Table Of ContentCell
Biology
of
Trauma
Editedby
John J. Lemasters, M.D., Ph.D.
Professor of Cell Biology and Anatomy
University of North Carolina at Chapel Hill
Constance Oliver, Ph.D.
Biomedical Science and Technology
Office of Naval Research
Arlington, Virginia
CRC Press
BocaRaton London Tokyo
LibraryofCongress Cataloging-in-Publication Data
Cellbiology oftrauma/editedbyJohnJ. Lemasters andConstance
Oliver.
p. cm.
Includesbibliographicalreferences andindex.
ISBN0-8493-2453-X
1. Traumatic shock. 2. Pathology, Molecular. I. Lemasters,John
J. II. Oliver, Constance.
RB150.S5C45 1995
617.2' l-dc20 94-30688
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PREFACE
The response of a multicellularorganism to traumaisremarkably complex
— virtually all the systems ofthe bodyrespondto anassaultagainstits physical
integrity. Traditionaltraumaresearchhas attemptedto bothcharacterizethose
systemic responses and identify the pathologic mediators invoked, and to
developpharmacologicinterventionsthatsuppress unfavorable responses and/or
promote favorable ones. The research reported in this volume represents an
other approach to trauma biology: a look at trauma’s consequences at the
molecular level in order to intervene at the cellular level. This approach has
been made possible by the recent explosion ofourknowledge regarding how
cells respond to their environment from the membrane to the gene, and the
evolution of elegant new tools to examine cellularresponses atthe molecular
level.Realizationofthe potentialofcell biologyfordirectingtraumaresearch
ers to new therapeutic targets formed the basis for a program initiated by the
OfficeofNavalResearchin 1988entitled“Cell BiologyofTrauma.”Many of
the investigations described in this book began under that program, and they
formedthe nucleus for a workshop ofthe same nameatthe University ofNorth
Carolinaat ChapelHill onJune 18-20,1993, organizedby Dr. JohnJ. Lemasters
ofthe University and Dr. Constance Oliver of the Office ofNaval Research.
This volume is an outgrowth of that workshop.
A recurrent theme in trauma, ranging from cold injury to hemorrhage, is
ischemia resulting from impaired blood flow. Obviously, the organs most
affected by ischemia are those that demand the most oxygen and substrate to
function. These organsare the heart, brain,andkidneyandtheyare particularly
vulnerableto impairment ofvascularflow. Manyofthelethalconsequencesof
trauma, especially in hemorrhage, can be traced to organ failure secondary to
ischemic injury.
Ischemic injury at the cellular level can be considered to consist of three
phases: (1) the assault on the cell caused by the initial sudden deprivation of
oxygen and nutrients, (2) the cellular adaptation to hypoxia in the absence of
exogenous nutrientsor removal ofwaste products,and(3)the cellularresponse
to the reintroduction ofoxygen and exogenous nutrients (reperfusion). While
considerable research has addressed the consequences of reperfusion, with a
focus on the toxic consequences ofexcess calcium ion uptake and membrane
damageby freeradicals, little attention hasbeenpaid to the molecularevents,
particularly the adaptive events, occurring in the first two phases. Those
molecular events, together with the development of therapeutic agents that
corrector exploit thoseevents,comprisethe focusofthisbook. Cytoprotective
agents discussed here consist of drugs of the 21-amino steroid family, the
prostaglandin polymer Calciphor, glycine, and modified perfusion/resuscita
tionfluids capable ofpreventingcytotoxicpHchanges. Thelatterwork points
to a need to critically reassess the role ofcellular acidosis and the therapeutic
procedures used to compensate for it in emergency medicine.
As ourawareness ofmechanisms forcellularregulationexpands, sodo the
potentialtherapeutictargetsin trauma. Itshouldalways be remembered that an
organ fails because its cells fail. Sorting out the intrinsic cellular processes
leadingto cell death from thoseimposed by systemicmediatorsand inflamma
tion will not be simple, but treatments that focus on the cell’s symptoms and
responses are likely to be broadly applicable in trauma medicine.
Jeannine A. Majde, Ph.D.
Program Manager, Biomedical Science and Technology
Office of Naval Research
THE EDITORS
JohnJ. Lemasters,M.D., Ph.D.,isProfessorofCellBiology andAnatomy
and Member of the Curriculum in Toxicology at the University of North
Carolina at Chapel Hill. Dr. Lemasters graduated in 1969 from Yale Univer
sity, New Haven, Connecticut, with a B.A. degree in psychology (cum laude
with honors) and obtained his M.D. degree and Ph.D. degree in anatomy and
cell biology in 1975 from the Johns Hopkins University School ofMedicine,
Baltimore, Maryland.
Dr. Lemasters is a member of the American Association for the Advance
ment ofScience, the American Association fortheStudy ofLiverDiseases, the
AmericanAssociationofAnatomists,the AmericanHeartAssociation, Coun
cil on Circulation, the American Physiological Society, the American Society
forBiochemistry andMolecularBiology, the Biophysical Society, the Ameri
can Society for Cell Biology, the Microscopy Society of America, and the
Society of Toxicology.
Dr. Lemasters serves on the editorial boards of the American Journal of
Physiology: CellPhysiology, Cell Calcium, and Hepatology. He has been the
recipient of many research grants from the National Institutes of Health, the
National Science Foundation, the AmericanHeartAssociation, andthe Office
ofNaval Research.
Dr. Lemastersis the author ofover200 papersand has previouslyeditedtwo
books. His current major research interests relate to ischemia/reperfusion
injury and organ preservation for transplantation surgery.
Constance Oliver, Ph.D., is a Program Officer in the Biomedical Science
and Technology Program at the Office ofNaval Research (ONR), Arlington,
Virginia. Prior to joining ONR she was a Research Biologist at the National
Institute ofDentalResearch, the NationalInstitutesofHealth, Bethesda,Mary
land. She received her B.A. degree from Northwestern University, Evanston,
Illinois, her M.S. from the University ofUtah, Salt Lake City, Utah, and her
Ph.D. from the University ofTexas at Austin, Austin, Texas.
Dr. Oliverhas overtwenty years of experience in the field of cell biology.
Her research has focused on structure-function relationships in the secretory
pathway in exocrine acinarcellsandinmastcellsJ She has examinedpackaging
ofsecretory proteins and formation ofsecretory granules, membrane traffick
ing and signaltransductionmechanisms in thesecells. Currently,Dr. Oliver is
managing researchprograms in Biomedical Science and Technology. She has
publishedextensively and hasmadenumerouspresentations at local, national,
and international conferences, workshops, and symposia based on her own
research. In addition, she has editedseveral booksand conferenceproceedings
and served on the editorial board of The Journal ofHistochemistry and Cy
tochemistry.
Dr. Oliver is a member of the American Society for Cell Biology, the
Histochemical Society, the Microscopy Society of America, the American
Association for the Advancement of Science, the Association for Women in
Science, andthe Chesapeake Society ofElectronMicroscopy. Inaddition, she
waselected to membershipin Sigma Xi, an honorary academic society, named
an Outstanding Young Woman ofAmerica, 1977, andreceived a Gold Medal
from Tokyo Dental College, 1984.
CONTRIBUTORS
Daniel Acosta, Jr., Ph.D. John D. Chen, M.D.
College ofPharmacy Department ofDermatology
University ofTexas Northwestern University School of
Austin, Texas Medicine
Chicago, Illinois
Sigrid Bachmann, Ph.D.
Department of Surgery
Free University ofBerlin John A. Cidlowski, Ph.D.
Germany Department ofPhysiology
University ofNorth Carolina at
John M. Bond, D.V.M., Ph.D. Chapel Hill
Department of Cell Biology & Chapel Hill, North Carolina
Anatomy
University of North Carolina at
Henry D. Connor, Ph.D.
Chapel Hill
Department ofPharmacology
Chapel Hill, North Carolina
University ofNorth Carolina at
Chapel Hill
Charles W. Broge, B.S.
Department ofPharmacology and Chapel Hill, North Carolina
Cell Biophysics
University of Cincinnati College of
Robert T. Currin, B.S.
Medicine Department of Cell Biology &
Cincinnati, Ohio Anatomy
School ofMedicine
Steven F. Bronk, B.S.
University ofNorth Carolina at
Department of Internal Medicine
Chapel Hill
Mayo Medical School
Chapel Hill, North Carolina
Rochester, Minnesota
Wayne E. Cascio, M.D.
Carla da Mouta, B.S.
Department ofMedicine Transplantation Laboratory
University ofNorth Carolina at American Red Cross
Chapel Hill Jerome Holland Laboratory
Chapel Hill, North Carolina
Rockville, Maryland
Enrique Chacon, Ph.D.
Department of Cell Biology & Dipak K. Das, Ph.D.
Anatomy Department of Surgery
University ofNorth Carolina at University of Connecticut School of
Chapel Hill Medicine
Chapel Hill, North Carolina Farmington, Connecticut
