edited by C E Putman

47 Models of Lung Disease: Microscopy and Structural Methods, edited by

J Gil

48 Electron Microscopy of the Lung, edited by D E Schraufnagel

49 Asthma: Its Pathology and Treatment, edited by M A Kaliner, P J.

Barnes, and C G A Persson

50 Acute Respiratory Failure: Second Edition, edited by W M Zapol and

F Lemaire

51 Lung Disease in the Tropics, edited by O P Sharma

52 Exercise: Pulmonary Physiology and Pathophysiology, edited by B J.

Whipp and K Wasserman

53 Developmental Neurobiology of Breathing, edited by G G Haddad and

Metabolism, edited by S C Wood, R E Weber, A R Hargens, and R.

W Millard

57 The Bronchial Circulation, edited by J Butler

58 Lung Cancer Differentiation: Implications for Diagnosis and Treatment,

edited by S D Bernal and P J Hesketh

59 Pulmonary Complications of Systemic Disease, edited by J F Murray

60 Lung Vascular Injury: Molecular and Cellular Response, edited by A.

Johnson and T J Ferro

61 Cytokines of the Lung, edited by J Kelley

62 The Mast Cell in Health and Disease, edited by M A Kaliner and D D.

Metcalfe

63 Pulmonary Disease in the Elderly Patient, edited by D A Mahler

64 Cystic Fibrosis, edited by P B Davis

65 Signal Transduction in Lung Cells, edited by J S Brody, D M Center,

and V A Tkachuk

66 Tuberculosis: A Comprehensive International Approach, edited by L B.

Reichman and E S Hershfield

67 Pharmacology of the Respiratory Tract: Experimental and Clinical

Re-search, edited by K F Chung and P J Barnes

68 Prevention of Respiratory Diseases, edited by A Hirsch, M Goldberg,

J.-P Martin, and R Masse

69 Pneumocystis carinii Pneumonia: Second Edition, edited by P D.

Walzer

70 Fluid and Solute Transport in the Airspaces of the Lungs, edited by R.

M Effros and H K Chang

71 Sleep and Breathing: Second Edition, edited by N A Saunders and C.

E Sullivan

72 Airway Secretion: Physiological Bases for the Control of Mucous

Hy-persecretion, edited by T Takishima and S Shimura

73 Sarcoidosis and Other Granulomatous Disorders, edited by D G.

James

74 Epidemiology of Lung Cancer, edited by J M Samet

75 Pulmonary Embolism, edited by M Morpurgo

76 Sports and Exercise Medicine, edited by S C Wood and R C Roach

77 Endotoxin and the Lungs, edited by K L Brigham

78 The Mesothelial Cell and Mesothelioma, edited by M.-C Jaurand and J.

Bignon

79 Regulation of Breathing: Second Edition, edited by J A Dempsey and

A I Pack

80 Pulmonary Fibrosis, edited by S Hin Phan and R S Thrall

81 Long-Term Oxygen Therapy: Scientific Basis and Clinical Application,

edited by W J O'Donohue, Jr.

82 Ventral Brainstem Mechanisms and Control of Respiration and Blood

Pressure, edited by C O Trouth, R M Millis, H F Kiwull-Sch ö ne, and

M E Schl ä fke

83 A History of Breathing Physiology, edited by D F Proctor

84 Surfactant Therapy for Lung Disease, edited by B Robertson and H W.

Taeusch

85 The Thorax: Second Edition, Revised and Expanded (in three parts),

edited by C Roussos

Szefler and D Y M Leung

87 Mycobacterium avium–Complex Infection: Progress in Research and

Treatment, edited by J A Korvick and C A Benson

88 Alpha 1–Antitrypsin Deficiency: Biology·Pathogenesis ·Clinical festations·Therapy, edited by R G Crystal

Mani-89 Adhesion Molecules and the Lung, edited by P A Ward and J C.

Fantone

90 Respiratory Sensation, edited by L Adams and A Guz

91 Pulmonary Rehabilitation, edited by A P Fishman

92 Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease,

edited by J.-P Derenne, W A Whitelaw, and T Similowski

93 Environmental Impact on the Airways: From Injury to Repair, edited by

J Chr é tien and D Dusser

94 Inhalation Aerosols: Physical and Biological Basis for Therapy, edited

by A J Hickey

95 Tissue Oxygen Deprivation: From Molecular to Integrated Function,

edited by G G Haddad and G Lister

96 The Genetics of Asthma, edited by S B Liggett and D A Meyers

97 Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions,

edited by R P Schleimer, W W Busse, and P M O ’ Byrne

98 Nitric Oxide and the Lung, edited by W M Zapol and K D Bloch

99 Primary Pulmonary Hypertension, edited by L J Rubin and S Rich

100 Lung Growth and Development, edited by J A McDonald

101 Parasitic Lung Diseases, edited by A A F Mahmoud

102 Lung Macrophages and Dendritic Cells in Health and Disease, edited

by M F Lipscomb and S W Russell

103 Pulmonary and Cardiac Imaging, edited by C Chiles and C E Putman

104 Gene Therapy for Diseases of the Lung, edited by K L Brigham

105 Oxygen, Gene Expression, and Cellular Function, edited by L Biadasz

Clerch and D J Massaro

106 Beta2-Agonists in Asthma Treatment, edited by R Pauwels and P M.

O ’ Byrne

107 Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A L.

Adjei and P K Gupta

108 Asthma in the Elderly, edited by R A Barbee and J W Bloom

109 Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D M.

Orenstein and R C Stern

110 Asthma and Immunological Diseases in Pregnancy and Early Infancy,

edited by M Schatz, R S Zeiger, and H N Claman

111 Dyspnea, edited by D A Mahler

112 Proinflammatory and Antiinflammatory Peptides, edited by S I Said

113 Self-Management of Asthma, edited by H Kotses and A Harver

114 Eicosanoids, Aspirin, and Asthma, edited by A Szczeklik, R J.

Gryglewski, and J R Vane

115 Fatal Asthma, edited by A L Sheffer

116 Pulmonary Edema, edited by M A Matthay and D H Ingbar

117 Inflammatory Mechanisms in Asthma, edited by S T Holgate and W.

W Busse

118 Physiological Basis of Ventilatory Support, edited by J J Marini and A.

S Slutsky

and J M Beck

120 Five-Lipoxygenase Products in Asthma, edited by J M Drazen, S.-E.

Dahl é n, and T H Lee

121 Complexity in Structure and Function of the Lung, edited by M P.

Hlastala and H T Robertson

122 Biology of Lung Cancer, edited by M A Kane and P A Bunn, Jr.

123 Rhinitis: Mechanisms and Management, edited by R M Naclerio, S R.

Durham, and N Mygind

124 Lung Tumors: Fundamental Biology and Clinical Management, edited

by C Brambilla and E Brambilla

125 Interleukin-5: From Molecule to Drug Target for Asthma, edited by C J.

Sanderson

126 Pediatric Asthma, edited by S Murphy and H W Kelly

127 Viral Infections of the Respiratory Tract, edited by R Dolin and P F.

130 Exercise-Induced Asthma, edited by E R McFadden, Jr.

131 LAM and Other Diseases Characterized by Smooth Muscle

Prolifera-tion, edited by J Moss

132 The Lung at Depth, edited by C E G Lundgren and J N Miller

133 Regulation of Sleep and Circadian Rhythms, edited by F W Turek and

136 Immunotherapy in Asthma, edited by J Bousquet and H Yssel

137 Chronic Lung Disease in Early Infancy, edited by R D Bland and J J.

Coalson

138 Asthma's Impact on Society: The Social and Economic Burden, edited

by K B Weiss, A S Buist, and S D Sullivan

139 New and Exploratory Therapeutic Agents for Asthma, edited by M.

Yeadon and Z Diamant

140 Multimodality Treatment of Lung Cancer, edited by A T Skarin

141 Cytokines in Pulmonary Disease: Infection and Inflammation, edited by

S Nelson and T R Martin

142 Diagnostic Pulmonary Pathology, edited by P T Cagle

143 Particle–Lung Interactions, edited by P Gehr and J Heyder

144 Tuberculosis: A Comprehensive International Approach, Second

Edi-tion, Revised and Expanded, edited by L B Reichman and E S.

Hershfield

145 Combination Therapy for Asthma and Chronic Obstructive Pulmonary

Disease, edited by R J Martin and M Kraft

146 Sleep Apnea: Implications in Cardiovascular and Cerebrovascular

Di-sease, edited by T D Bradley and J S Floras

147 Sleep and Breathing in Children: A Developmental Approach, edited by

G M Loughlin, J L Carroll, and C L Marcus

by J Roca, R Rodriguez-Roisen, and P D Wagner

149 Lung Surfactants: Basic Science and Clinical Applications, R H Notter

150 Nosocomial Pneumonia, edited by W R Jarvis

151 Fetal Origins of Cardiovascular and Lung Disease, edited by David J P.

Barker

152 Long-Term Mechanical Ventilation, edited by N S Hill

153 Environmental Asthma, edited by R K Bush

154 Asthma and Respiratory Infections, edited by D P Skoner

155 Airway Remodeling, edited by P H Howarth, J W Wilson, J

Bous-quet, S Rak, and R A Pauwels

156 Genetic Models in Cardiorespiratory Biology, edited by G G Haddad

and T Xu

157 Respiratory-Circulatory Interactions in Health and Disease, edited by S.

M Scharf, M R Pinsky, and S Magder

158 Ventilator Management Strategies for Critical Care, edited by N S Hill

and M M Levy

159 Severe Asthma: Pathogenesis and Clinical Management, Second

Edition, Revised and Expanded, edited by S J Szefler and D Y M.

Leung

160 Gravity and the Lung: Lessons from Microgravity, edited by G K Prisk,

M Paiva, and J B West

161 High Altitude: An Exploration of Human Adaptation, edited by T F.

Hornbein and R B Schoene

162 Drug Delivery to the Lung, edited by H Bisgaard, C O ’ Callaghan, and

G C Smaldone

163 Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by

R P Schleimer, P M O ’ Byrne, S J Szefler, and R Brattsand

164 IgE and Anti-IgE Therapy in Asthma and Allergic Disease, edited by R.

B Fick, Jr., and P M Jardieu

165 Clinical Management of Chronic Obstructive Pulmonary Disease, edited

by T Similowski, W A Whitelaw, and J.-P Derenne

166 Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A I.

169 Gene Therapy in Lung Disease, edited by S M Albelda

170 Disease Markers in Exhaled Breath, edited by N Marczin, S A

Kharito-nov, M H Yacoub, and P J Barnes

171 Sleep-Related Breathing Disorders: Experimental Models and

Thera-peutic Potential, edited by D W Carley and M Radulovacki

172 Chemokines in the Lung, edited by R M Strieter, S L Kunkel, and T.

J Standiford

173 Respiratory Control and Disorders in the Newborn, edited by O P.

Mathew

174 The Immunological Basis of Asthma, edited by B N Lambrecht, H C.

Hoogsteden, and Z Diamant

Lahiri, G L Semenza, and N R Prabhakar

176 Non-Neoplastic Advanced Lung Disease, edited by J Maurer

ADDITIONAL VOLUMES IN PREPARATION

Therapeutic Targets in Airway Inflammation, edited by N T Eissa and

D Huston

Respiratory Infections in Asthma and Allergy, edited by S Johnston and

N Papadopoulos

Acute Respiratory Distress Syndrome, edited by M A Matthay

Upper and Lower Respiratory Disease, edited by J Corren, A Togias,

and J Bousquet

Venous Thromboembolism, edited by J E Dalen

Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited

by N Siafakas, N Anthonisen, and D Georgopolous

Lung Volume Reduction Surgery for Emphysema, edited by H E.

Fessler, J J Reilly, Jr., and D J Sugarbaker

The opinions expressed in these volumes do not necessarily represent

the views of the National Institutes of Health.

The gods confound the man who first found out how to distinguish hours.Confound him, too, who in this place set up a sundial, to cut and hack myday so wretchedly into small portions!

Titus Maccius Plautus, 250–184BC

Nowadays, the portions may not be so small, as one is for sleep and theother is for wakefulness The balance between these two phases of our lifehas become an important issue for modern medicine and human behavior

To put it simply, this balance controls the rhythm of our life, at least up to apoint As is often the case in human biology, it is because of disruptions inthe equilibrium between sleep and wakefulness that clinicians and medicalresearchers have focused on learning about the mechanisms controlling therhythmicity of our life

Over the past decades, a good deal of work has been done tounderstand sleep and its disorders Although much more needs to be done,much is already known For example, we know that many of themanifestations of sleep disorders are circulatory (such as hypertension) or

iii

respiratory (apnea) or even a combination of both But, many otherfunctions, such as behavior, are also affected by sleep disorders.

This Lung Biology in Health and Disease series recognized very earlythe importance of research on sleep, its mechanisms, and its disorders Since

1981, the series has presented 12 volumes discussing sleep, including sixexclusively devoted to this function All along, however, one approach

to the study of sleep has been missing: the development and study ofwell-characterized animal models This is an obvious deficiency thatcontrasts with what has been done almost systematically in the study ofmost other known biological functions and their disorders Furthermore, it

is well known that what is viewed as ‘‘abnormal’’ in humans isoften ‘‘normal’’ in other species Thus, the study of animal models is apowerful tool for understanding human biology

This volume, edited by Drs David Carley and Miodrag Radulovacki,fills an important gap in this series of monographs, and in the field itself.Those who work in the field will benefit from the knowledge presented inthis volume, and so eventually will all the patients who can only dream of agood night’s sleep!

Drs Carley and Radulovacki and their authors are making animportant contribution As the editor of this series, I thank them for giving

me the opportunity to present this volume to the readership

Claude Lenfant, M.D.Bethesda, Maryland

Sleep-related breathing disorders have been recognized and described byastute clinicians for millennia The past several decades have witnessedintensive and accelerating investigation into the epidemiology, genetics,pathophysiology, and clinical as well as behavioral consequences of sleep-related breathing disorders The Lung Biology in Health and Disease serieshas played an important role in consolidating the accumulating knowledge

in this area and in providing a focused view of the state of the art The recentvolume Sleep Apnea, edited by Allan Pack, highlights the public healthsignificance of sleep-related breathing disorders in terms of their highprevalence and significant morbidity, as well as our lack of fully adequatetreatment options Despite these advances, progress toward defining theexact pathogenic mechanisms of sleep-related breathing disorders and theirconsequences has been slow Elucidation of these mechanisms willundoubtedly yield new insights to improve both diagnosis and treatment

of these disorders

A lack of well-defined animal model systems for sleep-relatedbreathing disorders has been an important factor limiting progress in thisarea of knowledge Over the past decade, several approaches have beendeveloped based on spontaneously occurring and experimentally induced

v

apnea and hypoxia in sleeping rodents, cats, dogs, sheep, and pigs Inparallel with these efforts, tools of modern molecular biology and functionalneuroanatomy have increasingly been applied to investigate the neurobiol-ogy of sleep and respiration The synthesis of these two approaches has led

to significant recent advances in understanding the pathogenesis of related breathing disorders and their consequences at the molecular,cellular, and integrative systems levels

sleep-Our goal in this volume is to provide a synthesis of the currentknowledge To this end, we present a series of comprehensive reviews ofexperimental approaches to the pathogenesis and consequences of sleep-related breathing disorders based on a solid foundation of basic science.Accordingly, we have divided the volume into four sections First, weprovide an introduction to the subject The second part illustrates theapplication of fundamental methods of modern neuroscience to importantquestions regarding brainstem control of sleep and breathing The thirdprovides comprehensive reviews of experimental methods utilizing experi-mentally induced breathing disorders in sleeping animals These methodsrepresent a valuable new approach to define the pathogenic mechanismsleading to the clinical consequences associated with sleep-related breathingdisorders such as sleep apnea Part Four highlights the complementarystrengths of several methods based on spontaneously occurring apnea inanimals to further our understanding of the causes of sleep-related breathingdisorders Parts Three and Four also emphasize the potential opportunitiesfor developing improved diagnostic and therapeutic strategies using theseexperimental approaches

Sleep-Related Breathing Disorders: Experimental Models and apeutic Potential is intended to serve the needs and interests of clinicianinvestigators and basic scientists alike It is our hope that clinicians willbroaden the scope of these experimental approaches, using evolvingknowledge of the epidemiology, genetics, risk factors, and pathobiology

Ther-of sleep-related breathing disorders, and that basic scientists, stimulated tosee the clinical relevance of their work, will continue to expand thearmamentarium of methods used to examine the control of sleep andbreathing in health and disease

We thank all the contributors to this volume for their thoughtful,thorough, and trenchant reviews We are especially grateful to Dr ClaudeLenfant for his encouragement, support, and assistance in producing thisvolume

David W CarleyMiodrag Radulovacki

Julie Arsenault, M.Sc Physiology and Respiratory Research Unit,University of Sherbrooke, Sherbrooke, Quebec, Canada

Helen A Baghdoyan, Ph.D Professor of Anesthesiology and cology, Department of Anesthesiology, University of Michigan, Ann Arbor,Michigan, U.S.A

Pharma-David W Carley, Ph.D Professor of Medicine, Bioengineering, andPharmacology, Department of Medicine, College of Medicine, University ofIllinois, Chicago, Illinois, U.S.A

Michael A Castellini, Ph.D Professor and Director, Institute of MarineSciences, University of Alaska Fairbanks, Fairbanks, Alaska, U.S.A.Nancy L Chamberlin, Ph.D Assistant Professor, Department of Neurol-ogy, Harvard Medical School, and Beth Israel Deaconess Medical Center,Boston, Massachusetts, U.S.A

vii

Maria F Czy_zzyk-Krzeska, M.D., Ph.D Associate Professor, Department

of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati,Ohio, U.S.A

Eugene C Fletcher, M.D Professor and Director, Division of Pulmonaryand Critical Care Medicine, Department of Medicine, University ofLouisville School of Medicine, Louisville, Kentucky, U.S.A

David Gozal, M.D Professor, Vice Chair for Research, and Director,Department of Pediatrics, Kosair Children’s Hospital Research Institute,University of Louisville School of Medicine, Louisville, Kentucky, U.S.A.Joan C Hendricks, V.M.D., Ph.D Professor, Department of ClinicalStudies, School of Veterinary Medicine, University of Pennsylvania,Philadelphia, Pennsylvania, U.S.A

Richard L Horner, Ph.D Assistant Professor, Departments of Medicineand Physiology, University of Toronto, Toronto, Ontario, Canada

R John Kimoff, M.D., F.R.C.P.(C) Director, Sleep Disorders Center,Respiratory Division, McGill University Health Centre, Montreal, Quebec,Canada

Leszek Kubin, Ph.D Research Associate Professor, Department of AnimalBiology, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.Ralph Lydic, Ph.D Bert La Du Professor, Department of Anesthesiology;Professor, Department of Physiology; and Associate Chair, AnesthesiologyResearch, University of Michigan, Ann Arbor, Michigan, U.S.A

Christopher Paul O’Donnell, Ph.D Associate Professor, Department ofMedicine, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.Jean-Paul Praud, M.D., Ph.D Professor, Department of Pediatrics andDepartment of Physiology and Surgery, University of Sherbrooke,Sherbrooke, Quebec, Canada

Miodrag Radulovacki, M.D., Ph.D Professor of Pharmacology andMedicine, Department of Pharmacology, University of Illinois, Chicago,Illinois, U.S.A

Sylvain Renolleau, M.D Pediatric and Neonatal Intensive Care Unit,Armand-Trousseau Children’s Hospital, Paris, France

Clifford B Saper, M.D., Ph.D James Jackson Putnam Professor andChairman, Department of Neurology, Harvard Medical School, and BethIsrael Deaconess Medical Center, Boston, Massachusetts, U.S.A

Richard Stephenson, Ph.D Associate Professor, Departments of ogy and Zoology, University of Toronto, Toronto, Ontario, CanadaKingman P Strohl, M.D Professor, Department of Medicine, CaseWestern Reserve University, and Louis Stokes Cleveland VA MedicalCenter, Cleveland, Ohio, U.S.A

Physiol-Sigrid Carlen Veasey, M.D Assistant Professor, Department of Medicine,University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A

Introduction iii

Part One OVERVIEW

1 Pathophysiology of Sleep-Related Breathing Disorders:

David W Carley and Miodrag Radulovacki

I Public Health Significance 4

III Age-Related Influences 7

Part Two GENERAL TECHNIQUES

2 Instrumentation and Methods for Chronic Studies of Sleep

xi

Richard L Horner, Richard Stephenson, and

Christopher Paul O’Donnell

I Overview: Research on Sleep and Breathing in Rodents 19

II Sleep Recordings in Rats 21III Sleep Recordings in Mice 32

IV Application of Plethysmography to Research in Sleep

and Breathing in Rodents 37

3 Neurochemical Evidence for the Cholinergic Modulation of Sleep

Ralph Lydic and Helen A Baghdoyan

I Experimental Models for Mechanistic Studies of REM

II The Cholinergic Model of REM Sleep Generation 59III Koch’s Postulates Are Satisfied by Cholinergic

Modulation of REM Sleep 60

IV Upper Airway Muscle Activity Is Modulated by

Cholinergic Pontine Mechanisms 62

V Cholinergic Pontine Mechanisms After Respiratory

VI Role of the Tongue and Hypoglossal Nucleus in Airway

VII Protein Profiling: Proteins Altering Pontine Ach Release

II Application of Genetic and Molecular Studies to OSA 112III Methods of Assessing Gene Expression in the CNS 113

IV Gene Expression Changes with the Sleep–Wake Cycle 117

V Neurotransmitter Receptor mRNA and Proteins

Expressed in Upper Airway Motoneurons 120

VI Molecular Regulatory Mechanisms Activated by

Hypoxia in Model Systems In Vitro 128VII Effects of Acute and Chronic-Intermittent Hypoxia onBrain Regions Relevant for Cognitive Functions and

III Effects of the OSA Model on Sleep Architecture 205

IV Changes in Ventilatory Control During Application of

V Changes in Arousal Responses to Respiratory Stimuli

During Application of the OSA Model 208

VI Changes in Cardiovascular Function During

Application of the OSA Model 210VII Perspective in Relation to Other Experimental Models 216

II Historical Perspective: The Need for an Animal Model

of Neonatal Respiratory Instability 224III Personal Experience in Preterm Sheep Deliveries 225

IV Studies of Respiration in Preterm Lambs 227

V Relevance of the Preterm Lamb Model 234

IV Neonatal Modulation of Adult Behavior 243

V Active Sleep and Neural System Behavior 246

VI Neonatal Perturbations and the Adult Ventilatory

VII Respiratory Pauses During Sleep Can Be Modified in

VIII Effects of Suppression of Active Sleep 250

IX Adult Ventilatory Consequences of Neonatal

10 The Laboratory Rat as a Model of Sleep-Related Breathing

II Characterization of the English Bulldog as a Natural

Model of Sleep-Disordered Breathing 298III Strengths and Weaknesses of the English Bulldog as a

IV Pathogenesis of OSDB in the English Bulldog 304

V Comparison of State-Dependent Changes in Upper

Airway Dilator Muscle Activity in Bulldogs and

VI Age-Related Changes in SDB and Upper Airway MuscleFunction in the English Bulldog 307VII Neural Mechanisms Underlying OSDB in the Bulldog 309

III Sleep-Associated Apnea 320

IV Asymmetric EEG Patterns During Sleep 328

Part One

OVERVIEW

Chicago, Illinois, U.S.A.

The last two decades have witnessed an exponential increase in knowledgeregarding sleep-related breathing disorders (SRBD) Significant strides havebeen made in our understanding of these disorders with respect toepidemiology and risk factors, pathogenesis, clinical and behavioralconsequences, and appropriate diagnostic and treatment strategies Still,work to understand these factors in terms of the underlying cellular andmolecular processes is in its infancy As detailed in the subsequent chapters

of this volume, fundamental tools and approaches of molecular biology andquantitative neuroscience are now being employed to study SRBDs Thenext decade should mark important advances in this area, with significantprogress in therapies directed at the specific pathophysiology of thesedisorders

Patients with SRBD can exhibit a spectrum of respiratory disturbancesduring sleep, including: central apneas, operationally defined as cessation ofrespiratory effort for more than 10 sec; obstructive apneas, characterized bycontinued inspiratory efforts against an occluded upper airway; mixedapneas, which present with an initial central component followedimmediately by an obstructive component; hypopneas, associated with

3

partial collapse of the upper airway and an attendant drop in pulmonaryventilation; and respiratory event-related arousals, characterized byincreased inspiratory force generation leading to arousal from sleep butnot impaired gas exchange (1) Disordered breathing events may be anormal phenomenon during transitions from wakefulness to sleep andduring rapid eye movement (REM) sleep in man (2,3) However, when thefrequency of disordered breathing events becomes high, daytime symptomsand clinical sequelae can result A generalized respiratory disturbance index(RDI) is most often used clinically to assess the overall frequency ofdisordered breathing events of any type during sleep Although early studiessuggested that healthy subjects rarely exhibited an RDI > 5 (2–5), it has thusfar proven impossible to identify a threshold RDI above which behavioral

or clinical morbidity results

I Public Health Significance

Sleep-related breathing disorders are a significant public health concern,with a prevalence in the U.S general population of at least 2–5% (6,7).Accumulating evidence suggests that morbid consequences of untreatedSRBD include hypertension, coronary artery disease, myocardial infarction,arrhythmia, stroke, dementia, depression, cognitive dysfunction, sexualdysfunction, and injury due to accidents Partinen and Guilleminault (8)demonstrated that sleep apnea patients to have three times the prevalence ofheart disease and four times the prevalence of cerebrovascular diseasecompared to the general population This may reflect the fact that the risk ofdeveloping hypertension, a major risk factor for cardiovascular andcerebrovascular disease, is elevated in patients with sleep apnea, irrespective

of age, gender, or body mass index (9,10) In a group of elderly nursinghome residents, Ancoli-Israel et al (11) demonstrated a strong correlationbetween apnea and dementia and between the severity of apnea and severity

of dementia Untreated sleep apnea has also been associated with increasedmortality (12,13)

Chapters 6 and 7 detail recent experimental approaches to thesystematic study of the pathophysiological consequences of SRBD in animalmodel systems These methods may help to define the causative pathwaysresponsible for the consistent associations of SRBD with both cardiovas-cular and cerebrovascular morbidity and mortality (8–10,12,13)

Significant neurocognitive changes are also commonly associated withSRBD Excessive daytime sleepiness is reported by almost every patient withsleep apnea and related syndromes (14) This symptom is often presumed toresult from the disruption of sleep continuity attendant to repetitive

disordered breathing events during sleep However, strong associationsbetween quantitative measures of sleepiness and sleep fragmentation haverarely been demonstrated Still, some correlation has been foundconsistently between SRBD severity and both subjective (15) and objective(16,17) assessments of sleepiness Impairment of mood, memory, problem-solving ability, vigilance, reaction time, and motor coordination have beenassociated with SRBD (18,19) Each of these impairments can negativelyimpact perceived quality of life, and can return toward normal, but oftennot to normal, with institution of therapy (20) Considerable work remains

to define the constellation of factors that contribute neurocognitive deficitsassociated with SRBD, and to the recovery of these functions withtreatment This understanding may yield strategies for better diagnosticand treatment procedures

II Pathogenic Mechanisms

No general agreement exists regarding mechanisms underlying the tion or termination of apneas during sleep It is now clear, however, that ingeneral, patients with primarily obstructive apnea have redundantpharyngeal tissue with relatively narrow and collapsible upper airways(for recent reviews, see Refs (21–24) These anatomical defects canpredispose to upper airway collapse during sleep, launching the viciouscycle of sleep apnea–arousal–ventilation that is a hallmark of the syndrome.Still, the change in behavioral state from wakefulness to sleep is necessaryfor airway collapse even in the most severe presentations of sleep apnea.Numerous investigations of state-dependent activation of upper airwaymuscles demonstrate the importance of active and coordinated control ofmotor outputs to the upper airway in avoiding airway collapse or flowlimitation (23–27; for a review, see Ref 28)

genera-It now appears that in most patients, total (apnea) or partial(hypopnea) collapse of the pharyngeal airway during sleep arises fromboth deficient airway anatomy and state-related influences on airway musclefunction Changes in airway geometry and collapsibility are associated withtransitions among behavioral states in everyone These changes primarilyresult from state-dependent alteration in reflex control of the intrinsic upperairway muscles (29) Activation of pharyngeal dilator muscles, such as thegenioglossus, can widen and stiffen the extrathoracic airways Someevidence suggests that augmented reflex activation of pharyngeal dilators,possibly by phasic negative intraluminal pressure, is an importantcompensatory mechanism during wakefulness in patients with obstructivesleep apnea (30) The ability to sense and respond to changes in inspiratory

resistence and negative pressure is attenuated during sleep even in healthyindividuals (31,32) Thus, a patient with an anatomically narrow airwaywho relies on reflex activation of dilator muscles to maintain airway patencyduring wakefulness will be vulnerable to airway collapse during sleep.This viewpoint suggests that interventions intended to specificallymaintain upper airway reflexes at their waking levels throughout sleep mightprovide an effective treatment strategy for obstructive SRBD Many of theintrinsic pharyngeal dilator muscles are directly innervated by neuronsresiding in the hypoglossal nucleus of the medulla (33,34) Unfortunately,the anatomy, connectivity, neuropharmacology, electrophysiology, andmolecular biology of this nucleus cannot be readily explored in man.Chapters 2–5 present approaches to these and related questions usingquantitative investigational methods applied in several animal systems.Factors independent of upper airway anatomy and physiology havealso been suggested to contribute to the pathophysiology of SRBD It hasbeen argued that general instability of ventilatory control producesfluctuating drive to the diaphragm and to the pharyngeal muscles inSRBD (35,36) Such fluctuations cause attendant alterations in upper airwayresistance and collapsibility even in normal individuals (35,37) In fact, O¨naland Lopata (38) showed that tracheostomized SRBD patients exhibitobstructive apnea when breathing through their anatomical upper airways,but exhibit central apneas when these airways are bypassed by thetracheostomy One study also demonstrated a desynchronization betweendiaphragmatic and pharyngeal muscle activation during sleep in patientswith obstructive apnea (39) Delayed activation of upper airway muscleswith respect to the diaphragm may allow negative pressure to develop in theupper airway at a time when it is vulnerable to collapse To date, thishypothesis has been neither confirmed nor rejected by subsequentinvestigation.

These findings suggest that unstable or desynchronized respiratorydrive is an important factor contributing to SRBD In circumstances wherethe upper airway is predisposed to collapse by anatomical or neuromuscularfactors, mixed and obstructive events may predominate In conditions wherethe upper airway is mechanically stable, central events may predominate.This view is in accord with the observation that most patients with SRBDexhibit a combination of central, mixed, and obstructive events within asingle sleep period Furthermore, a detailed understanding of central apneapathogenesis may provide important insights into the mechanisms ofobstructive events, and vice versa

These observations highlight an additional important gap in ourknowledge: little is known about the brainstem and forebrain mechanismsmediating state-dependent changes in respiratory control Virtually nothing

is known about the effects of aging on these central processes and nothing atall is known regarding possible defects in these mechanisms associated withsleep apnea syndrome This lack of knowledge stems in part from a paucity

of animal models to study naturally occurring apnea across all behavioralstates Chapters 8–12 describe recent work using animal models ofspontaneously occurring central and obstructive apnea and hypopnea.These model systems hold great promise to move us toward a detailedmechanistic understanding of SRBD from the level of the molecule to thewhole organism

III Age-Related Influences

A Developmental Aspects

Sleep-related breathing disorders can be expressed in all life stages Becausethe average child spends almost half of each day sleeping, SRBD can be ofparticular importance during childhood The breathing pattern becomeserratic during REM sleep, with variable tidal volume and respiratory rate,including central apneas, even in healthy children and adults (40–42) Thus,REM sleep is a state that can be provocative of SRBD This can beespecially important in children, because they sleep more than adults andspend a greater fraction of their sleep period in REM sleep than adults Inneonates, active sleep (an REM-like state) can occupy up to two-thirds oftotal sleep time (43), as compared to about one-fifth of sleep time in adults(44)

Central apneas, especially during REM sleep, are common in infantsand children (44) Central apneas in children have often been consideredsignificant if they are very frequent, are longer than 20 sec in duration, or areassociated with severe oxygen desaturation, arrhythmia, or arousal (45).However, in view of recent observations in normal infants, the clinicalsignificance of these events remains unclear (45) In contrast, obstructiveapneas in normal children are rare (46)

Sleep-related breathing disorders, particularly obstructive sleep apneasyndrome, are common in childhood Studies in the United States andBritain have shown similar prevalence rates of approximately 2% (47,48).The peak prevalence of childhood SRBD occurs at age 2–8 years (45).Although the data remain preliminary, it appears that SRBD occurs withequal frequency in children of each gender (48)

Obstructive SRBD in children is most often associated withadenotonsillar hypertrophy, and clinical improvement is usually observedafter adenotonsillectomy (49) Still, the pathogenesis of airway obstruction

in children, as in adults, appears to reflect a combination of anatomical and

neuromuscular factors As in adults, children with obstructive SRBD have

no difficulty maintaining airway patency during wakefulness, suggestingthat structural factors cannot be the sole causative factor In addition, noclear correlation has been demonstrated between airway or adenotonsillardimensions and SRBD incidence or severity in children (50,51) Moreover,some children with adenotonsillar hypertrophy as the sole recognizable riskfactor are not cured by adenotonsillectomy (49) Finally, one study reported

a group of children initially ‘‘cured’’ of obstructive SRBD by lectomy who experienced a recurrence of the disorder during adolescence(52)

adenotonsil-It is now feasible to investigate developmental aspects of SRBDpathogenesis and associated morbidity Spontaneous sleep-related centraland obstructive apneas have been described in preterm lambs as well as innewborn and infant rats These model systems already are proving valuablefor exploring maturational aspects of cardiorespiratory control as they maycontribute to SRBD For example, the importance of sleep continuity in theneonate for appropriate autonomic regulation in the adult is illustrated bythe observation that disruption of sleep continuity in newborn rats causedsignificant SRBD that persisted into adulthood (53) Applications of thisbasic investigational approach are detailed in Chapters 8 and 9

B Sleep-Related Breathing Disorders in the Elderly

The high prevalence of SRBDs in the elderly is well established (7,54–61).Although sleep apnea syndrome is most commonly diagnosed amongpatients in the fifth to seventh decades of life, studies of more generalpopulations reveal a clear age-related increase in sleep apnea that extends to

at least the eighth decade (54,61) Prevalence rates for apnea index greaterthan 5/hr are wide ranging: 28–67% for elderly males and 20–54% for elderlyfemales (61)

Several studies of elderly subjects reported correlations between apneaand dysfunctions including heart failure (62), sleep fragmentation (63,64),hypersomnolence (65), daytime sleepiness (66), neuropsychiatric deficits(67,68) and mortality (57) in heterogeneous groups that included patients.Elucidating the mechanisms underlying disordered breathing events willhelp to identify circumstances under which they represent a clinical riskfactor, and may suggest improved therapeutic modalities

Basic experimental approaches in animals have not yet been appliedsystematically to study age-related changes in the causes and consequences

of SRBD There is little doubt that the pace of such investigations will soonincrease Animal model systems play a valuable role in studies of age-relatedaspects of many disease processes Initial observations of age-related

changes in state-dependent respiratory function in animals are noted inChapters 10–12.

IV Other Risk Factors

A Behavioral

Although not a risk factor in the traditional sense, transitions fromwakefulness to sleep are clearly a necessary ‘‘permissive’’ factor forexpression of SRBDs, as used in this volume In normal subjects andpatients, disordered breathing events of all sorts are most especiallyassociated with the transitional state of ‘‘sleep onset’’ and with REM sleep(2,3,69) A significant gap in our current understanding of SRBD is adetailed knowledge of the anatomical connectivity and molecular basis ofaction for the brainstem and forebrain networks that govern sleep andarousal, and the means by which they influence respiratory function Basicapproaches and current work in this area are presented in Chapters 2–5

B Biometric

Numerous studies have confirmed strong and consistent correlationsbetween obesity and obstructive SRBD (70–72) Estimates for the relativerisk of SRBD due to obesity can be greater than 10 (70–72) The mechanismunderlying this effect, however, remains uncertain It has been suggestedthat excess fat deposition in the pharynx may be a direct contributor toSRBD pathogenesis, and overall obesity may be an indirect marker for suchupper airway changes In accord with this possibility, upper body or trunkobesity (73) and neck circumference (71) may be better predictors for SRBDthan overall body mass index Indeed, these may also prove to be usefulSRBD predictors in thin subjects

The basic impact of pharyngeal anatomy, tissue mechanics, andneuromuscular control on expression of SRBD is also being investigated inanimal model systems Obstructive and central apnea is spontaneouslyexpressed in both preterm lambs and neonatal rats, a setting in which thebony and cartilaginous support of the upper airways in not fully developed

In contrast, mature adult sheep and rats with fully developed andanatomically normal pharyngeal airways do not exhibit obstructiveSRBD, but rats demonstrate impressive respiratory pattern instability,including central apnea Ongoing work in this area is described in Chapters8–10

English bulldogs uniformly demonstrate significant whole-bodyobesity, including anatomically narrow pharyngeal airways with excessand redundant soft tissues marked by fat deposition These animals snore

and experience obstructive hypopneas during nonrapid eye movement(NREM) sleep, as well as frequent obstructive apnea and arterial oxygendesaturation during REM sleep Thus, this model system is well suited toexplore the whole-body and pharyngeal obesity in airway collapse duringsleep, although breeding and clinical management of these animals can bedifficult Work using bulldogs to investigate the pathophysiology of SRBDand to identify improved therapeutic strategies is presented in Chapter 11.The connection between obesity and SRBD is also being explored in obeserodents Genetically obese homozygous Zucker rats express SRBD in theform of central apnea with a frequency similar to that of phenotypically leanheterozygous rats However, obese rats may also experience transientobstructive events during sleep, whereas lean rats do not More recently,obese Zucker rats were demonstrated to have blunted reflex activation ofupper airway dilator muscles (74) It has even been suggested that bothobesity and SRBD may be due to leptin resistance These preliminaryfindings are discussed in Chapters 2 and 10.

Another important risk factor for SRBD is male gender Estimates forthe ratio of males to females with SRBD depend on the population andsampling methods employed, but range from about 3:1 to as high as 10:1(75) The reasons for the risk of male gender remain poorly defined Genderdifference in pharyngeal anatomy, neuromuscular control, respiratorycontrol, and body fat distribution have been suggested as potentialcontributors to the male-associated risk for SRBD The gender difference

in SRBD prevalence appears to narrow with age (60), suggesting thathormonal status may also play a role in predisposition to SRBD Thesequestions have not yet been systematically approached using the experi-mental methods and experimental model systems detailed in this volume.However, all of the approaches presented are suitable for investigations ofgender-related mechanisms

Congenital or acquired abnormalities of craniofacial structure can alsocontribute to SRBD risk, but appear to account for only a small fraction ofthe total prevalence For example, retrognathia, micrognathia, macroglos-sia, palatal abnormalities, and nasal septal abnormalities can contribute tothe development of SRBD

C Genetic

Genetic factors exert a strong influence Sleep-related breathing disorderscluster in families, with the relative risk being 2–4 times higher in first-degreerelatives of diagnosed patients (76) A significant fraction of the populationvariance in RDI may depend on genetic factors that may persist after theinfluences of obesity and craniofacial structure are removed (76) In

accordance, even thin relatives of patients with obstructive sleep apnea are

at increased risk for SRBD (77) Risk for SRBD is almost certainlypolygenic and complex; these facts have hindered human investigation inthis area The existence of rodent models of SRBD will provide animportant opportunity to examine the genetics of respiratory control and ofSRBD risk from a complimentary direction Preliminary work of this type isnoted in Chapters 2, 5, and 10

D Vascular

Only about 5% of adult patients with SRBD express purely central apneas(78) However, nearly 50% of patients with stable congestive heart failure(CHF) may exhibit SRBD characterized by central apneas (79) Moreover,Ancoli-Israel et al (62) demonstrated that increasing severity of centralSRBD was predictive of increasingly poor prognosis in patients with CHF.Central SRBD has also been reported in the context of acquired brainlesions of both vascular and nonvascular origin Anatomical lesions rangingfrom the cerebral cortex to the pons have been associated with a diathesis ofSRBD characterized by central apnea (80) A failure of experimentalmedullary lesions to elicit periodic breathing with central apnea led to thehypothesis that SRBD following brain injury resulted from a loss ofsupramedullary inhibition to an intrinsic brainstem oscillator (81)

These findings again emphasize the importance of understanding theinteractions between the brainstem respiratory control systems and thehomeostatic systems that regulate sleep and wakefulness (80) It is nowfeasible to approach such questions using modern tools of molecularbiology, neuropharmacology, neuroanatomy, and electrophysiology Thestate of the art in this field of inquiry is presented throughout the remainingchapters of this volume

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