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Ε. Faist J. L . Meakins F. W. Schildberg (Eds.)
Host Defense Dysfunction in Trauma, Shock and Sepsis Mechanisms and Therapeutic Approaches
With 416 Figures and 153 Tables
Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest
Table of Contents
Section 1
General Aspects/Perspectives
Progress in Trauma Care T h r o u g h Understanding the Cell Biology of in jury ( A . E . B a u e ) 3
Trauma, Sepsis and i m m u n e Defects (J. A. Mann ick ) 15
Cl inical Factors Influencing Host Defense Integri ty (J. L . Meakins) 23
The Intensive Care U n i t of T o m o r r o w ( H . J. Dieterich, Κ. Peter) 31
Section 2
Host Defense Integrity—Response and Stress
H o w the Immune System Discriminates Infectious Nonself from Noninfectious Self (C. A. Janeway Jr.) 39
Signal Transduct ion Mechanisms: Pathophysiologic Alterat ions ( Μ . M . Sayeed) 49
Neuroendocrine Regulat ion of Immune Func t ion (J. W. Holaday, J. R. Kenner , P. F. Smith, H . U . Bryant , E. W. Bernton) 59
VIII Contents
Beneficial Effects of Stress Response Blockade on Patients Undergoing Surgery (H . Kehlet) 67
The Impact of Preexisting Disease Condi t ions for Host Defense In tegr i ty i n Traumatized and Cri t ica l ly 111 Patients (Ν. V . Chris tou, J. M . Tellado) 73
Section 3
From Injury to Multiple Organ Failure: Sequential Steps of Host Defense Impairment
3.1 Shock and Ischemia
Oxygen Radical-Mediated Endothel ial Cell In jury (G. O. T i l l , P. A. Ward) 85
Characteristics of Neu t roph i l Dysfunction (G. F. Babcock, C. L . Whi te -Owen, J. W. Alexander, G . D . W a r d e n ) . . . 95
Endothelial Dysfunction as an Early Cri t ica l Event in Ischemia and Shock (A. M . Lefer, X . M a ) 107
Role of Oxidants, Proinf lammatory Agents, and Granulocytes in the Post Ischemic Intestine (P. Kubes, D . N . Granger) 113
Hepatic Parenchymal and Nonparenchymal Cells in Hemorrhage and Ischemia ( M . G. Clemens) 127
Acute L u n g In ju ry F o l l o w i n g Shock and M a j o r T rauma (G. Schlag, Η . Redl) 139
Hemorrhage-Induced Alterat ions in Cel l -Mediated I m m u n e Funct ion ( I . H . Chaudry, A. Ayala, D . M e l d r u m , W . Ertel) 149
3.2 Intermediate Inflammatory Phase
Sepsis and M u l t i p l e Organ Failure: The Result of Whole Body Inf lammation (R. J. Goris) 161
Contents IX
Mul t ip l e Organ Fai lure ( M O F ) , and Whole Body Inf lammat ion After M u l t i p l e T r a u m a (G. Regel, Η . C. Pape, F. K o o p m a n n , J. A. Sturm) 171
Neutrophi ls , Cytokines, Oxygen Radicals, and L u n g In ju ry (P. A. Ward , M . S. M u l l i g a n , J. S. Warren) 177
The Role of ß 2 - Leukocyte Integrins I n V i v o (S. R. Sharar, Ν . B. Vedder, W . J. Mi lesk i , C. L . Rice, J. M . Har lan , R. K . Winn ) 181
The Angry Macrophage and Its Impact on Host Response Mechanisms (R. V. Maier ) 191
Eicosanoids, Cytokines and Altered Metabol ic C o n t r o l in the Evo lu t ion of the Posttraumatic Host Defense Failure Syndromes (Adul t Respiratory Distress Syndrome and M u l t i p l e Organ Failure Syndrome) (J. H . Siegel) 199
Diagnostic Role of N e w Media tors and Markers of In f lammat ion i n Mul t i p l e Injured Patients (D. Nas t -Ko lb , Ch. Waydhas, M . Jochum, M . Spannagl, W . Machleidt , Κ Η . Duswald , L . Schweiberer) 221
Intravascular Ac t iva t ion of Polymorphonuclear Neut rophi l s i n Cr i t ica l ly 111 Anergic Patients (J. M . Tellado, Ν . V . Chris tou) 229
Mediators of Remote L u n g In jury ( Τ Lindsay, J. H i l l , C. R. Valerie, D . Shepro, Η . B. Hechtman) 235
3.3 Sepsis
Inmuno log ic Dyshomeostasis in M u l t i p l e Organ Failure: T i e Gut -L ive r Axis ( J . C Marshal l ) 243
T i m o r Necrosis Factor and Other Cytokines as Media tors of Clinical Sepsis (S F. L o w r y ) 253
T ie Protein C System in Septic Shock ((F. B. Taylor ) 263
X Contents
Leukocyte-Endothel ia l Interact ions i n T rauma and Sepsis ( H . Redl, G . Schlag, Η . P. Dinges, R. Kneidinger, J. Davies) 277
Role of Oxygen Radicals in M u l t i p l e Organ Failure ( H . P. Fr iedl , O. Trentz , G . O . T i l l , P. A. Ward) 287
Arachidonic Ac id M e t a b o l i s m i n Endotoxemia and Sepsis: Therapeutic Approaches (J. A. Cook , E. L i , P. V . Halushka) 297
Section 4
Immune Mechanisms for the Control of Infection Under Physiologic and Stressful Conditions
Biology and Func t ion o f C y t o t o x i c T-Cells (R. C Bleackley) 311
Immune Response o f Heat Shock Proteins (S. Η. E. Kaufmann) 317
Prostaglandins Media te the Expression o f a 72-kDa Heat Shock Protein i n H u m a n Fibroblas ts (A. E. Heufelder, Β. Ε. Wenzel , R. S. Bahn) 323
Glucocor t i co id - Immune System Interact ions in Injury and Sepsis (S. E. Calvano) 331
Hemorrhagic Shock Inh ib i t s Myelopoies is Independent of Bacterial Trans loca t ion ( D . H . Liv ings ton , J. Hseih, T . M u r p h y , B. F. Rush Jr.) 339
Monocyte H L A - D R Ant igen Expression: Its Reproducibi l i ty in Asymptomat ic Volunteers and Cor re la t ion wi th Cl in ica l Infection (W. G. Cheadle, M . J. Hershman, S. R. Wellhausen, Η. C Polk Jr.). . . . 349
Phenotypic and Func t iona l Characteristics of Peripheral B lood Lymphocytes in a Defined G r o u p o f Poly t rauma Patients (G. C. Spagnoli, M . Heberer, P. Vogelbach, R. Rosso, J. J ö r g e n s e n , F. Harder) 355
Cell-Mediated I m m u n i t y D u r i n g and After Cardiopulmonary Bypass (A. Paccagnella, S. DeAnge l i , M . M o r d a c c h i n i , G. Caenaro, A . Nie r i , P. Rosi, P. M i c h i l o n , M . Calo , G . Zanardo , L . Salvador, C. Fur lan, G. Simini) 359
Contents XI
Altera t ions in Funct ion and Phenotype of Monocy tes f rom Patients w i t h Septic Disease: Predictive Value and N e w Therapeut ic Strategies ( H . D . V o l k , Μ . Thieme, U . Ruppe, S. H e y m , W - D . Docke , D . Manger, S. Zuckermann , A. Golosubow, B. Nieter , Η . K l u g , R. van Baehr) . . . . 365
Effects o f Exercise on the Immune System w i t h Special Reference to N a t u r a l K i l l e r Cells (Β . K . Pedersen) 373
In terac t ion of Immune, Interferon, and O p i o i d Systems in Professional Athletes (E. Gotovtseva, I . Surkina, P. Uchakin , J. Shchur in , S. Pschenichkin, N . Kost , A. Zozulya, O. I lyinsky) 379
Section 5
Inflammatory Mechanisms in Traumatic and Septic Injury
Whi te Cells in Burn Patients (D . N . Herndon , T. C. Rutan, J. M l a k a r , D . F leming) 385
Fibronect in Degradation: A n In V i t r o M o d e l o f N e u t r o p h i l Mediated Endothel ia l Cell Damage ( K . D . Forsyth) 391
Adenosine Inhibi ts Postischemic Leukocyte Adherence to the Endothe l ium of Postcapillary Venules via A 2 -Recep to r ( D . Nol te , H . A. Lehr, Κ. Messmer) 399
Prostaglandin E t Inhibits the S t imula t ion of Neu t roph i l s I n V i t r o and I n V i v o and Improves Cardio-Respiratory Funct ions in M u l t i p l y Traumat ized Patients at Risk of A d u l t Respiratory Distress Syndrome (A. Dwenger, M . L . Ner i ich , E. Jonas, G . Schweitzer, J. A . Sturm, H . Tscherne) 403
Product ion and .Characterization of Peptide-Spechic M o n o c l o n a l Antibodies that Recognize a Neoepitope o n H o g C5a ( U . H ö p k e n , Α. S t rüber , Μ. Oppermann, Μ . M o h r , Κ . Η . M ü c k e , Η. Burchardi , Ο . Gö tze ) 411
The Oxidat ive Burst Reaction of Neu t roph i l s is Reduced by the Acute Phase Serum Amylo id -Α Protein (R. P. L inke , V. Bock, G. Valet, G. Rothe) 419
XII Contents
Interact ion of Pentoxifylline and Adenosine i n the I n h i b i t i o n o f Superoxide A n i o n Product ion of H u m a n Polymorphonuclear Leukocytes ( M . Thiel , Η . Bardenheur, C. Madler , K . Peter) 423
Adhesive Interactions of Neutrophi ls w i t h Endothel ial Cells (C. W . Smith, O. Abbassi, S. B. Shappell, D . C. Anderson, L . V. M c l n t i r e , Τ. K . Kish imoto) 431
Endothelial Cell S t imula t ion by A n t i - C D 9 Antibodies (K. D . Forsyth) 437
Decrease in Leukotriene Synthesis from Leukocytes Isolated in Septic Patients ( H . Lessire, B. M i l e , M . Pfisterer, Τ. Ν . Nguyen, Ε. Torwesten, C Puchstein, Β. M . Peskar) 443
Aggravation o f Ischemia-Reperfusion Injury in the Striated Muscle Microc i rcu la t ion by Acute Endotoxemia ( H . A. Lehr, Κ. Kawasaki , Τ. J. Galla , D . Nol te , K . Messmer) 449
Selective I n h i b i t i o n of Polymorphonuclear Leukocyte Oxidat ive Burst and C D l l b / C D 1 6 Expression by Prostaglandin E 2 (J. A. Lieberman, F. M . W a l d m a n , J. K . Horn ) 453
The Role of Lysosomal Cysteine Proteinases as Markers of Macrophage Ac t iva t ion and as Nonspecific Mediators of In f l ammat ion (W. Machleidt , I . Assfalg-Machleidt, A. Bi l l ing , D . F r ö h l i c h , Μ . Jochum, Τ. Joka, D . Nas t -Koib ) 459
Endothel in Mediates a C a 2 + Ac t iva t ion Signal in H u m a n Monocytes ( M . Hur iba i , D . S. Margol is , M . A. M c M i l l e n ) 465
N i t r i c Oxide Synthesis in Sponge M a t r i x Allografts Coincides w i t h the In i t i a t ion of the Allogeneic Response (J. M . Langrehr, J. Stadler, Τ. R. Bil l iar , W. H . Schraut, R. L . Simmons, R. A. Hoffman) 471
Neut roph i l Elastase Induces L u n g In jury Fo l lowing Lower L i m b Ischemia (R. Welbourn , G . Go ldman , D . Shepro, Η. B. Hechtman) 477
P M N Elastase i n Local Infection ( Κ M . Peters, K . Koberg , H . Kehren, Κ. W . Zilkens) 481
Contents XIII
Opioids from I m m u n e Cells Interact w i t h Receptors on Sensory Nerves to Inh ib i t Nocicept ion in In f lammat ion (C. Stein, A. H . S. Hassan, R. Przewlocki, C. Epplen, C. Gramsch, K . Peter, A. Herz) 485
Section 6
Hepatocellular Injury in Ischemia, Trauma and Sepsis
A n I n V i t r o M o d e l of Hepatic Failure in Septic Shock (T. H ä r t u n g , Α. Wendel) 493
Ischemia-Reperfusion In jury of the Liver: Role of Neut rophi ls and Xanthine Oxidase ( M . D . Menger, M . J. Mül le r , Η . P. Friedl , O. Trentz, K . Messmer). . . . 499
N i t r i c Oxide Regulates Prostaglandin E 2 Release by Rat Kupffer Cells (J. Stadler, Β. G . Harbrecht , Μ . D i Silvio, R. D . Cur ran , M . L . Jordan, R. L . Simmons, Τ . R. Bil l iar) 505
C3a and C5a i n Liver Transplantations D u r i n g Bypass, Reperfusion and the Postoperative Phase ( M . Ha r tmann , L . Verner) 511
Effect of Superoxide Dismutase on Altered Hepatic Calc ium Regulation D u r i n g Gramnegative Sepsis (S. Rose, J. D ike , V . B ü h r e n , O. Trentz, Μ . M . Sayeed) 517
Role of Liver Macrophages (Kupffer Cells) i n Bacterial Cell Wal l - Induced Hepatic In f lammat ion (T. Kossmann, C. Manthey, J. B. Allen, C. Morgant i -Kossmann, K . Ohura, S. E. Mergenhagen, S. M . Wahl) 523
T u m o r Necrosis Factor A l p h a Inhibi ts Hepatocyte M i t o c h o n d r i a l Respiration and Induces Release of Cytoplasmic Enzymes (J. Stadler, Β. G . Bentz, J. M . Langrehr, R. D . Curran , T. R. Bi l l iar , B. G . Harbrecht , R. L . Simmons) 527
M o d u l a t i o n of Hepatic M i t o c h o n d r i a l Fat Ox ida t ion and Hepatic Gene Transcr ip t ion by T u m o r Necrosis Factor (R. A. Barke, P. S. Brady, L . J. Brady) 531
XIV Contents
Increased Leukocyte Adhesion in Liver Sinusoids F o l l o w i n g Superior Mesenteric Ar tery Occlusion in the Rat (V. Bühren , Β . Maier , R. Hower , Μ . D . Menger, I . Marz i ) 539
Section 7
Cytokines and Modulation of Cytokine Action
Gene K n o c k o u t : New Approach to the Physiology of Cytokines (F. F. Csaikl , IJ . N . Csaikl , S. K . D u r u m ) 547
The Role of Inter leukin-1 and Other Macrophage-Derived Cytokines in Macrophage-T-Cell Interactions ( L . S. Davis, P. E. Lipsky) 5 5 7
Inter leukin-1-Induced Hypotension and the Effect of an Inter leukin-1 Receptor Antagonist (C. A. Dinare l lo) 5 7 1
Interleukin-8 (Neu t roph i l -Ac t iva t ing Peptide-1) and Related Chemotactic Cytokines ( M . Baggiolini) 5 7 7
Cellular and Molecu la r Mechanisms that Regulate the Produc t ion of Interleukin-8: The Potential Role of Chemotactic Cytokines in Acute Respiratory Distress Syndrome and M u l t i p l e Organ Failure (S. L . K u n k e l , S. W . Chensue, T. J. Standiford. R. M . Strieter) 583
Generat ion and Properties of Neu t roph i l -Ac t iva t ing Peptide 2 (NAP-2) (A. Walz, F. M e l o n i , R. Zwahlen, I . Clark-Lewis , B. Car) 593
Soluble and Ce l l Surface Receptors for T u m o r Necrosis Factor ( H . Engelmann, D . Aderka, Y . Nophar , O. Kemper , C. Brakebusch, Η . H o l t m a n n , D . Wallach) 5 9 9
Regulat ion o f C y t o k i n e Synthesis T h r o u g h Cyclic Nucleotides (S. Endres, H . J. Fü l le , Β. Sinha, D . Stoll , R. Gerzer) 609
Removal of C i r cu l a t ing Cytokines by Hemodialysis Membranes I n V i t r o ( G . Lonnemanm, R. Schindler, C. A. Dinare l lo , Κ. M . K o c h ) 613
M o d u l a t i o n o f M o n o k i n e Product ion I n V i t r o by H u m a n Intravenous
I m m u n o g l o b u l i n (J. P. Anderssan, S. Nagy, U . G. Andersson) 625
Contents XV
Trans forming G r o w t h Factor ß \ Upregulates the Inter leukin-2 Receptor α Promoter (C. S. Cocanour, F. M . Orson, D . Thomas, S. Rich) 6 2 9
Section 8
Cytokines in Acute Phase States and Trauma
Interact ions of Immunopa tho log ica l Mediators (Tumor Necrosis F a c t o r - α , - / i , Prostaglandin E 2 ) i n Traumatized Individuals (C. L . Mi l le r -Graz iano , G . Szabo, K . Kodys, B. Mehta) 637
I n V i t r o Product ion and Secretion of Interleukin-1 by H u m a n Monocytes After Surgical T rauma ( M . L . V u o t t o , E. Bresciano, D . Manc ino , Μ . T. Ielpo, M . R. Mos t i , G . De M a r t i n o , A. Barbarisi) 6 5 1
The Biological Characteristics of Cytokines and Their Interactions w i t h Prostaglandins F o l l o w i n g Hemorrhagic Shock (W. Ertel , E. Faist, I . H . Chaudry) 655
The Response of Inter leukin-1 and Inter leukin-6 i n Patients Undergoing M a j o r Surgery (R. J. Baigrie, P. M . Lamont , M . J. Da l lman , P. J. Mor r i s ) 665
Possible Role of Cytokines in the Stress Response of the Hypo tha lamo-P i tu i t a ry -Adrena l Axis D u r i n g Upper A b d o m i n a l Surgery (Y. N a i t o , S. Tamai , K . Shingu, K . Shindo, T. Shichino. T. Matsu i , O. Ebisui , J. Fukata, K . Yone, K . M o r i ) 673
The Synthesis of Stress Proteins i n Cul tured Cardiac Myocytes Is Induced by the Interleukins and T u m o r Necrosis Factor ( I . L ö w - F r i e d r i c h , D . Weisensee, P. M i t r o u , W . Schoeppe) 677
Effects o f T u m o r Necrosis Factor on the Hypotha lamic-P i tu i t a ry-Adrena l Axis ( K . Mea ly , B. G . Robinson, J. A . Majzoub, D . W . Wi lmore ) . 681
In te r leukin-2-Modula ted Cy tok ine Secretion in Thermal ly Injured Patients (J. Teodorczyk-Injeyan, B. Sparkes, W. Peters) 687
XVI Contents
Cytokine Treatment of Radiat ion-Induced Hemopoiet ic Suppression: Results of Inter leukin-6 and Granulocyte Colony-St imula t ing Factor in a M u r i n e Radia t ion M o d e l ( M . L . Patchen, T. J. Mac Vi t t ie , Β. D . Solberg, R. Fischer, L . M . Souza) 693
Circula t ing T u m o r Necrosis Factor i n Active Inf lammatory Bowel Disease (K . R. Gardiner, Μ . I . Hal l iday, F. L l o y d , S. Stephens, B. J. Rowlands) . 699
Interleukin-1 and T u m o r Necrosis F a c t o r - α Suppress Hypoxia- Induced Product ion of Ery thropoie t in I n V i t r o ( M . Wolff, W . Jelkmann, J. Fandrey) 705
Neopterin, Interferon-?, and Immunodeficiency States (D . Fuchs, Α. Hausen, G . Reibnegger, G . Weiss, E. R. Werner. G. Werner-Felmayer, H . W ä c h t e r ) 715
Systemic Cytokine Response to Strenuous Exercise ( H . Northoff , Μ . W. Baumstark, W. Α. Flegel, A. Berg) 719
Section 9
The Mediator Role of T N F in Sepsis
Act iva t ion of Neutrophi ls by T u m o r Necrosis F a c t o r - α D u r i n g Sepsis (G. Rothe, W. Kel lermann, J. Briegel, B. Schaerer, G . Valet) 727
Dist inct Subpopulations of H u m a n Peripheral B lood Monocytes Characterized by Absence of the C D 14 Surface M a r k e r , and Distinguished by H i g h or L o w Intracellular Glu ta th ione (R. L . Rabin, F. J. Staal, M . Roederer, M . M . Beiber, L . A. Herzenberg, Ν . Η . Teng) 737
The Role of Endotoxins in Burns: Anomalies in Cy tok ine Regulat ion of I m m u n i t y (R. A. Winchurch , D . Z h o u , A. M . Munster) 743
Role of T u m o r Necrosis Factor on Pseudomonas Aeruginosa Infect ion and on A n t i t u m o r A c t i v i t y i n Relation to Arachidonic Cascade ( N . Satomi, A. Sakurai, R. Haranaka, K . Haranaka) 751
Contents XVII
Survival f rom Cecal L iga t ion and Puncture and the F o r m a t i o n of Fibrous Adhesions in the Peritoneal Cavi ty Depend on Endogenous T u m o r Necrosis Factor (B. Echtenacher, W . Falk, D . N . M ä n n e l , P. H . Krammer ) 755
The Cellular Mechanisms of T u m o r Necrosis Factor-Induced M o r t a l i t y : A Possible Role for Platelet Act iva t ing Factor and/or the Eicosanoids (J. M . Moore , M . Hubbard , M . Earnest, P. Wi l l iams, A . DiSimone, N . Abumrad , J. R. Fletcher) 759
Section 10
Endotoxin—Mechanisms of Action and Protection from Shock
Molecular Mechanisms of Lipopolysaccharide-Induced Cytokine Product ion by Monocytes (R. R. Schumann, J. C. Math i son , P. S. Tobias, R. J. Ulevi tch) 767
Na tu ra l Endotoxic Shock Protect ion by Soluble C D 1 4 (C. Schutt, C. K r ü g e r , W . Schönfe ld , U . Grunwa ld , T. Schilling) 773
Use of M o n o p h o s p h o r y l L i p i d A as a Prohylactic for Sepsis and Shock (J. A. Rudbach, J. T . U l r i c h , Κ. Β. von Eschen, D . Beatty) 779
Hemodynamic and Pulmonary Response to Treatment w i th On-L ine Adsorp t ion on Po lymyx in Β D u r i n g Endotoxemia in Pigs (B. Stri t tmatter , W . Schneider, K . Massarrat, A. Eckhardt , Β. U . von Specht) 783
Apo l ipopro te in A - I Enriched L ipopro te in Attenuates T u m o r Necrosis Factor Product ion and Shock in an Anesthetized Rabbit Endotoxemia M o d e l (Α. P. H ü b s c h , J. E. D o r a n , P. G . Lerch, G . Hodler , J. J. Morgenthaler , H . -J. Heiniger) 789
Escherichia Co//-Induced Septic Shock in the Baboon: A n A n i m a l M o d e l for the Evalua t ion of Neutral is ing M o n o c l o n a l Antibodies to Phospholipase A 2 (R. Buchta, J-A, Green, G . M . Smith, C. Gabelish, D . Cairns, C. Salom, M . Conte, P. Mackie , R. Sublett, F. B. Taylor , I . A . Rajkovic, Κ F. Scott) 792
XVIII Contents
Leukotriene I n h i b i t o r and Antagonist Prevent Endo tox in Lethal i ty i n Carrageenan-Pretreated Mice (O. Masanor i , K . Masayuki , Y. Shin-Ichi , M . Yasuo, A. Shigematsu). . . 799
Effect of Type-Specific Ant iserum on the Pulmonary Hypertensive Response to G r o u p Β Streptococcus i n Piglets (J. B. Philips, M . Chwe, J. X . L i , Β. M . Gray, D . G. Pr i tchard, J. R. Oliver , K . Gran tham, W . Mena) 803
Detect ion of I g E Reactive w i t h Lipopolysaccharide in Plasma of Traumat ica l ly Injured Patients (J. T. D i Piro, R. G . H a m i l t o n , T. R. Howdieshell , D . Callaway, N . F. Adkinson) 807
Altered Guanine Nucleotide Protein Funct ion: Potential Role in Endo tox in Tolerance ( K . Coffee, P. V. Halushka, W . C Wise, J. A. Cook) 811
Section 11
Clinical Aspects of Multiple Organ Failure
The Pattern of Organ Failure F o l l o w i n g Severe T r a u m a — A Postmortem Study ( H . C. Pape, G . Regel, Kleemann, J. A. Sturm, H . Tscherne) 823
Hyper tonic Volume Therapy: A Feasible Regimen to Cont r ibute to the Prevention of M u l t i p l e Organ Failure? ( U . Kreimeier, L . Frey, A. Pacheco, K . Messmer) 831
A New Sepsis Scale for Burns: Corre la t ion w i t h Endo tox in and Host Response (A. M . Munster , Μ . Meek, R. A. Winchurch , C. Dickerson) 843
M u l t i p l e Organ Failure: Cl inical Characteristics of G u t - O r i g i n Septic States (J. R. Border) 851
Intraperi toneal Infections and M u l t i p l e Organ Failure (T. Hau) 857
The Role o f Empi r ica l Laparo tomy i n the Management of Sepsis and Mul t i sys tem Organ Failure ( H . C. Polk, P. Burgess, W . G . Cheadle) 863
Contents ΧΪΧ
Management of the W o u n d as Therapy for M u l t i p l e Organ Failure ( L . F l in t ) 867
Aggressive Enteral N u t r i t i o n Reduces Sepsis i n the Hypercatabolic In jured Patient (Ε. E. M o o r e , F. A. Moore ) 871
Cl in ica l -Media to r Correlat ions of M u l t i p l e Organ Failure and Preventive/Therapeutic Strategies: T o Block Stimulate, or Replace? Tha t is the Question (A. E. Baue) . 881
Section 12
The Pathophysiologic Impact of Bacterial Translocation and Strategies for Its Prevention
Bacterial Translocation F o l l o w i n g M a j o r Thermal Injury in Rats, Sheep, and Mini -P igs ( D . N . Herndon, S. T. Zeigler, T. C. Rutan, R. Saydjari, S. E. M o r r i s , G . I . Beerthuizen, R. Tokyay , C. M . Townsend) 893
Does Early Portal Bacteremia/Endotoxemia Prime for Postinjury M u l t i p l e Organ Failure? (F. A. Moore , Ε. E. Moore , R. S. Poggetti, O. J. McAnena) 899
Prevention of Bacterial Translocat ion w i t h Early Enteral Feeding—A Feasible Approach? (J. W. Alexander) 903
Gut -Der ived Infectious-Toxic Shock Syndrome: Therapeutic Chances w i t h Polyspecific Immunoglobu l ins ( H . Cottier, A. Häss ig , R. Kraf t ) 911
Maintenance of Gastrointest inal In tegr i ty After Burn In jury w i t h Specific Dietary Supplementation and Epidermal G r o w t h Factor (R. L . Zapata-Sirvent, J. F. Hansbrough, M . C. Cox, P. W o l f ) 917
Selective Decontaminat ion of the Digestive Tract: Open Questions and Controversies (L . L . Dever, W. G . Johanson Jr.) 925
XX Contents
Selective Decontamina t ion o f the Digestive Tract (SDD): Review of Available Cl in ica l Studies (C. P. Stoutenbeek, Η . K . van Saene) 931
Nonselective G u t Decontaminat ion for Avoidance of Bacterial Translocat ion i n Shock (J. Brand, A. Ekkernkamp. A. Helbig , G . M u h r ) 939
Section 13
Antibiotic Interactions with Host Defenses
Antibiot ics and Phagocytic Cell Func t ion : A Cri t ical Review (P. van der Auwera, M . Bonnet, M . Husson, F. Jacobs) 945
Interaction of Ant ib io t ics w i t h the Phagocyte Oxidat ive Burst (Μ. T. Labro , J. El Benno) 953
Intraphagocytic Cell Penetration and Intracellular Bioact iv i ty of Ant ibiot ics (A. Pascual) 965
Extraphagocytic K i l l i n g of Bacteria i n the Presence o f Ant ib io t ics (P. J. van den Broek) 971
Cell W a l l Inh ib i tors and Bacterial Susceptibility to Phagocytosis (A. M . Cuffini , N . A. Carlone, V. T u l l i o , G . Cavallo) 979
Protein Synthesis Inh ib i tors and Bacterial Susceptibility to Phagocytosis (C. G. Gemmell) 987
Section 14
The Role of Nutrition in Host Defense
Augmenta t ion of Host Defense Reactivity w i th Special Nutr ients (J. W. Alexander) 995
The Role of Structured Lip ids in Host Defense Interactions (R. A. Forse, G. L . Blackburn , B. R. Bistr ian) 1003
Contents XXI
M a n i p u l a t i o n of Cytokine Synthesis T h r o u g h Dietary Lipids (S. Endres, S. N . Meydani , C. A. Dinare l lo ) 1013
Die tary Fish O i l Prevents Postischemic Leukocyte /Endothel ium Interact ion T h r o u g h Inh ib i t i on of Leukotr iene Biosynthesis ( H . A. Lehr, D . Nol te , C. H ü b n e r , Κ. Messmer) 1017
Die tary Requirement for Preformed Purine and Pyr imidine Bases for Intact Funct ion of Cellular Immune Response: A Review (L . G . Kabbash, A. R. Forse) 1023
Relationship of Plasma Acute-Phase Prote in to A m i n o Ac id Levels D u r i n g High-Dose Branched Chain A m i n o Acid Support in Sepsis (C. Chiarla , I . Giovannin i , J. H . Siegel, Μ . Castagneto) 1029
Section 15
New Insights into the Mechanisms of Wound Healing
W o u n d Management and the Stress Response (D. N . Herndon, R. L . Rutan, T. G Rutan , J. M . M l a k a r ) 1037
The Role of the W o u n d in Posttraumatic Immune Dysfunction ( M . C. Regan, A. Barbul) 1043
The Role of G r o w t h Factors in the Regulat ion of W o u n d Repair ( D . R. K n i g h t o n , V. D . Fiegel, G. D . Phil l ips) 1051
A n Adverse W o u n d Environment Reduces Leukocyte Phagocytosis and Protein Synthesis (B. R. Moelieken, S. J. Mathes, A. Amerhauser, D . C. Price, Τ. Κ Hunt ) 1065
Basic Fibroblast G r o w t h Factor Inh ib i t s the Release of Oxygen Radicals by H u m a n Granulocytes (W. Macheiner, C. O i smül le r , W. Pohl , Μ . Micksche) 1079
The Influence of Liver Regeneration o n Skin W o u n d Heal ing and Lymphocyte G r o w t h Features ( N . Zarkovic , I . Stipancic, M . Hrzenjak, Z . I l ic , S. Kis , I . Vuckovic , M . Jurin) 1085
X X I I Contents
Section 16
Therapeutic Immunomodulatory Approaches: Prevention
Therapy of Secondary T-Cel l Immunodeficiencies w i t h Biological Substances and Drugs: A n Update (J. W . Hadden, Ε. M . Hadden) 1097
Progress in Antiinfective Perioperative I m m u n o m o d u l a t o r y Therapy w i t h Simultaneous Admin i s t r a t ion of Blocking and Enhancing Agents (E. Faist, A. Markewi tz , S. Endres, D . Fuchs, L . H ü h n e r , S. Lang) . . . 1109
Effect of I m m u n o m o d u l a t i o n of Skin Test Reactivity F o l l o w i n g Trauma (W. Browder, D . Wil l iams, G . Ol ivero , P. M a o , A. Franchello, F. Enrichens) 1131
Therapeutic Use of Cytokines: A n i m a l Models ( M . L . Rodr ick, Ν . Μ . Moss, D . Β. Gough , P. G . Horgan , Β. M . Crowley, M . G O 'Riorda in , R. G . M o l l o y , J. A. Mann ick ) 1135
The Rationale for Gamma-Interferon Admin is t ra t ion in T r a u m a Patients ( H . C. Polk, Jr., S. Galandiuk , G Sonnenfled, W. G . Cheadle) 1145
Immunomodula to r s of the Thermal In jury Response (J. M . Mlaka r , J. P. Waymack) 1153
Section 17
Endotoxin Neutralization with IV-Immunoglobulins and Monoclonal Antiendotoxin Antibodies
Antiendotoxic Therapy wi th Polyclonal and Polyvalent Immunoglobul ins : I n V i t r o and I n V i v o Studies ( D . Berger, S. Schleich, Μ . Seidelmann, Η . G . Beger) 1163
The Use of Polyvalent I m m u n o g l o b u l i n G in Patients w i t h Sepsis and M u l t i p l e Organ Failure (G. Pilz, Κ. Werdan) 1175
Cl in ica l Effects of I m m u n o g l o b u l i n Admin i s t r a t ion in Patients w i t h M a j o r Burn Injury (A. M . Munster) 1187
Contents X X I I I
Treatment of Gram-Negat ive Septic Toxic Diseases w i t h an I m m u n o g l o b u l i n Preparat ion Conta in ing I g G , I g M , and IgA: A Prospective Randomized Cl in ica l T r i a l ( I . Schedel, U . Dreikhausen, B. Nentwig , M . H ö c k e n s c h n e i d e r , D . Rauthmann, S. Bal ikc ioglu , R. Coldewey, Η . Deicher) 1193
Immunotherapeut ic Strategies for Passive Immuniza t ion Against Pseudomonas aeruginosa (L . Saravolatz, J. K i l b o r n , J. Pennington) 1205
Bind ing Characteristics of the Ant iendotox in A n t i b o d y Xomen-E5 to Bacterial Whole-Cel l Antigens (K . J. Gorel ick, D . M . W o o d , J. B. Parent, E. L i m , Κ. D . Knebel , D . Μ . Fishwi ld , D . T. Reardan, P. W . T r o w n , P. J. Conlon) 1211
Immunotherapy w i t h H u m a n Ant iendo tox in Antibodies in the Treatment of Gram-Negat ive Sepsis: Practical Considerations (C. H . Worte!) 1219
The Use of A n t i b o d y Specificity and Affini ty i n Determining the Protectiveness o f H u m a n M o n o c l o n a l Antibodies Against Fatal infections w i t h Nosocomia l Gram-Negat ive Bacteria ( U . Bruderer, A. B. Lang, B. By l , A. Crusiaux, J. Deviere) 1223
Section 18
Interventional Strategies in the Therapy of Septic Shock
Potential Benefits of Platelet Ac t iva t ing Factor Receptor Antagonists in Endotoxemia/Sepsis (J. R. Fletcher, J. A. M o o r e , A. G . DiSimone, N . Abumerad, P. Wi l l i ams , J. Pol lard , J. Coll ins , E. Graves) 1229
Phospholipase A 2 : A New Target for M o n o c l o n a l A n t i b o d y Therapy in Sepsis (K . F. Scott, G . M . Smith , J. A. Green, C. Salom, C. Gabelish, D . Cairns, A. Tseng, P. Mackie , R. Buchta, R. Lee, I . A. Rajkovic) . . . 1237
Admin i s t r a t ion of Antiadhesion Molecules: A Feasible Approach? (R. K . W i n n , S. R. Sharar, W . J. Mi lesk i , C. L . Rice, J. M . Har lan) . . . 1243
Local Admin i s t r a t i on o f Inter leukin-2 Protects Mice from Lethal In t r a -Abdomina l Bacterial Sepsis (R. Richards, D . R. Green) 1251
X X I V Contents
M u r i n e In t raabdomina l Abscess: Immune M o d u l a t i o n w i t h Interferon-y (S. Galandiuk, S. Appel , J. D . Pietsch, W . G . Cheadle, H . C. Polk, Jr.) . 1257
Acute Resuscitation and An t iox idan t Therapy (Β. E. Hedlund. P. E. Hal laway) 1263
Cl inical Indications for the Admin i s t r a t i on of Oxygen Radical Scavengers (J. H i l l , T. Lindsay, C. R. Valer i , D . Shepro, Η . B. Hechtman) 1271
First Experiences w i t h Recombinant H u m a n Superoxide Dismutase Therapy in Polytraumatized Patients ( I . M a r z i , V . B ü h r e n , Α. Schü t t l e r , Ο . Trentz) 1279
Subject Index 1285
The Role of Lysosomal Cysteine Proteinases as Markers of Macrophage Activation and as Nonspecific Mediators of Inflammation
W . M a c h l e i d t 1 , I . Assfalg-Machleidt 1 , A. B i l l i n g 2 , D . F r ö h l i c h 2 , Μ . Jochum 3 , Τ. J o k a 4 , and D . N a s t - K o l b 5
Introduction
A major p o r t i o n of the lysosomal proteinases responsible for intracellular degradat ion of phagocytized proteins are cysteine proteinases, the "acid" cath-epsins Β, H , L , and S (see [ 1 ] for review). As we have shown previously [ 2 , 3 ] , increased cysteine proteinase act ivi ty is found in b lood plasma of polyt rauma-tized and septic patients as well as i n local inf lammatory secretions such as bronchoalveolar lavage fluid and peri tonit is exudate. M o s t of this act ivi ty is due to cathepsin B, which is relatively stable at neutral p H (half-life about 30 m i n at p H 7.4) and is protected in the fo rm of reversible complexes w i th its en-dogenenous protein inhibi tors (stefins, cystatins, and kininogens). Here we report some evidence for the role of cathepsin Β as a marker of macrophage ac t iva t ion and of lysosomal cysteine proteinases as potential nonspecific mediators of inf lammat ion.
Materials and Methods
Cysteine proteinase act ivi ty and complexed polymorphonuclear ( P M N ) elastase were determined by f luorometric assay and enzyme-linked immunosorbent assay as described [2 , 3 ] . The organizat ion of cl inical studies and sampling protocols were reported i n detail elsewhere [4 , 5 ] . Proteolysis of fluorescein isothiocyanate I g G (Sigma) by human cathepsin Β (Medor , Herrsching, F R G ) and peri toni t is exudate was performed as described [ 6 ] .
1 Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie der Universität München, Geothestraße 33, 8000 Munich 2, F R G
2 Chirurgische Klinik und Poliklinik der Universität München, Klinikum Großhadern, 3 Abteilung für Klinische Chemie und Klinische Biochemie, Chirurgische Klinik Innenstadt der
Universität München, 4 Chirurgische Universitätskliniken, 4300 Essen, F R G 5 Chirurgische Klinik Innenstadt der Universität München.
Host Defense Dysfunction in Trauma, Shock and Sepsis Eds. Faist/Meakins/Schildberg r Springer-Verlag, Berlin Heidelberg 1993
460 W. Machleidt et al.
Results and Discussion
Cathepsin Β as Marker of Macrophage Activation. P M N granulocytes contain only minute amounts of cathepsin Β (1.5 ng /10 6 cells), whereas high levels of cathepsin B, L , and Η have been found in monocytes, macrophages, and other cells of the reticuloendothelial system [3 , 7, 8 ] . Therefore cathepsin Β may be considered as a marker for the activi ty of the monocyte/macrophage system. This hypothesis was supported by different patterns of release of cathepsin Β and P M N elastase dur ing inf lammat ion in patients.
Cathepsin Β of b lood plasma after major t rauma reaches its m a x i m u m at least 6 h earlier than complexed P M N elastase (Fig. 1). This early cathepsin Β activi ty of b lood plasma proved to be a sensitive and specific parameter for the predict ion of subsequent mul t ip le organ failure (Nas t -Ko lb et al., this volume). I n al l groups of patients, cathepsin Β activity returned to only slightly elevated levels w i t h i n 3 days after the trauma. Early cathepsin Β act ivi ty does not discriminate between lethal and reversible organ failure. A nearly constant elastase/cathepsin Β rat io around 300 was observed dur ing the first 3 days in all patients, followed by a slow decrease in the groups wi th reversible organ failure and wi thou t organ complications. I n patients developing lethal organ failure the elastase/cathepsin Β ratio increased to 500-600 and remained high after the 3rd day (Fig. 2).
As determined wi th cell lysates, an elastase/cathepsin Β rat io of 3000-6000 wou ld be expected i f bo th enzymes were released from P M N granulocytes [ 3 ] .
10
8
"55 Ε
6 Ο c φ i n
4 V) «0
LU
2
0 0 6 12 18 2 4 30 36 4 2 4 8
Time after accident [h]
Fig. 1. Cathepsin Β activity ( · ) and complexed PMN elastase ( Δ ) of blood plasma in the early phase after major trauma. Both enzymes were expressed as multiples of their normal values (50 mU/I for cathepsin B, 90 ng/ml for PMN elastase). Mean values ± S E M of 29 patients without organ complications ( ) and 29 patients with reversible multiple organ failure ( )
The Role of Lysosomal Cysteine Proteinases as Markers of Macrophage Activation 461
600
0 2 4 6 8 10 12 14
Day
Fig. 2. Elastase/cathepsin Β ratio in blood plasma of patients after severe multiple injury. Mean values ± S E M for 29 patients without organ complications (Ο), 29 patients with reversible multiple organ failure (A), and 11 patients with lethal multiple organ failure ( • )
0 2000 4000 6000 8000 10000
Elastase/Cathepsin Β
Fig. 3. Elastase/cathepsin Β ratio in peritonitis exudates {n = 166). Cumulative percentage of samples as a function of increasing elastase/cathepsin Β ratio. Shaded area, range of elastase/cathepsin Β ratios found within lysates of PMN granulocytes from healthy persons
This rat io was indeed found i n a few peritonitis exudates containing high
numbers of neutrophils (Fig. 3). I n the major i ty of samples, however, much
lower elastase/cathepsin Β ratios were observed, support ing the or ig in of
cathepsin Β from cells other than neutrophils. Elastase/cathepsin Β ratios close
462 W. Machleidt et al.
ο
04
miiHiliMtiiHilmii
iiiiimliiiiiiiiiliiiii
IgG (Control)
i l i i M j M
IgG + Cathepsin Β (2 %, w/w)
1 IgG + Exudate
i
Λ lllllllllllll
II η π 11
IgG + Exudate + E-64 (25 μ,Μ)
1
l l M l l l i l ^ ^
Time ( m i n ) 120 0 Time ( m i n ) 120
Fig. 4. Degradation of immunoglobulin G (IgG) by isolated human cathepsin Β and by E-64 sensitive proteinase activity in peritonitis exudate. Fast gel chromatography of fluorescein isothio-cyanate labeled IgG and its fragments on a Superose 12 column
to 1 were found in bronchoalveolar lavage f luid conta ining a large number o f alveolar macrophages.
Cysteine Proteinases as Nonspecific Mediators of Inflammation. Direct evidence for a role of cysteine proteinases in proteolyt ic pathomechanisms of inf lammat ion comes from studies wi th peri tonit is exudates. Peritonitis exudates reveal strong proteolyt ic act ivi ty which is paralleled by deficient opsonic capacity and high levels of the lysosomal proteinases P M N elastase and cathepsin Β [ 6 ] . Using fluorescence-labeled protein, degradation of I g G by cell-free supernatant of peritonitis exudate was demonstrated in v i t ro (Fig. 4). Part of this degradat ion can be prevented by addi t ion of E-64, a specific inact ivator of cysteine proteinases, indicat ing that lysosomal cysteine proteinases are involved. Catalytic amounts of isolated human cathepsin Β (see Fig . 4) and L are able to Proteolyse I g G in v i t ro effectively.
Conclusions
Cathepsin Β seems to be a useful marker for the act ivi ty o f phagocytes of the monocyte/macrophage system that can be fol lowed easily i n b lood plasma and inflammatory secretions of patients. The observed very early release of cathepsin Β after blunt major injury raises new questions about the role of macrophages in the reaction sequence of the inf lammatory process.
The Role of Lysosomal Cysteine Proteinases as Markers of Macrophage Activation 463
Cysteine proteinases of monocytes/macrophages may play a role as nonspecific mediators of inf lammat ion comparable to that of the serine proteinases elastase and cathepsin G from P M N granulocytes.
Acknowledgements. We wish to thank Prof. Hans Fritz, Munich, for stimulating discussion and generous support. The expert technical assistance of Mrs. Gerda Behrens and Mrs. Rita Zauner is greatly appreciated. The investigations were supported by the Sonderforschungsbereich 207 of the University of Munich.
References
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