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

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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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2. Assfalg-Machleidt I, Jochum M, Klaubert W, Inthorn D, Machleidt W (1988) Enzymatically active cathepsin Β dissociating from its inhibitor complexes is elevated in blood plasma of patients with septic shock and some malignant tumors. Biol Chem Hoppe Seyler 369 [Suppl]: 263-269

3. Assfalg-Machleidt I, Jochum M, Nast-Kolb D, Siebeck M, Bulling A, Joka T. Rothe G, Valet G, Zauner R, Scheuber HP, Machleidt W (1990) Cathepsin Β —indicator for the release of lysosomal cysteine proteinases in severe trauma and inflammation. Biol Chem Hoppe Seyler 371 [Suppl]: 211-222

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5. Billing Α, Fröhlich D, Kortmann H, Jochum Μ (1989) Die Insuffizienz der inlraabdominellen Infeklabwehr bei eitrigen Peritonitis—Folge einer gestörten Fremdkörperopsonierung. Klin Wochenschr 67:349-356

6. Billing Α, Fröhlich D, Assfalg-Machleidt I, Machleidt W, Jochum Μ (1991) Proteolysis of defensive proteins in peritonitis exudate: pathobiochemical aspects and therapeutical approach. Biomed Biochim Acta 50:399-402

7. Kominami E , Tsukahara T, Bando Y, Katunuma Ν (1985) Distribution of cathepsins Β and Η in rat tissues and peripheral blood cells. J Biochem 98:87-93

8. Howie AJ, Burnett D, Crocker J (1985) The distribution of cathepsin Β in human tissues. J Pathol 145:307-314