REHABILITATION OF SPORTS INJURIES:SCIENTIFIC BASIS

VOLUME X OF THE ENCYLOPAEDIA OF SPORTS MEDICINE

AN IOC MEDICAL COMMITTEE PUBLICATION

IN COLLABORATION WITH THE

INTERNATIONAL FEDERATION OF SPORTS MEDICINE

EDITED BY

WALTER R. FRONTERA

BlackwellScience

REHABILITATION OF SPORTS INJURIES:SCIENTIFIC BASIS

IOC MEDICAL COMMISSION

SUB-COMMISSION ON PUBLICATIONS IN THE SPORT SCIENCES

Howard G. Knuttgen PhD (Co-ordinator)Boston, Massachusetts, USA

Harm Kuipers MD, PhDMaastricht, The Netherlands

Per A.F.H. Renström MD, PhDStockholm, Sweden

REHABILITATION OF SPORTS INJURIES:SCIENTIFIC BASIS

VOLUME X OF THE ENCYLOPAEDIA OF SPORTS MEDICINE

AN IOC MEDICAL COMMITTEE PUBLICATION

IN COLLABORATION WITH THE

INTERNATIONAL FEDERATION OF SPORTS MEDICINE

EDITED BY

WALTER R. FRONTERA

BlackwellScience

© 2003 International Olympic CommitteePublished by Blackwell Science Ltda Blackwell Publishing companyBlackwell Science, Inc., 350 Main Street, Malden, Massachusetts 02148-5018, USABlackwell Science Ltd, Osney Mead, Oxford OX2 0EL, UKBlackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton South, Victoria 3053, AustraliaBlackwell Wissenschafts Verlag, Kurfürstendamm 57, 10707 Berlin, Germany

The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

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First published 2003

Library of Congress Cataloging-in-Publication Data

Rehabilitation of sports injuries : scientific basis / edited byWalter R. Frontera.

p. cm. — (The Encyclopaedia of sports medicine ; v. 10)“An IOC Medical Commission publication in collaborationwith the International Federation of Sports Medicine.”Includes bibliographical references and index.

ISBN 0-632-05813-71. Sports injuries. 2. AthletesaRehabilitation.

I. Frontera, Walter R., 1955– II. IOC Medical Commission.III. International Federation of Sports Medicine. IV. Series.

RD97 .R439 2002617.1’027adc21

2002007253

ISBN 0-632-05813-7

A catalogue record for this title is available from the British Library

Set in 9/12 Palatino by Graphicraft Limited, Hong KongPrinted and bound in Great Britain by MPG Books Ltd, Bodmin, Cornwall

Commissioning Editor: Andrew RobinsonProduction Editor: Julie ElliottProduction Controller: Kate Charman

For further information on Blackwell Science, visit our website:www.blackwellpublishing.com

List of Contributors, vi

Forewords, viii

Preface, ix

Part 1: Epidemiology andPathology

1 Epidemiology of Sports Injuries:Implications for Rehabilitation, 3w.r. frontera

2 Pathophysiology of Injury, 10m.l. schamblin and m.r. safran

Part 2: Basic Science of TissueHealing and Repair

3 Skeletal Muscle Regeneration After Injury:Cellular and Molecular Events, 35a.-x. bigard and e. fink

4 Tissue Healing and Repair: Tendons andLigaments, 56b.w. oakes

5 Tissue Healing and Repair: Bone andCartilage, 99k.-m. chan, h.c.l. ho and c.w.c. tong

Part 3: Practical Issues6 Physiological and Performance

Consequences of Training Cessation in Athletes: Detraining, 117i . mujika and s. padilla

7 Physiological and Functional Implicationsof Injury, 144c.j . standaert and s.a. herring

8 Psychological Factors in Sports InjuryRehabilitation, 160b.w. brewer and a.e. cornelius

Part 4: Clinical RehabilitationInterventions

9 Pharmacological Agents and Acupuncturein Rehabilitation, 187j .k. silver and j . audette

10 Physical Modalities and Pain Management, 204j .m. press, c.t. plastaras and s.l. wiesner

11 Flexibility and Joint Range of Motion, 232m. schwellnus

12 Strength and Endurance, 258g. grimby and r. thomeé

13 Proprioception and Coordination, 274j . j . gonzález iturri

14 Functional Rehabilitation and Return toTraining and Competition, 288w.b. kibler and t.j. chandler

15 Orthoses in the Prevention andRehabilitation of Injuries, 301w. micheo and a. esquenazi

Index, 317

Contents

v

J . AUDETTE MD, Instructor, Department ofPhysical Medicine and Rehabilitation, SpauldingRehabilitation Hospital, Harvard Medical School, Boston MA, USA

A.-X. BIGARD MD, Department of HumanFactors, Centre de Recherches du Service de Santé desArmées, BP 87 La Tronche, 38702, France

B.W. BREWER PhD, Associate Professor,Department of Psychology, Springfield College,Springfield, Massachusetts 01109, USA

K.-M. CHAN MD, Chair Professor and Chief ofService, Hong Kong Centre of Sports Medicine & SportsScience, Department of Orthopaedics & Traumatology,Chinese University of Hong Kong, Prince of WalesHospital, Hong Kong

T.J . CHANDLER EdD, Associate Professor,Exercise Science, Sport, and Recreation, MarshallUniversity, Huntington WV, USA

A.E. CORNELIUS PhD, Center for PerformanceEnhancement and Applied Research, Department ofPsychology, Springfield College, 263 Alden Street,Springfield, MA 01109, USA

A. ESQUENAZI MD, Director, Gait and MotionAnalysis Laboratory Moss Rehabilitation Hospital,Department of Physical Medicine and Rehabilitation,Jefferson College School of Medicine and Department ofBioengineering, Drexel University, Philadelphia PA, USA

E. FINK PhD, Department of Human Factors, Centrede Recherches du Service de Santé des Armées, BP87, La Tronche, 38702, France

W.R. FRONTERA MD, PhD, Chairman,Department of Physical Medicine and Rehabilitation,Spaulding Rehabilitation Hospital, Harvard MedicalSchool, Boston MA, USA

J . J . GONZÁLEZ ITURRI MD, Departmentof Physical Medicine and Rehabilitation, University ofNavarra, 31007 Pamploma, Spain

G. GRIMBY MD, PhD, Professor Emeritus,Department of Rehabilitation Medicine, GöteborgUniversity, Göteborg, Sweden

S.A. HERRING MD, Clinical Professor,Departments of Orthopedics and Rehabilitation Medicine,University of Washington, Seattle, Washington, USA

H.C.L. HO MBChB, Department of Orthopaedicsand Traumatology, The Chinese University of HongKong, Prince of Wales Hospital, Hong Kong

W.B. KIBLER MD, Medical Director, LexingtonSports Medicine Center, Lexington, KY 40504, USA

W. MICHEO MD, University of Puerto Rico,Medical Sciences Campus, School of Medicine,Department of Physical Medicine, Rehabilitation andSports Medicine, San Juan PR 00936-5067

I . MUJIKA PhD, Department of Research andDevelopment, Medical Services, Athletic Club of Bilbao,Basque Country, Spain

B.W. OAKES MD, Associate Professor, Department of Anatomy and Cell Biology, Faculty of Medicine, Monash University, Clayton 3168,Melbourne, Australia

List of Contributors

vi

list of contributors vii

M. SCHWELLNUS MD, PhD, AssociateProfessor, Sports Science Institute of South Africa, The University of Cape Town, Cape Town, South Africa

J .K. SILVER MD, Assistant Professor, Departmentof Physical Medicine and Rehabilitation, SpauldingRehabilitation Hospital, Harvard Medical School, Boston, MA, USA

C.J . STANDAERT MD, Clinical AssistantProfessor, Department of Rehabilitation Medicine,University of Washington, Seattle, Washington, USA

R. THOMEÉ PhD, Department of RehabilitationMedicine, Göteborg University, Göteborg, Sweden

C.W.C. TONG MBChB (Hons), Department ofOrthopaedics and Traumatology, The Chinese Universityof Hong Kong, Prince of Wales Hospital, Hong Kong

S.L. WIESNER MD, Chief, Occupational HealthDepartment, The Permanente Medical Group, 280 WestMacArthur Boulevard, Oakland, California 94611-5693,USA

S. PADILLA MD, PhD, Department of Researchand Development, Medical Services, Athletic Club ofBilbao, Basque Country, Spain

C.T. PLASTARAS MD, RehabilitationInstitute of Chicago, Center for Spine, Sports andOccupational Rehabilitation, 1030 N. Clark Street,Chicago, IL 60610, USA

J .M. PRESS MD, Rehabilitation Institute of Chicago, Center for Spine, Sports and OccupationalRehabilitation, 1030 N. Clark Street, Chicago, IL 60610,USA

M.R. SAFRAN MD, Co-Director Sports Medicine,Department of Orthopaedic Surgery, University ofCalifornia San Francisco, San Francisco, California94143, USA

M.L. SCHAMBLIN MD, Department ofOrthopaedic Surgery, University of California, Irvine,California, USA

viii

Forewords

The sports medical care of athletes is oftenwrongly assumed to comprise simply the im-mediate treatment of injuries and of systemicmedical problems. The considerable time and theextensive effort devoted by medical and alliedhealth personnel, both to the prevention ofinjuries and to the rehabilitation of athletes frominjuries which curtail or prevent training andcompetition, are frequently overlooked.

This new volume in the Encyclopaedia ofSports Medicine series addresses all of theimportant issues related to the rehabilitation ofthe injured athlete. Dr Frontera and his team ofexpert contributing authors present the cuttingedge of knowledge relative to the basic scienceand accompanying practical considerationsregarding tissue injury and repair.

This volume provides an excellent comple-ment to the volumes already published. Theseries now includes the preparation of an athletefor competition, the prevention of sports injuries,the immediate treatment of injuries, and therehabilitation that must occur to bring an athleteback to training and competition.

My congratulations go to the editor and authorsfor their excellent work and to the IOC MedicalCommission for providing this admirable contri-bution to sports medicine literature.

Dr Jacques ROGGEIOC President

The general aim of the Encyclopaedia of SportsMedicine series is to present the latest and most

authoritative information available relative to abroad range of topic areas included under therubric of Sports Medicine. The earlier volumes ofthe Encyclopaedia series have addressed a widevariety of areas of interest relative to both sportsmedicine and the sport sciences. Following thegeneral interest publication of Vol. I, The OlympicBook of Sports Medicine, succeeding volumes were devoted to the more definitive topics ofendurance, strength and power, prevention andtreatment of injuries, the child and adolescentathlete, sports nutrition, women in sport, andbiomechanics.

The publication of this volume further rein-forces the intense interest that the IOC MedicalCommission has in the health and welfare of the athletes of the world. Not only does optimalrehabilitation assist in returning an injured athlete to training and competition, but a care-fully administered programme of rehabilitationserves to prevent the recurrence of the sameinjury or the occurrence of additional injuries. A high-quality programme of rehabilitation is ofimportance to all athletes, their coaches, and theteams and nations that they represent.

This volume will stand for many years as themost comprehensive and authoritative referenceon sports injury rehabilitation available both for clinicians and sports scientists. I extend both my appreciation and my congratulations to DrFrontera and each of the contributing authors.

Princes Alexandre de MERODEChairman, IOC Medical Commission

Conceptual framework

Rehabilitation is, by definition, the restoration ofoptimal form (anatomy) and function (physiol-ogy). It is a process designed to minimize the lossassociated with acute injury or chronic disease,to promote recovery, and to maximize functionalcapacity, fitness and performance. The process of rehabilitation should start as early as possibleafter an injury and form a continuum with othertherapeutic interventions such as the use of pharmacological agents. It can also start before or immediately after surgery when an injuryrequires a surgical intervention. The rehabilita-tion of the injured athlete is managed by a multi-disciplinary team with a physician functioningas the leader and coordinator of care. The teamincludes, but is not limited to, athletic trainers,physiotherapists, psychologists, and nutrition-ists. The rehabilitation team works closely withthe athlete and the coach to establish the rehab-ilitation goals, to discuss the progress resultingfrom the various interventions, and to establishthe time frame for the return of the athletes totraining and competition.

Injuries during sports competitions may resultfrom high forces during actions or movementsinherent to the sport. The rehabilitation plan

must take into account the fact that the objectiveof the patient (the athlete) is to return to the sameactivity and environment in which the injuryoccurred. Functional capacity after rehabilitationshould be the same, if not better, than before in-jury since avoiding the conditions associated withthe injury is not, in many cases, an alternative.

The sequence of events resulting from a sports-related injury that may lead to a reduction orinability to perform in sports can be framedusing a disability model widely used in the fieldof rehabilitation medicine (Fig. 1). In this context,the ultimate goal of the rehabilitation process isto limit the extent of the injury, reduce or reversethe impairment and functional loss, and prevent,correct or eliminate altogether the disability.

From a clinical perspective it is possible todivide the rehabilitation process into threephases. The goals during the initial phase of therehabilitation process include limitation of tissuedamage, pain relief, control of the inflammatoryresponse to injury, and protection of the affectedanatomical area. The pathological events thattake place immediately after the injury couldlead to impairments such as muscle atrophy andweakness and limitation in the joint range ofmotion. These impairments result in functional

Preface

Pathology (injury) Impairment Functional loss DisabilityStrain Contracture Inability to Inability to Sprain Muscle atrophy run, jump compete Fracture and weakness in sports

Fig. 1

ix

losses, for example, inability to jump or lift anobject. The extent of the functional loss may beinfluenced by the nature and timing of the thera-peutic and rehabilitative intervention during theinitial phase of the injury. If functional losses aresevere or become permanent, the athlete nowwith a disability may be unable to participate inhis/her sport.

The goals during the second phase of rehabili-tation include the limitation of the impairmentand the recovery from the functional losses. Anumber of physical modalities are used to en-hance tissue healing. Exercise to regain flexibility,strength, endurance, balance, and coordinationbecome the central component of the interven-tion. To the extent that these impairments andfunctional losses were minimized by early inter-vention, progress in this phase can be accelerated.

The final phase of rehabilitation represents thestart of the conditioning process needed to returnto sports training and competition. Understand-ing the demands of the particular sport becomesessential as well as communication with thecoach. This phase also represents an opportunityto identify and correct risk factors, thus reducingthe possibility of re-injury. The use of orthoticdevices to support musculoskeletal function andthe correction of muscle imbalances and inflexi-bility in uninjured areas should receive the atten-tion of the rehabilitation team.

Structure of this volume

This volume contains a total of 15 chaptersdivided into four sections. The first section cov-ers relevant basic concepts of the epidemiologyand pathology of sports injuries. The implica-tions of the patterns of sports injury for rehabili-tation are discussed and the physiological andcellular response to tissue injury reviewed indetail. The second section contains three chap-ters on the basic science of tissue healing andrepair of the five most frequently injured tissuesin sports: muscles, tendons, ligaments, bones,

x preface

and/or cartilage. Section three includes threechapters on practical issues of great significanceto the outcome of the rehabilitation process. The treatment and rehabilitation of injuries inathletes requires, in many cases, the reduction or complete cessation of training. Injuries anddetraining alter basic physiological mechanismsand the functional capacity of the athlete. Theseeffects must be taken into consideration espe-cially at the beginning of the second phase of therehabilitation process. It is a common mistake toconsider the physical rehabilitation of the athletedisconnected from the psychological recovery.The last chapter of this section addresses relevantemotional and psychological aspects of sportsrehabilitation.

The last section of the book includes sevenchapters that discuss the most commonly usedinterventions in clinical rehabilitation. The use of pharmacological agents, physical modalities,and the various types of therapeutic exercise areall discussed in detail. Particular attention isgiven to the use of orthotic devices and to func-tional rehabilitation and issues related to thereturn to training and competition.

All authors have made a serious attempt tosummarize the relevant scientific literature. It isour interest to discuss the evidence, if any, thatsupports current rehabilitative strategies.

Acknowledgements

I would like to thank all authors for their timeand excellent contributions to this volume. I also wish to express special thanks to ProfessorHoward Knuttgen, Chair of the Sub-commissionon Publications of the IOC Medical Commissionfor his guidance. Final thanks to the IOC MedicalCommission and the International Federation of Sports Medicine for having established thisimportant Encyclopedia of Sports Medicine.

Walter R. FronteraBoston, Massachusetts

PA RT 1

E P I D E M I O L O G Y A N DPAT H O L O G Y

Introduction

The study of the relationships among the vari-ous factors determining the frequency and dis-tribution of diseases and/or injuries in a human community is known as epidemiology. The basicelements of epidemiology have been applied tothe study of a frequent, albeit unintended, con-sequence of the practice of sport; i.e. injuries tothe musculoskeletal system.

Understanding the incidence and prevalenceof injuries based on variables such as type andnature of the injury, age group, nature of the sport,gender and time since the onset of symptoms,among others, has contributed to the develop-ment of programmes aimed at the prevention andtreatment of injured athletes (Walter & Hart 1990).Most importantly, these studies have resulted

in the identification of risk factors for sportsinjuries (Macera et al. 1989) and modifications inthe competitive rules in various sports. Althoughresearch in epidemiology has proved essential forthe development of preventive and therapeuticinterventions, the relationship between the epi-demiology of sports injuries and the process ofrehabilitation of the injured athlete has not receivedsimilar attention.

Some authors have proposed a model that uses epidemiological information to generatepreventive strategies (Van Mechelen 1993). Thesequence of prevention is illustrated in Fig. 1.1.In this model, the identification of the problemand description using epidemiological outcomesleads to the study of the mechanisms of injuryand the naming and grouping of risk factors.Based on that information, preventive measures

Chapter 1

Epidemiology of Sports Injuries:Implications for Rehabilitation

WALTER R. FRONTERA

3

1 Establishing the extent of the injuryproblem: incidence and severity

2 Establishing aetiology andmechanism of sports injuries

3a Introducing apreventive measure

4 Assessing the effectiveness byrepeating step 1

3b Introducing arehabilitation programme

Fig. 1.1 The sequence ofprevention and rehabilitation.(Adapted from Van Mechelen1993.)

designed to reduce the risk and/or severity ofthe injuries are designed and implemented. Fin-ally, the measures are evaluated by repeating the description of the problem (step 1) after the intervention. We suggest that this useful modelcould be expanded by including, as part of theintervention strategies, effective rehabilitation pro-grammes that contribute to symptom resolution,limit functional losses, and restore physiologicalfunction and performance.

From a clinical point of view, an analysis ofsports injuries by pattern, type, incidence andseverity, together with an improved under-standing of the physiological losses associatedwith these injuries, could help us design betterrehabilitative interventions. Further, this know-ledge could help us explain the extent to whichthe lack of effective rehabilitation itself becomesa risk factor predisposing injured athletes to therecurrence of an existing injury or to new injuriesin a different, but related, anatomical area. Forexample, a high incidence of chronic injuriescould indicate that proper rehabilitation did not follow the treatment of the symptoms in theacute inflammatory phase. It should be under-stood that, for the competitive athlete, resolutionof the acute symptoms, such as pain, and clinicalsigns, such as swelling, is not the goal of thesports medicine practitioner. Restoration of form,and more importantly, function after resolutionof the symptoms is necessary for optimal sportsperformance. Further, as our understanding ofthe physiological losses associated with the mostcommon sports injuries improves, it will be pos-sible to anticipate the functional deficits resultingfrom those injuries. Thus, the implementation ofappropriate rehabilitation programmes will befeasible.

The purpose of this chapter is to illustrate how data on the pattern of injuries in varioussports populations can help us restore form andfunction after injury. It is not the author’s inten-tion to present an exhaustive and critical reviewof the literature on the epidemiology of sportsinjuries but to interpret some existing data in the context of the goals of a standard rehabilita-tion programme. It will suffice to demonstrate

4 epidemiology and pathology

a reasonable association between the two. Fur-ther, most of the observations included in thischapter are descriptive of a sports injury cliniclocated in a sports training centre and not in a hospital or medical centre. The descriptivenature of these observations limits the extent to which we can draw conclusions and onlyallows us to make preliminary observations andspeculations. Finally, it is not intended to presentan analysis of the incidence of sports injurieswith considerations of the population at risk or the difference in exposure (hours duringwhich an athlete risks injury) (Wallace 1988).These factors appear to be less relevant in clinical rehabilitation.

Patterns of sports injuries

It is common to examine the distribution of injuriesin relation to other variables of interest like age group, type of injury (traumatic vs. overuse),time since onset of symptoms, whether the injuryoccurred during training or competition, ana-tomical area, specific diagnosis and severity ofinjury. These variables are of significant interestwhen rehabilitation is our main focus. Let usexamine briefly the influence of these factors onour rehabilitation strategies.

Type of injury (traumatic vs. overuse)

Roughly 45–60% of all injuries treated in a sports medicine clinic can be classified as over-use injuries. This is particularly true in sports likegymnastics (Fig. 1.2) where soft tissues and jointsare subject to unusual positions and stresses.Risk factors for overuse injuries include muscleweakness, muscle strength imbalance and ana-tomical misalignment (Knapik et al. 1991). Anexamination of these risk factors suggests thatproperly designed rehabilitation programmesand the use of rehabilitation devices such as foot orthotics could contribute to a reduction inthe incidence and prevalence of overuse sportsinjuries.

Clearly, the situation may be different whenthe analysis is restricted to clinical encounters

epidemiology of injury 5

in an emergency department. Many traumaticinjuries (Fig. 1.3) are more acute and severe,resulting frequently in immobilization and pro-longed rehabilitation.

Time from onset

Epidemiological studies show that, when thetime from onset of symptoms is considered, most(70.2% of a total of 1650) injuries treated in anambulatory sports medicine clinic are chronic in nature (Frontera et al. 1994). In other words,the time between the onset of symptoms and theevaluation in the clinic is longer than 2 weeks.There are several potential reasons or scenariosthat could explain this observation. As men-tioned above, an insidious onset in the absence of obvious trauma with a slow progression of the injury could result in a delay in making aclinic appointment to get the signs and symptomsevaluated. This is typical of the overuse injuriesthat have become so prevalent in sports like running, swimming and baseball.

Another possibility could be that the symptomsare not well defined, at least initially, making thediagnosis by a physician difficult. It is also con-ceivable that the incorrect therapeutic modalityor rehabilitation intervention was chosen to initi-ate treatment or that the patient did not completethe treatment as prescribed by the physician forother reasons. These two situations could prolongthe acute stage resulting in the persistence ofsymptoms. Moreover, many injuries occur dur-ing training sessions when health care profes-sionals may not be available to immediately treat

Fig. 1.2 Repetitive stress associated with high-volumetraining results in overuse injuries in many athletes invarious sports including gymnastics. M.O. Huilan atAtlanta, 1996. (© Allsport, Doug Pensinger, 1996.)

Fig. 1.3 Falls in cycling can resultin significant traumatic injuries.

the injured athlete. The athlete may delay seek-ing help or may initiate treatment him/herself ifthe symptoms are not severe or disabling, andtissue damage may increase in the absence ofacute therapeutic intervention. Finally, it is alsopossible that the correct treatment was appliedresulting in resolution of the symptoms but thatproper rehabilitation of impairments and func-tional losses did not follow the therapeutic inter-ventions. In other words, the athlete is allowedback into training and competition based on theabsence of pain and inflammation but not on the recovery of strength, flexibility or enduranceneeded for successful performance in sports.

In the absence of appropriate rehabilitation,acute, subacute or chronic injuries frequentlyresult in significant physiological and functionallosses that place the affected anatomical area(and adjacent tissues and joints) at risk for rein-jury. Recovery from these losses becomes one ofthe most important goals of the rehabilitationprogramme. The extent of these losses is illus-trated by a clinical epidemiology study publishedby Holder-Powell and Rutherford in 1999. Theseauthors evaluated the strength of various musclegroups in asymptomatic subjects with history ofa sports injury. The injuries occurred between0.75 and 42 years before the evaluation (mean =9.7 ± 11 years).

The most important observation in that studywas a decrement of concentric, eccentric and staticstrength in the knee extensor muscles of the in-jured limb many years after the injury (Fig. 1.4).This was the case even when the muscle groupwas distant from the injured area. In other words,the authors of the study observed weakness ofthe knee extensors in patients with injuries suchas fractures of the leg and sprains of the ankle ligaments. The degree of weakness present in the hamstrings, on the other hand, was minor in some cases and non-existent in others, sug-gesting that the rehabilitation approach must bemuscle specific.

In another study, Croisier et al. (2002) demon-strated that athletes with strains of the hamstringshad significant strength deficits. More import-antly, these investigators showed that if those that

6 epidemiology and pathology

have significant deficits complete a rehabilitationprogramme, in this study consisting of isokineticstrengthening concentric and eccentric exercises,muscle weakness is reversed. Further, the incid-ence of postrehabilitation injuries in the 12 monthsfollowing return to their sport was zero.

Anatomical distribution of injuries

When the incidence of sports injuries is ana-lysed by anatomical region, the most frequentlyinjured areas are the knee (Fig. 1.5), shoulder and ankle (Garrick 1985; DeHaven & Lintner 1986;Frontera et al. 1994). Of course the anatomical

100

80

60

40

20

0

I/UI%

75.284.8 80.4 86.6

Quadriceps Knee Fracture AnkleType of injury

Fig. 1.4 Concentric peak torque of the knee extensorsof the injured side measured at 30 degrees per secondand expressed as a percentage of the uninjured side(I/UI) in subjects with different types of injuries. Theinjuries occurred an average of 9.7 years before theevaluation. (Adapted from Holder-Powell &Rutherford 1999.)

Fig. 1.5 An acute knee injury in a judo player,Girolamo Giovinazzo of Italy at Sydney, 2000. (© Allsport, Clive Brunskill, 2000.)

epidemiology of injury 7

distribution of injuries in a particular sport can be very specific. In other words, basketball players may suffer more injuries to the knee than to the shoulder but the situation in swimmers isthe reverse.

Knowledge of the anatomical distribution ofinjuries in a particular sport is essential to developa training programme that maximizes sport-specific conditioning and minimizes the risk ofinjury. Further, because deconditioning associatedwith rest could potentially affect muscle groupsproximal and distal to the injured area, know-ledge of this anatomical distribution of injuriesby sport could be vital for the rehabilitation ofthe injured athlete. A well-planned rehabilita-tion programme should include exercises for theinjured area as well as for those areas at risk ofinjury in the specific sports activity.

Most frequent diagnoses

Most sports injuries are relatively mild and do notrequire surgical intervention. Independent of thelevel of competition, the most frequent diagnosesare in descending order: tendonitis (or tendinosis),first degree strains (muscle tendon unit), firstdegree sprains (ligament and capsular injuries),patellofemoral pain and second degree sprains.The best course of action in these cases is appro-priate conservative intervention to control symp-toms such as pain and swelling, followed bycomprehensive rehabilitation. The indicationsfor surgery in these cases are few and rehabilita-tion becomes the most effective intervention whenfast return to practice or competition and preven-tion of future injuries are the most important goals(DeHaven & Lintner 1986; Matheson et al. 1989).

Severity of injury

The severity of the injury can be judged by thenature of the diagnosis, the duration and natureof the treatment, the time lost from sports trainingor competition, and/or the presence and degreeof permanent damage (Van Mechelen 1993). Thereis usually a positive correlation between sever-ity, functional loss and the need for extended

rehabilitation. Clearly, when the severity is high,longer periods of immobilization or rest areneeded for tissue healing. As a result, largerphysiological losses are experienced by the athlete and deconditioning of uninjured areas is more extensive. Under these conditions, itshould be anticipated that rehabilitation will lastlonger.

Rehabilitation and thepreparticipation exam

Every competitive athlete must undergo a pre-participation medical examination on a regularbasis. The preparticipation exam is an ideal situ-ation in which to: (i) treat existing medical condi-tions early before the competition; (ii) anticipatethe health care needs of the athlete; (iii) educatethe athlete and his/her coach regarding healthissues such as vaccinations and prevention ofdisease and injury; and (iv) discuss topics such asdoping in sports.

Another important element of the preparti-cipation exam is the identification of risk factorsfor medical conditions in general and for sportsinjuries in particular. The process of identifyingrisk factors can make use of the epidemiologic-al evidence published in the sports medicine literature. Findings such as joint contractures orreduced flexibility, muscle weakness and musclestrength asymmetry represent ideal opportunit-ies to do ‘preventive rehabilitation’. The restora-tion of normal form and function in these casesdoes not necessarily follow a sports injury but maybe important in the prevention of future injuries.In addition, rehabilitation may prove to be bene-ficial for sports performance because an enhancedlevel of flexibility, cardiovascular endurance andmuscle strength and endurance, alone or in com-bination, are required in almost any sport.

Health services in internationalcompetitions

The study of the pattern of disease and injuries in international sports competitions can help theteam physician make plans regarding, among

other things, the composition of the health careteam travelling with sports delegations, the equip-ment and medical supplies necessary to deliverhealth care (including rehabilitation services) inan Olympic village, the most commonly used andpermitted medications, and the therapy modalitiesneeded for rehabilitation (Frontera et al. 1997).

As the number of athletes and competitionsincrease and new transportation methods facilit-ate travel, health professionals will be challengedto respond to the needs of the travelling athleteexposed to different environmental conditions,pathogens and demanding training regimes.

Although disorders of the respiratory and gastrointestinal tracts are very common amongtravelling athletes, the main cause of morbidityduring an international competition is injuries tothe musculoskeletal system (Fig. 1.6).

The five most common injuries or disordersaffecting the musculoskeletal system (total num-ber of diagnoses = 966) include: first degreestrains (23.1%), tendinitis/tendinosis (18.7%), con-tusion (12.7%), myositis (10.9%) and first degreesprains (10%). All of these diagnoses could bene-fit from rehabilitative interventions to control thesymptoms in the acute stage and to restore physio-

8 epidemiology and pathology

logical and functional capacity in later stages. In fact, in the above study, typical rehabilitationinterventions such as physical therapy modalities(cold packs, hot packs, ultrasound, transcutane-ous electrical stimulation, massage, therapeuticexercises) were needed in 23.1–36.9% of the totalnumber of cases.

It is important to note that, just like in the caseof the sports injury clinic discussed above, theonset of symptoms preceded the competition inmany cases. Thus many injuries could be classifiedas chronic in nature. High-performance athletesoften continue to train and compete even in thepresence of symptoms and signs of injury, andmay delay proper treatment and rehabilitation ofan injury to participate in important competitions.Thus, it is reasonable to speculate that some ofthe injured athletes did not receive appropriaterehabilitation after the initial insult. These twoobservations make the inclusion of rehabilitationservices in precompetition assessment and plansfor a sports delegation an absolute necessity.

Conclusion

The study of the epidemiology of sports injuriescan be as valuable to rehabilitation as it is to pre-vention. Many injuries may occur because therehabilitation of a previous injury was not com-plete. Understanding risk factors associated withsports injuries can help in the design of rehabil-itation strategies resulting in a lower incidenceand severity of injuries. Rehabilitation principlescan be applied in a sports injury clinic but also aspart of the health care services for a travellingteam. The following chapters will discuss the scientific basis of current rehabilitation practices.Every sports medicine practitioner should befamiliar with these principles and apply them intheir work with athletes.

References

Croisier, J.-L., Forthomme, B., Namurois, M.-H.,Vanderhommen, M. & Crielaard, J.-M. (2002)Hamstring muscle strain recurrence and strengthperformance disorders. American Journal of SportsMedicine 30, 199–203.

Resp.17.2%

Other25.7%

Skin5.8%

GI12.2%

MSK39.1%

Fig. 1.6 Distribution of diagnoses (n = 2468) in a healthclinic during international sports competitions bysystem. GI, gastrointestinal; MSK, musculoskeletal.(Adapted from Frontera et al. 1997.)

epidemiology of injury 9

DeHaven, K.E. & Lintner, D.M. (1986) Athletic injuries:comparison by age, sport, and gender. AmericanJournal of Sports Medicine 14, 218–224.

Frontera, W.R., Micheo, W.F., Aguirre, G., Rivera-Brown, A. & Pabon, A. (1997) Patterns of disease andutilization of health services during internationalsports competitions. Archivos de Medicina del Deporte14, 479–484.

Frontera, W.R., Micheo, W.F., Amy, E. et al. (1994)Patterns of injuries in athletes evaluated in an inter-disciplinary clinic. Puerto Rico Health Sciences Journal13, 165–170.

Garrick, J.G. (1985) Characterization of the patient population in a sports medicine facility. Physician andSportsmedicine 13, 73–76.

Holder-Powell, H.M. & Rutherford, O. (1999) Unilaterallower limb injury: its long-term effects on quad-riceps, hamstring, and plantarflexor muscle strength.Archives of Physical Medicine and Rehabilitation 80,717–720.

Knapik, J.J., Bauman, C.L., Jones, B.H., Harris, J.M. &Vaughan, L. (1991) Preseason strength and flexibilityimbalances associated with athletic injuries in female

collegiate athletes. American Journal of Sports Medicine19, 76–81.

Macera, C.A., Pate, R.R., Powell, K.E., Jackson, K.L.,Kendrick, J.S. & Craven, T.E. (1989) Predictinglower-extremity injuries among habitual runners.Archives of Internal Medicine 149, 2565–2568.

Matheson, G.O., Macintyre, J.G., Taunton, J.E.,Clement, D.B. & Lloyd-Smith, R. (1989) Musculo-skeletal injuries associated with physical activity inolder adults. Medicine and Science in Sports and Exercise21, 379–385.

Van Mechelen, W. (1993) Incidence and severity of sportsinjuries. In: Sports Injuries: Basic Principles of Preven-tion and Care (Renström, P.A.F.H., ed.). BlackwellScientific Publications, Oxford: 3–15.

Wallace, R.B. (1988) Application of epidemiologic prin-ciples to sports injury research. American Journal ofSports Medicine 16 (Suppl. 1), 22–24.

Walter, S.D. & Hart, L.E. (1990) Application of epi-demiological methodology to sports and exercise science research. In: Exercise and Sports Sciences Reviews(Pandolf, K.B. & Holloszy, J.O., eds). Williams &Wilkins, New York: 417–448.

Introduction

No matter what the age of an athlete, the level ofcompetition or the sport, inflammation is likely toaffect an individual at some point in their endeav-ours. Whether an injury is one of chronicity,related to repetitive movements, or one of acuteonset, related to trauma, the detrimental effects onathletic performance are well documented. Toofrequently the complexity of the inflammatoryprocess is not fully understood and inflammationis treated as an unwanted hindrance to athleticperformance, however, it is truly a complex net-work of vascular and cellular responses designedto facilitate the repair of traumatized tissue (Bryant1977; Gamble 1988; Martinez-Hernandez 1988).

The development of an inflammatory reactionto an injury is complex, utilizing many of thebody’s systems to mediate its purpose. The goalof any inflammatory reaction is to resolve thepathological insult and restore the anatomy to a level of physiological function identical ornearly identical to preinjury status. Ideally thiscan be accomplished by removing diseased ordamaged tissue with the subsequent regenera-tion of normal anatomical tissue. However, thisis often not the case. Too frequently the insult isfar too great or perpetrated over too long a period,resulting in increased tissue destruction. Thisoften leads to scar tissue formation that in turnmay propagate a continued inflammatory reac-tion. A persistent inflammatory action, therefore,may be harmful to an individual’s athletic per-formance, as well as to the individual.

Although in the recent past, understanding ofthe mediators of inflammation has vastly im-proved, many factors responsible for induction,regulation and resolution remain indefinable.This lack of understanding remains an elusivecornerstone in treatment for both the physicianand the athlete. The purpose of this chapter is toprovide an understanding of our current know-ledge of the complex nature of the pathophysi-ological mechanisms, which function to mediatea host’s response to tissue injury. This knowledgeis then utilized in later chapters to understandspecific tissue responses to injury as related tothe athlete.

Cytokines

Inflammation may be seen in a variety of circum-stances that affect the human body. It may occuras a defensive response to foreign material or as a response to mechanical trauma, toxins or in the face of abnormalities such as neoplasia. Theaccumulation and activation of leucocytes seemsto play an essential role in nearly all forms ofinflammation. Following the influx of leucocytesin the acute phase of inflammation, its pro-pagation and amplification is mediated by bothhumoral and cellular components of the immunesystem.

Cytokines are cellular proteins that are themediators of physiological activity, including the inflammatory process. There are proinflam-matory and anti-inflammatory cytokines, whichmodulate their effect by binding to receptors

Chapter 2

Pathophysiology of Injury

MARK L. SCHAMBLIN AND MARC R. SAFRAN

10

pathophysiology of injury 11

on target cells. Through this interaction the up-regulation or down-regulation of cellular activitymay be propagated. In the acute phase responseof inflammation, cytokines appear to be respons-ible for a myriad of physiological modificationsoccurring both locally at the site of the patho-logy and also at regions distant from the insult(Rosenberg & Gallin 1993).

The functions of cytokines are varied. A givencytokine may initiate and regulate cellular activ-ities in numerous cells simultaneously. At thesame time, more than one cytokine may induce a particular biological activity (Table 2.1). Inter-leukin 1 (IL-1), a common cytokine seen ininflammation, acts on virtually all leucocytes,endothelial cells, monocytes and hepatocytes toup-regulate the expression of adhesion mole-cules, cytokines and arachidonic acid meta-bolites (Rosenberg & Gallin 1993). It results inneutrophil accumulation, fibroblast prolifera-tion, angiogenesis, acute phase protein syn-thesis and metabolic alterations such as fever.Similar activity is seen in other proinflamma-tory cytokines, such as tumor necrosis factoralpha (TNF-α), IL-6, IL-4, IL-10 and transform-ing growth factor beta (TGF-β). An excellentexample of this biological redundancy can beseen with IL-1 and TNF-α. Both of these cyto-kines result in the up-regulation of adhesionmolecules, accumulation of leucocytes, proteinsynthesis and angiogenesis (Rosenberg & Gallin1993; Bemelmans et al. 1996).

Local cytokines react with their receptors in an autocrine, paracrine and endocrine fashion(Fig. 2.1). The autocrine pathway allows for theamplification of the cytokine-induced inflam-matory process. The paracrine pathway allowscytokines to influence cells in the local environ-ment, leading to the accumulation of inflammat-ory cells. The induction of acute phase proteinsynthesis in the hepatocytes is an example of anendocrine mechanism of peripherally circulat-ing cytokines (Akira et al. 1993; Dinarello 1996).By utilizing these three mechanisms of action,the cytokine is able to alter the local tissue as well as the acute phase response in the face ofinflammation.

The regulation of cytokine function is of critical importance. Secondary to a cytokine’s powerful ability to modify biological behaviour,the body has evolved numerous cellular andmolecular mechanisms to control their activity.The predominant mechanism of regulation occursat the level of gene transcription. Cytokines are not stored, but rather created de novo fol-lowing cellular activation. Antigen stimulation leads to increased transcription within 30 min. A steady-state level is seen in anywhere from 4 to 8 h (McDonald et al. 1993; Jain et al. 1995;Serhan 1997). With the cessation of the stimulus,return to the baseline will usually occur in 24 h.A second form of regulation is the conversion ofan inactive form of the cytokine to the activeform. This mechanism is seen in the conversionof a procytokine within the cytosol to the cyto-kine IL-1β, as well as the formation of TNF-α,which is formed in its active state but limited tothe cell membrane. Cleavage of the membrane-bound TNF-α by converting enzymes facilitatessecretion.

The ability to down-regulate the inflammatoryprocess is as important as the ability to initiate it. Chronic inflammation or failure to control an

(a) (b)

(c)

Fig. 2.1 Cytokines mediate their effects via threemechanisms of action. (a) Autocrine: the release ofcytokines by a cell allows binding to receptors on thecell of origin. (b) Paracrine: most cytokines have asmall radius of activity and mediate their effects onadjacent cells. (c) Some cytokines (IL-1 and TNF)mediate their activity via endocrine mechanisms.

Table 2.1 The actions of selected cytokines including source, targets and activities.

Cytokine Cell source Cell target Biological activity

IL-1α Monocytes All cells Up-regulation of adhesion molecule expression IL-1β Macrophages Macrophage emigrations

Acute phase protein synthesis

IL-2 T-cells T-cells T-cell activation and proliferation B-cells Enhanced monocyte and macrophage cytolytic activityMonocytesMacrophages

IL-3 T-cells Monocytes Stimulation of haematopoietic progenitorsMast cells MacrophagesNK cells Mast cells

Eosinophils

IL-4 T-cells T-cells Stimulates T-cell and B-cell differentiationMast cells B-cells Anti-inflammatory action on T-cells, B-cells and monocytesBasophils Monocytes

MacrophagesNeutrophilsEosinophils

IL-5 T-cells Eosinophils Regulates eosinophil migration and activationMast cells BasophilsEosinophil

IL-6 Monocytes T-cells Induction of acute phase proteinsMacrophages B-cells T-cell and B-cell differentiationB-cells Epithelial cells

IL-8 Monocytes Neutrophils Induces neutrophil, monocyte and T-cell migrationMacrophages T-cells Neutrophil adherenceT-cells Monocytes AngiogenesisNeutrophils Macrophages Histamine release

IL-10 Monocytes Monocytes Inhibits macrophage proinflammatory cytokine productionMacrophages Macrophages Inhibits differentiation of T-cellsT-cells B-cells Inhibits NK cellsB-cells T-cells

Mast cells

TNF-α Monocytes All cells Fever, anorexia and proinflammatory cytokine productionMacrophages Enhanced capillary permeabilityMast cells Acute phase protein synthesisBasophilsNK cellsB-cellsT-cells

TNF-β T-cells All cells Cell cytotoxicityB-cells

TGF-β Most cell types Most cell types Down-regulates T-cell and macrophage responsesStimulates angiogenesis

IFN-α All cells All cells Stimulates T-cell, macrophage and NK cell activityDirect antitumour effectsAntiviral activity

IFN-γ T-cells All cells Regulates macrophage and NK cell activationNK cells T-cell differentiation

Immunoglobulin production by B-cells

IFN, interferon; IL, interleukin; NK, natural killer; TGF, transforming growth factor; TNF, tumour necrosis factor.

pathophysiology of injury 13

inflammatory process may lead to host tissuedamage. There are several mechanisms utilizedin the down-regulation of inflammation. Theseinclude production of activated complementinhibitors, apoptosis of inflammatory cells andproduction of anti-inflammatory cytokines suchas IL-4, IL-10, IL-13 and TGF-β (Feng et al. 1996).IL-4 and IL-10, perhaps the best known of theanti-inflammatory cytokines, appear to mediatean anti-inflammatory effect on the T-cell pre-dominantly, but also B-lymphocytes, mast cells,basophils and endothelial cells, as well as a variety of others (Feng et al. 1996).

Cytokines are potent proteins in the initiation,propagation and regulation of the inflammatoryprocess. In this regard they are not alone, as thebody synthesizes various types of proteins tomediate these same functions. Among these areprostaglandins and leukotrienes, which will bediscussed in the subsequent sections.

Prostaglandins

Along with cytokines, prostaglandins are amongstthe best-defined mediators of the inflammatoryresponse. Since their discovery in 1931, advancesin their structure, function and physiologicalmechanisms have afforded an increased under-standing of these molecules (Kurzok & Lieb 1931).Independent work by two groups demonstratedarachidonic acid conversion to prostaglandin

E2 via the enzyme cyclooxygenase (Goldblatt1933; Von Euler 1935; van der Pouw et al. 1995).From this finding it was thought that essentialfatty acids served merely as a precursor to pro-staglandin synthesis. This has subsequently beenshown to be only one of the many functions offatty acids, albeit an important one.

There are many ways of inducing prosta-glandin synthesis that appear to be cell specific. In macrophages, prostaglandin E2 (PGE2) andthromboxane A2 (TxA2) are stimulated by the pre-sence of antigen–antibody complexes (Poranovaet al. 1996). Cytokine receptors on mast cells stimulate the synthesis and secretion of PGD2(Murakami et al. 1994). IL-1 and TNF-α stimula-tion of endothelial cells and fibroblasts leads toPGE2 as well as PGI2 production. The productionof prostaglandins is accomplished by the break-down of membrane phospholipids by phos-pholipase A2 with the subsequent formation ofarachidonic acid. Arachidonic acid is then con-verted to PGG2 via cyclooxygenase 1 and 2. PGG2then may be converted into various prostaglandinsby prostaglandin synthase (Fig. 2.2).

Investigations of the role of prostaglandinswithin the inflammatory cascade are extensive.In general, their function has been delineated by their injection into both animal and humansubjects with subsequent monitoring of theireffects. Another area of focus is the role of non-steroidal, anti-inflammatories in the regulation

Membrane phospholipids

ProstaglandinD2

ProstaglandinG2

ProstaglandinF2

ProstaglandinI2

ThromboxaneA2

Arachidonic acid

Prostaglandin G2

Prostaglandin H2

Phospholipase A2

Cyclooxygenase 1 and 2

Cyclooxygenase 1 and 2

Prostaglandin synthasesFig. 2.2 The synthesis ofprostaglandins and thromboxaneA2 from the membranephospholipids, utilizingphospholipase A2,cyclooxygenase andprostaglandin synthase.

of cyclooxygenase function. Throughout thesestudies, one thing has remained clear, the bio-logical responses instigated by the presence ofprostaglandins are wide ranging and varied innature. In an attempt to simplify their function,their actions may be broken down into four general areas of the inflammatory process: fever,pain, oedema and leucocyte regulation.

Fever appears to be a complex neuroendocrineresponse to both infection and inflammation. A variety of proinflammatory mediators appear to serve as a stimulant to fever production. Vari-ous cytokines, which will be discussed in latersections, assist in the stimulation of the ther-moregulatory centre by stimulating both the syn-thesis of the PGE family as well as mediating a direct effect on the thermoregulatory centreitself. Increased levels of PGE2 have been demon-strated in the cerebral spinal fluid of febrile animals. This PGE2 is most probably synthesizedwithin the central nervous system as a result ofbacterial-induced cytokine release. PGE2 appearsto modulate its effect on thermoregulatory centreswithin the hypothalamus; however, the specificreceptor of action remains elusive (Feldberg &Saxena 1971; Milton & Wendlandt 1971). Cyclo-oxygenase inhibitors, specifically cyclooxygenase2 inhibitors, given to human subjects modulatean antipyretic effect, lending further support tothe role of prostaglandins in the induction of afebrile state.

In experimental models, the injection of pro-staglandins in itself does not induce a painfulresponse. However, in the presence of pro-staglandins, particularly PGE2 and PGI2, theresponse to painful stimuli is greatly increased(Ferreira et al. 1978). It is unclear which of thesetwo prostaglandins serves to accentuate thepainful stimuli to the greatest extent or if differ-ent individuals respond to different stimuli inaltered manners. In some experimental studies,PGE2 appears to predominate while in othersPGI2 appears to be the prime mediator of anincrease in the nociceptive response (Mnich et al.1995; Plemons et al. 1996).

Similar to the response seen in pain, the injec-tion of prostaglandins alone does not stimulate

14 epidemiology and pathology

oedema. In states of inflammation, however, anincrease in oedema is seen by the ability of pro-staglandins to dilate the vasculature leading to increased blood supply to traumatized areas(Moncada et al. 1973; Wheeldon & Vardey 1993).In the presence of inflammation, increased vas-cular permeability is present secondary to theaction of many proinflammatory mediators; thisincreased permeability coupled with increasedblood flow stimulates excessive oedema. Experi-mental models also support this finding, as the injection of prostaglandins, specifically PGE2and PGI2, coupled with bradykinin or platelet-aggregating factor (PAF) (powerful stimulants to increased permeability) stimulate oedematousstates (Von Euler 1934).

In an apparent contradiction, the systemicadministration of prostaglandins appears to medi-ate an anti-inflammatory effect (Kunkel et al. 1979;Fantone et al. 1980). Circulating prostaglandins(PGE2 and PGD2) inhibit neutrophils, monocytesand circulating T-lymphocytes. The inhibition of neutrophils is accomplished by inhibition ofactivation as measured by chemotaxis and super-oxide production (Wedmore & Williams 1981).The inhibition of monocytes is mediated via thedecreased production of various proinflamma-tory mediators such as TNF-α (Kunkel et al. 1986).T-lymphocyte inhibition is seen as a decrease inT-cell proliferation, a decrease in released cyto-kines and a decrease in the number of migratingT-cells (Goodwin et al. 1977; Shaw et al. 1988; Betz& Fox 1991; Trinchieri 1995). Through these threemechanisms, systemic prostaglandins appear toinhibit the inflammatory reaction, whereas, asdiscussed previously, the local accumulation of prostaglandins accentuates the inflammatoryresponse.

As one can see, in recent years, the role ofprostaglandins has been greatly elucidated andtheir involvement in the inflammatory reactionhas been well documented. Secondary to theircomplex nature, however, it is highly probablethat their involvement is even more signific-ant than is currently known. Recent advances in understanding the nature of these moleculeshave led to improved pharmacological agents,

pathophysiology of injury 15

such as specific cyclooxygenase inhibitors in anti-inflammatory medications. Despite the success ofthese agents, one thing is clearaprostaglandinsare merely a fraction of the known types of pro-inflammatory mediators that affect the humanbody in the face of pathology.

In addition to mediators such as cytokines and prostaglandins, the body’s immune systemis composed of a highly complex series of cellularand plasma-derived components. The cellularcomponent consists of a variety of cell types,each with a specific function. These cells interactin a well-orchestrated manner to improve theefficiency of the immune response. The cell typesare variable and functions range from stimulat-ing the aggregation of leucocytes to presentingforeign material to the actual destruction andremoval of the offending pathogen. Some of the more important cellular components of theinflammatory process will be outlined in the following pages.

Mast cells and basophils

Several components of the immune system playa critical role in inflammatory reactions. Tissuemast cells and circulating basophils are haemato-poietically derived cells, which express a varietyof surface receptors that allow them to migrate to specific tissue locations, interact with cells and tissues, and respond to activation molecules.Both types of cells contain granules, which serveas storage for histamine, serotonin, cytokinesand proteases. When IgE-sensitized mast cells or basophils are stimulated by either antigens or C3a and C5a (complement anaphylatoxins),the granules are released resulting in the secre-tion of these mediators. These in turn induce areversible cell contraction in the endothelium,leading to the formation of gap junctions (Blacket al. 1972; Arrang et al. 1983). This increases the permeability of the vasculature leading toincreased tissue oedema. Both mast cells as wellas basophils may be induced to release histamineand serotonin by other means, including phys-ical stimuli such as trauma or proteins secretedby activated platelets and neutrophils.

Macrophages

Macrophages are present throughout a variety ofhost tissues (Fig. 2.3). These cells are able to reactto abnormalities such as ischaemia or metabolicdisturbance by initiating an inflammatory reac-tion. When local processes are insufficient andunable to remove the host tissue of the initiat-ing stimuli, macrophages along with other cells can mobilize other forms of leucocytes (poly-morphonuclear neutophils in particular) by the activation of local endothelium and by the pro-duction of a variety of chemokines, cytokinesand other lipid mediators of the inflammatoryreaction (Table 2.2) (Bacon & Schall 1996). If thepathology continues and becomes one of chron-icity, macrophages are able to up-regulate theirmicrobicidal activity (Bell et al. 1994). When con-sidering the role of macrophages in the initiation,propagation and resolution of inflammation, it is important to remember that each macrophagecontains variable receptors on its membrane,allowing it to regulate the biosynthesis and secre-tion of substances in response to stimuli from thehost tissue (Peterson et al. 1987).

As noted previously, macrophages interact witha variety of cells within the human body. Theseinteractions are complex and reciprocal in nature.Non-haemopoietic cells, such as endothelium, aredramatically affected by the secretory productsof the macrophage, and in turn have a profoundeffect on the ever-adapting macrophage itself.

Fig. 2.3 Electron micrograph of a macrophage.

In this way, one can see how the macrophage isan important component in the regulation of theinflammatory process.

Neutrophils

These cells maintain the ability to mobilize fromthe blood to the tissue with subsequent degranula-tion in a matter of seconds. Their major functionin the inflammatory cascade is one of endocytosis(eating) or exocytosis (secreting) (Bainton 1980).In the normal adult human, a polymorphonuclearneutrophil is found in one of three environments:bone marrow, blood or tissues. The bone marrowis the site where proliferation and maturationoccurs. Following the phase of proliferation andmaturation, the neutrophils are released into theblood where they circulate for approximately 10days. They then migrate into the tissues wherethey survive for approximately another 1–2 days.Their ultimate fate after this is unknown (Bainton1980).

Four distinct populations of granules have beenidentified within neutrophils by cytochemicaland cell-fractionation procedures (Borregaard &

16 epidemiology and pathology

Cowland 1997). The azurophil granules con-tain myeloperoxidase (an antibacterial enzyme),lysozyme and lysosomal enzyme, as well as avariety of other agents (Table 2.3) (Klebanoff &Clark 1978). Specific granules by definition do notcontain peroxidase (Cramer & Breton-Gorius 1987;Livesey et al. 1989; Mutasa 1989; Path et al. 1996).These granules contain numerous agents includ-ing lysozyme and lactoferrin (Bretz & Baggiolini1974). Gelatinase granules are subsets of specificgranules, and are therefore peroxidase negative(Borregaard & Cowland 1997). They are namedfor their high content of gelatinase found in theirgranules (Borregaard et al. 1993; Kjelsen et al. 1993;Borregaard & Cowland 1997). Secretory vesiclesare a group of vesicles that are easily mobilized tothe surface; they are remarkable for the presenceof alkaline phosphatase within the membrane aswell as the presence of albumin (Borregarrd et al.1990; Borregaard 1996).

The degranulation of neutrophils is mediatedby the presence of an injury. The azurophil andsecretory granules can be released independ-ently (Williams & Morley 1973; Wright et al.1977; Presentey 1984). However, depending on

Table 2.2 Macrophage-derived secretory products.

CytokinesIL-1 Multiple local and systemic host defence functionsTNF-α Multiple local and systemic host defence functionsIFN-α/β Antiviral, immune modulationIL-6 Acute phase responseIL-10 Inhibits proinflammatory cytokinesTGF-β Inhibits activation of macrophages and other cells

Complement proteinsMost components Local opsonization and complement activationCoagulation factors Initiation and regulation of clot formationAdhesion and matrix molecules Localization and migration

Modulates cellular interactions and phagocytosis

Bioactive lipidsCyclooxygenase, lipoxygenase Mediators of inflammationPlatelet-activating factor

Antimicrobic activitySuperoxide anion Killing and stasis of microbial targetsHydrogen peroxideNitric oxide

pathophysiology of injury 17

the stimuli, concomitant release is required to accentuate the bactericidal effects. There appearsto be a hierarchy in ability to mobilize granules(Borregaard et al. 1993). The hierarchy for mobilization for excretory function appears to besecretory vesicles, gelatinase granules, specificgranules and finally azurophilic granules beingthe least likely to be mobilized (Borregaard 1996).When activated, the specific granules, gelatinasegranules and the secretory vesicles bind to theplasma membrane via cytochrome b558 subunits.Their contents are readily released; however theylack the ability to generate reactive oxygen mole-cules without the contents of the azurophilicgranules, specifically myeloperoxidase (Klebanoff& Clark 1978; Pryzwansky et al. 1979).

The clinical importance of proper neutrophilfunction can be seen in a variety of hereditarydisease states such as acute myelogenous leuk-aemia, congenital dysgranulopoietic neutropeniaor Chediak–Higashi syndrome (Bainton 1975;Bainton et al. 1977). In congenital dysgranulo-poietic neutropenia there is a defective syn-thesis and degradation of azurophilic granules,an absence or marked deficiency of specific

granules and autophagia. Patients with this dis-ease suffer severe life-threatening infections. InChediak–Higashi syndrome, a rare autosomalrecessive disease, there is a presence of abnorm-ally large inclusions within the neutrophil, whichappear to be abnormal azurophilic granules(Davis & Douglas 1971; Ohashi et al. 1992). Thesepatients demonstrate an increased susceptibilityto infection.

Eosinophils

Eosinophils are a type of leucocyte identifi-able by its bilobed nuclei and large eosinophilicgranules. The large granules in the eosinophilcontain peroxidase; however, this peroxidase ischemically different than the peroxidase found inneutrophils (Bujak & Root 1974). Eosinophil per-oxidase appears to have no role in the bactericidalactivity of eosinophils. The granules also containa variety of proteins including major basic pro-tein (MBP), an eosinophil cationic protein, whichdoes appear to be cytotoxic to either parasites ormammalian cells. MBP is also responsible for theinduction of histamine release by basophils and

Table 2.3 Contents of neutrophil granules and vesicles.

Azurophil granule Specific granule Gelatinase granule Secretory vesicle

Cd63 Cd66 Cd11b Alkaline phosphataseCd68 Cd67 Cytochrome b558 Cytochrome b558β-glycerophosphatase Cytochrome b558 Diacylglycerol-deacylating enzyme Cd11bAcid mucopolysaccharide Fibronectin-R Plasminogen activator-R Cd14α1-antitrypsin G-protein subunit Acetyltransferase Cd16α-mannosidase Laminin-R β2-microglobulin Plasminogen activator-RHeparin-binding protein Thrombospondin-R Gelatinase AlbuminBactericidal permeability Plasminogen Lysozyme Tetranectin

increasing protein activator-Rβ-glycerophosphatase Collagenaseβ-glucuronidase GelatinaseCathepsins HistaminaseDefensins HeparanaseElastase LactoferrinLysozyme LysozymeMyeloperoxidase SialidaseProteinase-3 β-microglobulinSialidase TNF-R

TNF, tumour necrosis factor.

mast cells (Peretz et al. 1994). There are fourknown inherited abnormalities of eosinophils.An absence of eosinophil peroxidase, an auto-somal recessive trait, usually results in no clinic-ally detectable symptoms (Wright & Gallin 1979;Pouliot et al. 1997). Chediak–Higashi syndromemanifests with large abnormal granules, seen in the eosinophil as well (Davis & Douglas 1971).A third type of abnormality was found in an individual family. It appears to be inherited in anautosomal recessive fashion. Their eosinophilsdemonstrated large grey inclusion bodies; how-ever, they manifested without any clinical abnor-mality (Tisdale 1997). The fourth abnormality isan absence of specific granules seen in both neu-trophils as well as eosinophils, presenting withrepeated infections (Roos et al. 1996).

Platelets

Platelets, with their lack of a nucleus, may appearto be simple in nature but they serve a pivotalrole in the regulation of haemostasis, thrombosisand inflammation. Platelet formation is accom-plished by the fragmentation of megakaryocytecytoplasm. In the circulatory system, plateletsappear to be passive, smooth discs. However, theymaintain the ability to recognize a site of injury,adhere to this site and serve in the activation andpropagation of thrombus, as well as mediate theinflammatory pathway. Their lifespan is from 7to 10 days and in a healthy individual their countcan range from 150 000 to 440 000/μl. Plateletscontain a circumferential band of microtubules,which serve to maintain the discoid shape, as wellas an abundance of both actin and myosin withinthe platelet. These microtubules are responsiblefor the change in shape and spicule formationseen in platelets following activation.

Platelets are noted to have granules containinghistamine, serotonin and TxA2, amongst otherproteins. It is unclear whether these mediatorsare developed within the megakaryocyte and are transferred to the platelet via the frag-mentation process or whether they are absorbed from the plasma. Regardless, these factors, whenreleased, serve to instigate and propagate many

18 epidemiology and pathology

physiological reactions associated with plateletfunction.

Haemostasis is the culmination of three inter-active systems including vascular endothelium,blood platelets and plasma proteins of both theintrinsic and extrinsic coagulation pathways. Thisprocess serves to arrest the loss of blood fromvessels that have been mechanically traumatized,for example in muscular sprains, strains andfractures. When discontinuity of a vessel occurs, aseries of responses termed primary haemostasisensues. Following trauma, the vessel wall quicklyretracts and platelets immediately adhere to thesubendothelial collagen. Adherence to the vesselwall prompts platelet activation, which leads to propagation of the thrombus. This is con-tinued until occlusion of the traumatized vesseloccurs. The initial adherence is mediated by vonWillebrand factor found in the plasma as well asvon Willebrand factor released from activatedplatelet and endothelial cells. Following adhesionand activation (i.e. granule release), P-selectin, aplatelet granule membrane glycoprotein, trans-locates to the cellular surface (Berman et al. 1986;McEver 1991; Frenette & Wagner 1997). This glycoprotein mediates the adhesion of leucocytessuch as monocytes and neutrophils. Activationof the platelet eicosanoid pathway occurs, lead-ing to the formation of arachidonic acid (Serhanet al. 1996; Sarraf et al. 1997). Arachidonic acid is released where it is immediately converted toPGH2. This is then converted to TxA2, a potentvasoconstrictor (O’Rourke et al. 1997). The activ-ated platelet undergoes a change in shape withthe formation of spicules. This change allowsmore effective binding between platelets as wellas increased binding to factor X and activation offactor VII of the extrinsic coagulation cascade.

The platelet not only serves an important rolein the regulation of the coagulation cascade, but serves as an important source of vasoactivemediators as well. Following vascular injury, act-ivation of the coagulation cascade or exposure tothe basement membrane stimulates platelets torelease a variety of factors. These factors includeserotonin, TxA2 and histamine. Serotonin and his-tamine are generally released from cytoplasmic