Handbook of Mediators in Septic Shock

Edmund A. Neugebauer

• Publisher: CRC Press
• Year: 2019
• Print ISBN: 9781315892023
• eBook ISBN: 9781351088022
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Handbook of Mediators in Septic Shock presents a comprehensive, systematic evaluation of the various putative mediators of septic shock through the use of meta-analysis. Experts of individual mediators have objectively evaluated the collective literature using classical Koch-Dale Criteria for causal relationships. A decision tree approach has been used to analyze the existing evidence for each of the four Koch-Dale Criteria for each individual mediator of septic shock. The book provides an integrated perspective that describes how these many mediators interact. It also covers how advances in mathematical modeling of complex realities are applied to the field of septic shock pathogenesis. CRC Handbook of Mediators in Septic Shock will be a useful reference for emergency room and intensive care physicians, trauma specialists, pathophysiologists, physiologists, biochemists, pharmacologists, and others interested in the topic. Features

Part I.
Toxins

Chapter 1
Endotoxins in Septic Shock

Carolyn S. Cody and David L. Dunn

TABLE OF CONTENTS

I. Introduction

II. Physicochemical Characteristics of Endotoxins

A. Introduction

B. Structure of Endotoxin

1. Effects of Extraction Methods

2. Polysaccharide Regions

3. Lipid-α

III. Biologic Effects of Endotoxins

A. Introduction

B. Cytokine Response

1. Introduction

2. TNF-α

3. Interleukins

C. Effects on Organ Systems

1. Cardiovascular Effects

2. Pulmonary Effects

3. Gastrointestinal Effects

IV. Antibodies Directed Against Endotoxins

A. Introduction

B. Polyclonal Antibodies

1. Serotype-Specific Antibodies

2. Cross-Reactive Antibodies

a. Antibodies Directed Against Common Gram-Negative Bacterial Antigens

b. Antibodies Directed Against Core LPS

c. Antibodies Directed Against Lipid A

C. Monoclonal Antibodies

1. Serotype-Specific Antibodies

2. Cross-Reactive Antibodies

a. In Vitro Evaluation of Cross-Reactivity

b. Protection Studies in Animal Models

c. Protection Studies in Human Subjects

D. Meta-Analysis of the Protective Capacity of Antiendotoxin Antibodies

1. Decision Tree: Test Nodes

a. Is the Study Design Appropriate?

b. Is the Shock Model Clinically Relevant?

c. Are Other Causes of Shock Excluded?

d. Are Antibody Controls Appropriate?

e. Is Antibody Dosage Appropriate?

f. Is Response Caused by Antibody Itself?

2. Decision Tree 2: Test Nodes

a. Has the Antibody Demonstrated Protective Capacity?

b. Are Monoclonal or Polyclonal Antibodies more Protective?

c. Are Serotype-Specific Antibodies more Protective than Anti-Deep-Core/Lipid A Antibodies?

d. Does Antibody Class or Subclass Affect Protective Capacity?

e. Does Whole Cell or Endotoxin Immunization Produce more Protective Antibodies?

f. Does Antibody Reactivity In Vitro Correlate with Protective Capacity?

g. Are Human Antibodies more Protective than Those Made in Other Species?

h. Do Protective Antiendotoxin Antibodies Affect the Activity of Second Mediators?

V. Summary

Acknowledgments

References

I. Introduction

Despite antibiotic therapy, aggressive hemodynamic monitoring, fluid resuscitation, and metabolic support, Gram-negative bacterial sepsis remains a lethal disease in normal and immunocompromised patients. A large body of data has accumulated, providing evidence that the mechanisms which underlie the lethality of this disease are derived from the complex interactions of the host with both the intact organism and Gram-negative bacterial endotoxins. Nearly 100 years ago, Richard Pfeiffer, working with lysates of heat-killed Vibrio cholerae, found that exposure of animals to these lysates resulted in shock and death.¹ He termed the heat-stable component of these cultures endotoxin, and distinguished its effects from those of bacterial exotoxins. Bacterial endotoxins were initially defined by virtue of their pyrogenicity, and were subsequently found to be: (1) unique components of Gram-negative bacteria, (2) ubiquitous among Gram-negative organisms, and (3) localized to the Gram-negative bacterial cell wall.² Extraction procedures first developed by Boivin and Mesrobeanu permitted the characterization of endotoxins as lipopolysaccharide (LPS)-protein-phospholipid complexes. Subsequent preparation of protein-free LPS by Westphal and others, identified LPS as the active component of endotoxin.^{2, 3 and 4} Further chemical studies demonstrated that LPS consisted of a nontoxic polysaccharide portion, some components of which were shared among bacterial genera, and a toxic, highly conserved lipid moiety (lipid A), which has been associated with the majority of the deleterious effects of endotoxin.

LPS exerts diverse physiologic, biochemical, and immunologic effects that act in concert upon host tissues to produce what has been characterized as the “septic state or response” or “sepsis”. Shwartzman documented the localized tissue necrosis that occurs after initial local injection of endotoxin is followed by systemic endotoxemia, and subsequently demonstrated that disseminated intravascular coagulation was a sequela of endotoxemia.^5,6 Other investigators have characterized the host response to endotoxin as consisting of a variety of components that include fever, systemic acidosis, disordered substrate and oxygen utilization, abnormal metabolism, hyperkalemia, hyperglycemia, decreased systemic vascular resistance, elevated cardiac output, and hypotension. It is now apparent that the majority of these responses do not result from the direct effects of endotoxin upon host cells and tissues. Rather, they are the end results of complex interactions of endotoxin with humoral and cellular components of host defenses that culminate in the release of secondary mediators of sepsis. Several groups of investigators have developed experimental models which make it clear that endotoxin initiates and perpetuates the release of cellular mediators that act to further augment host mediator responses and, via excessive mediator secretion, cause target organ damage, organ failure, and death.

The development of antibodies (Abs) against endotoxins has provided a new therapeutic modality with which to intervene in the cascade of events leading to Gram-negative bacterial septic shock and death. Initial studies demonstrated the protective capacity of polyclonal, serotype-specific antiendotoxin Abs during experimental Gram-negative bacterial sepsis. Since that time, polyclonal and monoclonal antiendotoxin Abs with reactivity against conserved LPS saccharide moieties and against lipid A have been developed and tested in experimental models of sepsis and in clinical trials. Major controversies exist regarding the ability of antiendotoxin Abs to exert protective capacity during Gram-negative bacterial sepsis, despite in vitro and in vivo evidence of functional capacity of cross-reactive antiendotoxin Abs that includes: (1) neutralization of endotoxicity, (2) enhancement of bacterial clearance, and (3) abrogation of LPS-stimulated production of secondary mediators of sepsis. The current controversy may be summarized with the following questions:

1. Do clinical studies and experimental models of sepsis clearly demonstrate a reduction in mortality associated with the administration of antiendotoxin Abs?
2. What are the characteristics of antiendotoxin Abs that contribute to protective capacity?

In response to these questions, we will utilize the methodology of meta-analysis to evaluate the ability of antiendotoxin Abs to exert protective capacity and to identify those characteristics that are required to produce protective capacity.

In this chapter, we will first review the structure and biochemistry of endotoxin, with an emphasis upon those portions of the molecule that confer antigenicity and toxicity. Second, we will present an overview of the physiologic and biologic effects of endotoxin at both the systemic and cellular levels. In the third section, we will discuss the development and testing of antiendotoxin Abs, and last will be presented a meta-analysis of the protective capacity of antiendotoxin Abs with an attempt to define characteristics that produce protective capacity.

II. Physicochemical Characteristics of Endotoxins

A. Introduction

Endotoxins (LPS) are a heterogeneous group of macromolecules with an approximate molecular weight of 200,000 that reside in the outer membrane of the cell wall of Gram-negative bacteria. Endotoxin is composed of protein and LPS molecules that are shed from bacteria during active growth and are released in copious amounts when cell lysis occurs. LPS is an integral membrane component composed of three distinct structural regions that include:

1. An outer polysaccharide structure [O-antigen (O-Ag)] that is unique and comprises the major antigenic determinants for each bacterial strain
2. A core polysaccharide that links outer polysaccharide to lipid A and is structurally similar among many bacterial genera
3. Lipid A, the toxic moiety of LPS that is extremely homogeneous among Gram-negative microorganisms.

A series of rough mutant organisms (so-named due to their characteristic colonial morphology) that do not express the O-Ag region on their cell surface due to mutations that produce enzymic deletions has bee...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• PART I: TOXINS
• PART II: BIOGENIC AMINES
• PART III: OLIGO- AND POLYPEPTIDES
• PART IV: PROTEINS
• PART V: FATTY ACID DERIVATIVES
• PART VI: VARIA
• PART VII: FUTURE PERSPECTIVES
• Appendix (Discussion Forum)
• Index