Inflammatory cytokines in obstructive jaundice Citation for published version (APA): Bemelmans, M. H. A. (1994). Inflammatory cytokines in obstructive jaundice. Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.19940527mb Document status and date: Published: 01/01/1994 DOI: 10.26481/dis.19940527mb Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 11 Oct. 2021 INFLAMMATORY CYTOKINES IN OBSTRUCTIVE JAUNDICE UM 37rr>!iaTra«o ra OTY-J YHOTAMMAJT/I INFLAMMATORY CYTOKINES IN OBSTRUCTIVE JAUNDICE PROEFSCHRIFT ^ ^-,!ii!>V-.' M ! 4 ter verkrijging van de graad van doctor aan de Rijksuniversiteit Limburg te Maastricht, op gezag van de Rector Magnificus, Prof. dr. H. Philipsen, volgens het besluit van het College van Dekanen, in het openbaar te verdedigen op vrijdag, 27 mei 1994 om 16.00 uur door Marcus Henricus Adrianus Bemelmans geboren op 7 februari 1964 te Maastricht UPM UNIVERSITAIRE PERS MAASTRICHT Promotores Prof. dr. D.J. Gouma Prof. dr. P.B. Soeters Co-promotor Dr. W.A. Buurman ? ;tf S?«O /it ^ Beoordelingscommissie Prof. dr. R.W. Stockbrtigger (voorzitter) Prof. dr. L.A. Aarden (Vrije Universiteit) Prof. dr. P.W. de Leeuw Prof. dr. F.C.S. Ramaekers Prof. dr. G.N.J. Tytgat (Universiteit van Amsterdam) Prof. dr. E.F.M. Wouters O M.H.A. Bemelmans. Maastricht 1994 CIP-DATA KONINKLIJKE BIBLIOTHEEK, DEN HAAG Bemelmans, Marcus Henricus Adrianus Inflammatory cytokines in obstructive jaundice / Marcus Henricus Adrianus Bemelmans. - Maastricht: Universitaire Pen Maastricht. - III. Thesis Maastricht. - With ref. - With summary in Dutch. ISBN 9O-5278-I37-O Subject headings: jaundice / cytokines Layout: Karin Scheele. A Point. Maastricht Production: Datawyse. Maastricht / Krips Repro Meppel /« memory 0/ m>- iro/A^r To my CONTENTS CHAPTER 1. Preface S Introduction: 1. Inflammation 2. Inflammatory aspects 2.1 Inflammatory aspects of gastro-intestinal diseases 2.2 Inflammatory aspects of obstructive jaundice 3. Cytokines 4. Interleukin-6 5. Tumor Necrosis Factor 6. Soluble TNF Receptors 7. Cytokines 7.1 Cytokines in gastrointestinal diseases 7.2 Cytokines in obstructive jaundice 8. Aim of the thesis CHAPTER 2. Introduction to and discussion of the experimental work 19 References to chapters 1 and 2 27 CHAPTER 3. Cytokines TNF and IL-6 in biliary obstruction in mice 39 CHAPTER 4. The effect of anti-TNF treatment on circulating Tumor Necrosis Factor and mortality after surgery in jaundiced mice 51 CHAPTER 5. Increased levels of TNF and soluble TNF receptors in biliary obstruction in mice; prognostic importance of sTNFR-P55 and sTNFR-P75 but not of TNF for mortality after surgery 61 CHAPTER 6. Influence of nephrectomy on Tumor Necrosis Factor clearance in a murine model 77 CHAPTER 7. Tissue distribution and clearance of soluble murine TNF receptors in mice 95 CHAPTER 8. LPS induced sTNF-Receptor release in vivo in a murine model: investigation of the role of TNF, IL-1, LIF, and IFN-y CHAPTER 9. Evidence that T-cell activation by anti-CD3 induces soluble TNF Receptor release in a murine model: effect of pentoxifylline, methylprednisolone, anti- TNF, and anti-IFNy 127 CHAPTER 10. Increased plasma levels of soluble Tumor Necrosis Factor receptors in sepsis syndrome: correlation with plasma creatinine 143 CHAPTER 11. Summary / Samenvatting 155 Dunkwoord 165 Publications 169 -i/ ! :)iU: !•:- i ,-.•)' Curriculum Vitae 171 Chapter 1 PREFACE AND INTRODUCTION PREFACE Surgical procedures are generally associated with local and more general inflammtfOiy changes as a response to the surgical trauma ( 1 ). These inflammatory changes revet] a good correlation with the septic complications after surgical procedures. Especially the septic complications are responsible for the high morbidity and mortality after surgery (2). Thus far, monitoring and detection of inflammation was of great importan- ce for the surgeon to prevent these septic complications. Moreover, more knowledge of the pathophysiology which is underlying the complications associated with inflam- mation after surgery could lead to a better understanding and eventually to a more successful prevention of such complications. To assess the presence of inflammation, surgeons for a long time had only the posses- sion over the classical hallmarks of inflammation such as "dolor, rubor, calor, tumor, and functio laesa". In the early days of modern surgery, sedimentation rate of crythro- cytes (ESR), and leucocyte count and differentiation rate became available for monitor- ing inflammation which was followed more recently by the recognition of acute phase proteins (APP). The levels of the APP were upregulated in response to trauma, inflammation, burns, and sepsis and their increases are related to the magnitude of the trigger (3,4). Nevertheless, the earliest increase in APP is observed approximately 6 hours after the initial event (CRP, SAA) with peak levels after 24-48 hours. Other acute phase proteins are much slower and the first response is observed after 24-48 hours (a-acid glycoprotein, C3, C4) (5). Because of this late increase, these measure- ments added limited extra information to the clinical view of the surgeon. Moreover, they were of little value for a better understanding of the pathophysiology of the inflammatory response. In the mid-1960s, several biological markers derived from lymphocytes were dis- covered in biological fluids which regulate growth and function of a variety of leuko- cytes. In the past decades it became evident that these regulatory proteins were member of a large family of proteins that regulate various immune mechanisms, which were called cytokines. A definition for cytokines was proposed by Balkwell and Burge in 1989: "Cytokine is one term for a group of protein cell regulators, variously called lymphokines, monokines, interleukins, and interferons, which are produced by a wide variety of cells in the body, play an important role in many physiological responses, are involved in the pathophysiology of a range of diseases, and have therapeutic potential" (6). Cytokines were suggested to play an important role in inflammatory processes, for example during surgery. It was hypothesized that during surgery a selective hypo- perfusion of the bowel was present, leading to a local ischemia. The local ischemia lead to a damage of the mucosal integrity and eventually to activation of the immune system and subsequent cytokine release. At this moment many cytokines are known: Intcrlcukin-1 (IL-1) till IL-13, interferons, growth inhibitory/stimulatory cytokines and chemotactic cytokines (7-12). Although their functional properties are as yet far from being elucidated, it is clear that cytokines are very powerful and specific proteins. They exert their action by binding to specific high affinity receptors and can already be active at picomolar concentrations. The cytokines IL-1, IL-6 and Tumor Necrosis Factor (TNF), also called inflammatory cytokines, have been shown to play an impor- tant role in septic shock (13,14). In line with this observation, antibodies against these cytokines or receptor antagonists have been shown to protect experimental animals against a lethal endotoxic shock, supposedly because of inactivation of TNF (15-19). An interesting phenomenon is the observation that several cytokine receptors, which arc present on cell membranes, can be liberated in inflammatory situations and circu- late thereafter in soluble form (20). They can bind to cytokines in the circulation and inactivate the proteins. The latter property was supported by data which showed that injection of soluble TNF receptors protected against a lethal endotoxic shock in mice, supposedly because of inactivation of TNF (21). However, they can also prolong the presence of their ligands in the circulation by stabilization of the complex (22). Knowledge of such cytokines and cytokine receptors could give more insight