Eicosanoids in Invertebrate Signal Transduction Systems

by David W. Stanley

Overview

This volume generates a new paradigm for researching and understanding the biological meaning of eicosanoids. Eicosanoid is a general term for oxygenated metabolites of certain polyunsaturated fatty acids. The compounds are extremely important in human biology, in which they are well understood. Their importance to humans, however, has tended to overshadow their broader biological significance. David Stanley seeks to change that in this book, providing a general sketch of the medical background on eicosanoids and then developing a detailed critical treatment of eicosanoid actions in invertebrates and some lower vertebrates.

Stanley looks at the role of eicosanoids in, for example, invertebrate reproduction, immunity, and ion transport physiology. As he explains, eicosanoids also mediate important ecological interactions, particularly host-parasite interactions. Drawing on these physiological and ecological actions, the book develops a "biological paradigm," under which we understand that eicosanoids probably exert important actions in most, if not all, animals. Because eicosanoids mediate crucial events in the lives of animals, they are endowed with unusual explanatory power. Research designed to increase our understanding of eicosanoids has thus yielded and will continue to yield important new information about animal biology. In addition to representing a major advance in our understanding of eicosanoids in animals, this book serves as an unusually comprehensive and accessible introduction to eicosanoid research in general.

Originally published in 1999.

The Princeton Legacy Library uses the latest print-on-demand technology to again make available previously out-of-print books from the distinguished backlist of Princeton University Press. These editions preserve the original texts of these important books while presenting them in durable paperback and hardcover editions. The goal of the Princeton Legacy Library is to vastly increase access to the rich scholarly heritage found in the thousands of books published by Princeton University Press since its founding in 1905.

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ISBN-13:	9781400865055
Publisher:	Princeton University Press
Publication date:	07/14/2014
Series:	Princeton Legacy Library , #86
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Eicosanoids in Invertebrate Signal Transduction Systems

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By David W. Stanley

PRINCETON UNIVERSITY PRESS

Copyright © 2000 Princeton University Press
All rights reserved.
ISBN: 978-0-691-00660-4

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CHAPTER 1

Introduction: A Theory of the Biological Significance of Eicosanoids

Eicosanoid is the most general term for all biologically active, oxygenated metabolites of three C20 polyunsaturated fatty acids, namely 20:3n-6, 20:4n-6, and 20:5n-3. The term was originally coined by Corey et al. (1980) based on the Greek root for twenty. The nomenclature and structures of these acids and their eicosanoid products are detailed in chapters 2 and 3. There are three main groups of eicosanoids: the prostaglandins, the epoxyeicosatrienoic acids, and the lipoxygenase products, including leukotrienes and an array of other compounds. Most of us are probably familiar with prostaglandins because they mediate some reactions associated with injury and discomfort. For example, the swelling and inflammation associated with minor injuries are mediated by certain prostaglandins. Aspirin and other analgesics used to relieve these symptoms function by inhibiting prostaglandin biosynthesis.

With a view to introducing the goal of this book, let us begin with a few background points. First, the study of eicosanoids is deeply rooted in mammalian systems. Second, eicosanoids offer powerful insights and are very important clinical tools in human and animal medicine. Third, due to their importance to humans, the literature on eicosanoids in mammalian systems dwarfs the corresponding literature on invertebrates. What follows from these points is a human, or perhaps mammalian-centered, understanding of the significance of eicosanoids. The purpose of this volume is to suggest another, far wider theory on the biological significance of eicosanoids, anticipated in the early reviews of Stanley-Samuelson (1987, 1991). Stanley and Howard (1998) called this theory the "biological paradigm" of eicosanoids.

Under this model, we recognize that eicosanoids were drawn into various roles as signal transduction moieties very early in cellular life. As cellular life forms evolved into more complex metazoan animals, the individual cells involved already had considerable experience in the use of eicosanoids as modulators of events. Coordination and communication among cells in metazoan life, of course, is far more complicated than in unicellular life, and eicosanoids were available for recruitment into new biological roles. The numbers and types of roles continued to increase throughout all stages of animal evolution. Under the biological paradigm, we look beyond the well-established picture of eicosanoids in mammalian systems to appreciate the many and quite varied eicosanoid actions in all animals. The lengthy history of animal evolution created many opportunities for selecting new, sometimes very subtle, eicosanoid actions. Because eicosanoids were recruited into many biological roles, we also recognize the explanatory power of these compounds. By "explanatory power," we convey the idea that new information on eicosanoids will provide important insights into biological systems.

Appreciating the biological paradigm of eicosanoids effectively turns the traditional, mammalian-centered approach to physiological and related research inside-out. We can imagine a dichotomy. In a traditional approach to physiology, people study a system, with an interest in discovering which molecules are responsible for regulating events within the system. On the other side of the dichotomy, the biological paradigm offers an alternative approach. Instead of discovering eicosanoid actions through detailed research into specific physiological and pathophysiological phenomena, we can gain tremendous new insights into animal processes from research aimed at discovering and understanding eicosanoid actions. For an example, in chapter 5 we will review work designed to reveal eicosanoid actions in invertebrate immunity. This work yielded the first insights into some of the biochemical events that operate between bacterial infections and cellular reactions to the infections in insects. Let us view the biological paradigm through the lens of a brief history of our understanding of eicosanoids.

Serious students of the history of science typically approach their scholarship through one of three routes. One is the sociology of scientific knowledge, which tries to understand the social structures and processes within the scientific community. A second focuses on the cultural meaning of science within local cultures, and a third approach is concerned with the intellectual content of science within a historical context. The history of any area of science is necessarily a complex matrix. This is especially true for scientific discovery in the twentieth century, during which more than 90 percent of all the world's scientists have lived out their careers. We might believe, as practitioners of science, that a history of any area of science would be treated best by scientists. For a number of good reasons, scientists often are not the best historians of science, and a sophisticated, scholarly history of eicosanoids probably should be left to the specialized training and perspectives of historians.

The purpose of this brief history is less ambitious than professional historical research. Instead, my goal is to provide a perspective on the biological paradigm and a context for comprehending the state of our knowledge of eicosanoids in invertebrates. Inquiry into the biologic roles, biochemistry, and chemistry of eicosanoids is less than seventy years old, and the modern phases are much younger. The study of eicosanoids began with investigations in human reproduction, and only secondarily and much later expanded to embrace invertebrates. And we will see that the first work on invertebrates had more to do with eicosanoids in humans than with zoological inquiry.

We generally place the original investigations of eicosanoids in the early 1930s. Although they were not so named, prostaglandins were the first group of eicosanoids recorded in the scientific literature. The discovery process began with physiological observations. In their work on human reproductive physiology, Kurzrok and Lieb (1930) found a certain pharmacological activity in human seminal fluids. This paper probably marks the beginning of our appreciation of the clinical significance of prostaglandins. Kurzrok and Lieb were interested in the biochemistry of semen, and they developed an assay for the influence of semen on the smooth muscle of human uteri. They found that semen stimulated uterine smooth muscle contractions. Soon after this first paper, Goldblatt (1933) postulated a substance in semen responsible for causing smooth muscle contractions. In his 1936 paper, von Euler extended these findings, noting that something in the semen from humans and a few other mammals stimulates smooth muscle (he used the term "plain muscle") contractions and vasodilation. Von Euler also gave us the term "prostaglandin", because the substances were associated with the prostate gland. Based on the acidic taste of semen, von Euler thought the pharmacological substances were probably organic acids.

An earlier paper by Jappelli and Scafa (1906) foreshadowed the pharmacological actions of compounds from the prostate gland. These individuals created aqueous extracts of canine prostates, then injected the extracts into dogs and rabbits. The extracts caused respiratory paralysis and altered heartbeat rates, in some cases killing the experimental animals. The authors concluded that the prostate produces materials of powerful pharmacological actions. These materials are various eicosanoids.

These early studies, suggesting that prostaglandins were something to be reckoned with, are of greater historical than strictly scientific interest. Advances into the biological meaning of prostaglandins had to await a chemical breakthrough, which would not emerge until the early 1960s. Swedish chemist Bengt Samuelsson suggested this would be a suitable problem for his student, Sune Bergstrom. In 1962, some thirty years after the first clinical study, they reported the chemical structures of three prostaglandins, PGE, PGF1, and PGF2 (Bergstrom et al. 1962). They also inferred from the structures that prostaglandins must be biosynthesized by oxygenation of C20 polyunsaturated fatty acids. These findings stimulated increased interest in prostaglandins and helped accelerate research.

While not to be taken in a strictly linear sequence, because a great deal of effort intervened, another major stimulation of research into prostaglandins came from the work of a British pharmacologist, Robert Vane. In a now-classic, and relatively simple, series of experiments, Vane demonstrated that the conversion of 20:4n-6 into prostaglandins by in vitro enzyme preparations was inhibited in a dose-dependent way by the common analgesic, aspirin. Aspirin is a potent pharmaceutical product. Many symptoms of illness and injury, including fever, inflammation, swelling, and pain, are attenuated or completely relieved by aspirin. Vane's demonstration that prostaglandin biosynthesis is inhibited by aspirin laid bare the suggestion that prostaglandins exert a wide range of pathophysiological influences within the human body.

Samuelsson, Bergström, and Vane illuminated a completely new frontier of pharmaceutical research, for which they shared a Nobel prize in the early 1980s. The relationship among 20:4n-6, prostaglandins, and human health became plain, and an industrial and academic research enterprise was launched. The chemical structures of additional prostaglandins and other eicosanoids were soon determined. In the 1970s, the structures of certain hydroxyeicosatetraenoic acids and of leukotrienes were determined (Samuelsson 1983), and structures of lipoxins were determined in the 1980s (Serhan 1994). The presence of eicosanoids in virtually every mammalian tissue and body fluid was progressively uncovered. In a widening array of physiological experiments, additional eicosanoid actions in humans and other mammals were discovered. Eicosanoids were found to influence many organ-level and system-level phenomena, including kidney function, alimentary canal physiology, and a very lengthy list of other elements in human physiology. Possibly some of the most prominent eicosanoid actions involve their influence on mammalian host-defense systems. These eicosanoid actions will be treated in greater detail in later chapters. Beside an increasing number of eicosanoids actions, as research results accumulated, the overall picture of eicosanoids became more complicated. One complication, for example, was finding that some eicosanoid actions seem contradictory. For instance, prostaglandins stimulate contraction in some smooth muscle preparations, and inhibit contraction in others. Of course, a great deal of research was focused on nonhuman mammals, and the significance of eicosanoids in veterinary medicine emerged.

While research accelerated in pace and in discovery, there remained technical barriers to gaining increased understanding of eicosanoids. Because prostaglandins are very potent biological regulators, they are naturally produced in very small amounts. It was difficult to obtain sufficient quantities of prostaglandins for physiological studies. This barrier was partly overcome through the efforts of Dr. John Pike and his colleagues at the Upjohn Company in Kalamazoo, Michigan. Following the discovery that seminal vesicles biosynthesize prostaglandins at relatively high rates, Pike developed a large-scale enzymatic prostaglandin biosynthesis system. This system yielded milligram quantities of prostaglandins, which Pike provided to many research groups. Many papers in the late 1970s and early 1980s attest to the success of his system by acknowledging him as the source of prostaglandins for research.

Accurately determining the natural quantities of eicosanoids in biological sources is another daunting technical barrier. Again, because these are biologically potent compounds, they typically occur in very low quantities in tissues. Moreover, in many tissues, the very act of homogenizing tissues stimulates a burst of prostaglandin biosynthesis, making accurate quantitative determinations even more tenuous. Contemporary techniques to quantify eicosanoids include radioimmunoassays, combined gas chromatographymass spectrometry, interfaced liquid chromatography-mass spectrometry, and detection of fluorescent derivatives on high-performance liquid chromatography. Compared to those used in the early days, these techniques are reliable and relatively easy. Nonetheless, all remain beset with technical problems and potentials for formation of confounding artifacts.

Obtaining some, but not all, prostaglandins for biomedical research became a little more practical soon after the first report of eicosanoids in an invertebrate. Analytical chemists A. J. Weinheimer and R. L. Spraggins were interested in natural products of marine origins. In their fifteenth paper on natural products in coelenterates, they reported an unusual finding. The gorgonian octacoral, Plexaura homomalla, contains high quantities of two prostaglandins within its tissues (Weinheimer and Spraggins 1969). The prostaglandins were a little different from the ones known from mammals, because one was a 15-epi-derivative of PGA2 and the other was its acetate methyl ester. More importantly, at 1.5% to 9% of dry tissue mass, the quantities of these products were astonishingly high. This discovery was greeted with tremendous interest within the prostaglandin community, not because of a scholarly interest in the biology of corals, but because the coral represented a commercial opportunity to harvest prostaglandins.

Coral was harvested, the prostaglandins were extracted in large quantities, and they were chemically modified into prostaglandins of biomedical importance. Of course, harvesting coral on a commercial scale brought along with it concerns for the long-term sustainability of the coral (Theodor, 1977; Berte 1981). There also followed a broad search for other natural, especially marine, sources of prostaglandins. Bundy (1985) reviewed these efforts, which turned up literally hundreds of invertebrate species whose tissues contained what we might call physiological quantities of prostaglandins. Bundy's comment that these small quantities of prostaglandins would not do anybody any good—except the animals in which they were found—adequately reveals the commercial, human-centered tone of the early investigations into the presence of prostaglandins in invertebrate animals.

The main thrust of this volume is about the biological significance, as opposed to the mere presence, of eicosanoids in invertebrates. Detailed listings of species in which eicosanoids have been detected will not contribute much to biological theory. Nonetheless, it is useful to establish the point that eicosanoids have been detected in species representing virtually every major metazoan phylum. As a convenience, Table 1 cites the early publications reporting the presence of prostaglandins and other eicosanoids, without reference to biological studies, in invertebrates. Peered back on from our zoological perspective, the broad-ranging searches for natural sources of prostaglandins represent an early phase in moving from a strictly mammal-centered viewpoint to our biological paradigm for understanding the biology of eicosanoids.

E. J. Corey, a Nobel laureate in chemistry, was recognized, not for any single success in synthesizing difficult compounds, but for introducing the idea of designing effective holistic strategies in organic synthesis. While natural product chemists were scouring the outer reaches of invertebrate taxa in search of prostaglandins, Corey turned his attention to the problem of synthesizing prostaglandins and other eicosanoids. In 1980 he and his colleagues reported the synthesis of 5-hydroperoxyeicosatetraenoic acid (Corey et al. 1980). This breakthrough was the first of many successes in synthesizing eicosanoids, and it effectively erased the barrier of obtaining sufficient quantities of prostaglandins and other eicosanoids for physiological and pharmacological research. Compounds that were once available only as gifts from John Pike are now routinely purchased from competing commercial firms at nearly negligible prices. This important advance in chemistry obviated the searches for natural sources of eicosanoids as commercially promising activities.

(Continues...)

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Table of Contents

Foreword by Ralph W. Howard ix
Acknowledgments xi
Chapter 1. Introduction: A Theory of the Biological Significance of Eicosanoids 3
Chapter 2. Eicosanoid Structures and Biosynthesis 11
The Mammalian Model of Eicosanoid Biosynthesis 12
Chapter 3. Polyunsaturated Fatty Acids 34
Essential Fatty Acids 34
C20 Polyunsaturated Fatty Acids in Insects 39
The Complete Biosynthesis of 18:2n-6 in Insects 39
Biosynthesis of C20 Polyunsaturated Fatty Acids 43
Patterns of Polyunsaturated Fatty Acid Metabolism in Insects 50
Chapter 4. Eicosanoids in the Reproductive Biology of Invertebrates 55
Eicosanoids in Insect Reproduction 55
Eicosanoids as the Barnacle Hatching Factor 74
Eicosanoids in Scallop Reproduction 79
Prostaglandins in Crayfish Vitellogenesis 82
Prawns 86
Eicosanoids in the Reproduction of Molluscs 87
Prostaglandins Influence Organismal-Level Events through Their Actions on Cells in the CNS 92
Eicosanoid Actions at the Cellular Level 94
Chapter 5. Eicosanoids in Invertebrate Immunity 109
Eicosanoids in Insect Cellular Immune Reactions to Bacterial infections 111
Eicosanoids Mediate Clearance of Injected Bacteria from Insect Heinolymph Circulation 112
Eicosanoids Mediate Nodulation Reactions to Bacterial Infections 117
Hypothesis: Eicosanoids Mediate Nodulation Reactions to Bacterial Infections in Most, If Not All, Insect Species 124
The Biochemistry of Eicosanoid Systems in Immune Tissues 133
Chapter 6. Eicosanoids in Invertebrate Ion Transport Physiology 152
Chapter 7. Emerging Eicosanoid Actions 173
Eicosanoids in Invertebrate Temperature Biology 173
Eicosanoids in InsectPeptide Hormone Signal Transduction 178
Eicosanoids in Development and Regeneration in Hydroids 183
Chapter 8. Eicosanoids Mediate Ecological Interactions 188
Eicosanoids in Predator Avoidance 188
Eicosanoids in Host-Parasite Interactions 194
Prostaglandin Biosynthesis Inhibitors in Insect Defensive Secretions: Do these Compounds Act in Insect Chemical Ecology? 231
Chapter 9. A Research Prospectus: Approaching the Frontiers 235
How Do Eicosanoids Work? 236
Understanding Departures from the Mammalian Background 237
The Enzymes Associated with Eicosanoids 239
Eicosanoids and Neurobiology 241
The Molecular Biology of Eicosanoids 243
An Epilogue 244
Abbreviations Used in References 245
References 249
Taxonomic Index 273
Subject Index 275