The fate of platelet-activating factor

THE FATE OF PLATELET-ACTIVATING FACTOR: PAF ACETYLHYDROLASES FROM PLASMA AND TISSUES

Tada-atsu Imaizumi, Diana M. Stafforini, Yoshiji Yamada, Guy A. Zimmerman, Thomas M. Mclntyre, and Stephen M. Prescott

I. II. III. IV.

ABSTRACT INTRODUCTION PATHOLOGICAL AND PHYSIOLOGICAL ACTIONS OF PAF PAF ACTS BY BINDING TO A RECEPTOR SYNTHESIS OF PAF A. Enzymatic Mechanisms B. Formation of Oxidatively Fragmented Phospholipids That Are Structurally Similar to PAF

Advances in Lipobiology Volume 1, pages 141-162. Copyright © 1996 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-635-5 141

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V. DEGRADATION OF PAF AND OXIDIZED PHOSPHOLIPIDS BYTHEPAFACETYLHYDROLASE A. Biochemical Characteristics of the PAF Acetylhydrolase(s) B. Properties ofthe Plasma Form of the PAF Acetylhydrolase C. The PAF Acetylhydrolase From Human Plasma Prevents Oxidative Modification of LDL D. Population Studies of PAF Acetylhydrolase Activity in the Plasma of Normal Human Subjects and Animals E. Genetics ofthe Plasma PAF Acetylhydrolase F. The Plasma PAF Acetylhydrolase in Disease G. Intracellular PAF Acetylhydrolase ACKNOWLEDGMENTS REFERENCES

148 148 149 150 151 152 152 155 156 156

ABSTRACT Platelet-activating factor (PAF) likely mediates a variety of physiological and patho­ logical events. There is abundant evidence that the concentration of PAF in blood or tissues is influenced by its rate of degradation. Two forms ofthe degradative enzyme, PAF acetylhydrolase, have been purified and studied in detail. Changes in the activity of the plasma enzyme have been observed in human diseases, physiological re­ sponses, and in animal models, suggesting that it may be a key step. The plasma PAF acetylhydrolase has several interesting properties including marked substrate speci­ ficity and association with lipoproteins. Studies that define the molecular basis for these properties and elucidate the role ofthe enzyme in physiological processes should be forthcoming, and will provide insight into the function of PAR

I. INTRODUCTION Platelet-activating factor (PAF, l-0-alkyl-2-acetyl-5«-glycero-3-phosphocholine) is a potent phospholipid autacoid that has diverse actions. The structure of this compound v^as elucidated by two different groups: one seeking to characterize a factor in the blood of rabbits undergoing anaphylactic shock, and the other trying to identify an endogenous compound that lowered blood pressure (reviewed in Hanahan, 1986; Snyder, 1987; Prescott et al, 1990; Venable et al., 1993a). The trivial name, PAF, is incomplete as it refers to only the earliest recognized effect. However, this name has found general acceptance while others have not. PAF acts by binding to a specific receptor, which has recently been characterized in detail following the cloning of its cDNA, and its expression in heterologous cells. The synthesis of PAF can occur through one of two described synthetic pathways, and the synthetic process is tightly regulated. PAF is degraded by PAF acetylhydrolase, which catalyzes the hydrolysis ofthe esterified acetate at the sn-2 position.

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In this chapter we will review how PAF is made and has its effects, and will concentrate on the PAF acetylhydrolase, which is an unusual phospholipase that catalyzes the hydrolysis of PAF and its analogs. In particular, we will analyze the evidence that this enzyme may have a major role in limiting the actions of PAF and, conversely, that a decrease in its activity may unmask PAF bioactivity.

II. PATHOLOGICAL AND PHYSIOLOGICAL ACTIONS OF PAF PAF has multiple physiological and pathological actions. It probably is a mediator of physiological inflammation, may facilitate normal hemostasis, and likely con­ tributes to several stages of events in reproduction. Moreover, there is evidence that it is one of the pathological mediators in asthma and other allergic responses, vascular damage including ischemia and reperfusion injury, various forms of shock (particularly endotoxic shock), and other syndromes in which there is a marked inflammatory response (e.g., the adult respiratory distress syndrome and inflam­ matory bowel disease). The evidence that PAF participates both in normal responses and diseases was reviewed recently (Yue et al., 1991; Zimmerman et al, 1992) and will only be summarized here. The in vitro effects of PAF include activation of platelets and leukocytes including neutrophils, monocytes, and macrophages, which support a role in thrombosis and inflammation. Many other cells and tissue respond as well—^there is glycogenolysis in perfused livers, growth in smooth muscle cells, and activation of neural cells. Intravenous infusions of PAF into animals result in a marked increase in vascular permeability, adhesion of leukocytes to endothelium, decreased cardiac output, hypotension, shock, and death. Selective administration in vivo or to isolated tissues has been shown to cause contraction of uterine muscle, bronchoconstriction, and ulcers in the gastrointestinal tract. PAF has been found in the plasma of patients with sepsis, and in blood and tissues of animal models of disease (Yue et al., 1991; Zimmerman et al., 1992). Finally, one of the main lines of evidence supporting a role for PAF in pathological events is that pharmacological agents that antagonize its binding to its receptor have been found to attenuate certain diseases where PAF is the suspected mediator (Yue et al., 1991; Zimmerman et al., 1992). The effects of PAF on cells and tissues are concentration-dependent, and the earliest response (threshold) is usually between 10~^^ to 10"^ M, although effects at lower concentrations have been described. The concentration of PAF in blood or tissues depends on the difference between the rates of synthesis and degradation. Most of the cells that are capable of synthesizing PAF do not do so under basal conditions, but only when they are activated. One mechanism for pathological effects, then, would be the inappropriate activation of the synthetic pathways. Conversely, PAF is rapidly degraded by the actions of the PAF acetylhydrolase, and a decreased activity of this enzyme could allow the accumulation of concentrations of PAF that would provoke a pathological response.

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A variety of cells (e.g., neutrophils, macrophages, and endothelial cells) synthe­ size PAF when stimulated and which of them is the source of PAF observed in sepsis and other disease circumstances is not known. We have shown that PAF is synthesized by activated endothelial cells but is not secreted (Prescott et al., 1984; Mclntyre et al, 1985). However, the PAF made by monocytes and macrophages is secreted, as is a portion of the PAF synthesized by neutrophils (Elstad et al., 1988). Although endothelial cells do not secrete PAF, it is expressed on the surface of the cells where it serves as a component of the signal for the binding of neutrophils to endothelial cells (Zimmerman etal., 1990;Lorantetal., 1991,1993). This probably is a homeostatic response since the adhesion of leukocytes to the endothelium is the first step in physiological inflammation. However, inappropriate or excessive expression of the adhesion signal followed by the attraction and activation of large numbers of leukocytes could result in further vascular damage due to the secretion of proteases and oxygen radicals by the leukocytes.

III. PAF ACTS BY BINDING TO A RECEPTOR PAF exerts its effects through a receptor that has been well characterized pharma­ cologically, and many potent antagonists have been developed. Most of those described are competitive antagonists although they usually share no structural homology with PAF. The competitive nature of their actions is potentially a drawback since PAF may often be expressed at a surface and/or in a restricted environment. If so, the effective concentration could be extremely high and overcome the blockade by a competitive antagonist—even a potent one. Several groups have isolated cDNAs encoding the receptor (Gibson et al., 1991; Honda et al., 1991; Ye et al, 1991; Kunz et al., 1992; Seyfried et al., 1992), and have shown that it is a member of the family of receptors linked to G-proteins, as suggested previously by pharmacological and biochemical studies. The receptor is linked to turnover of phosphatidylinositol, changes in intracellular calcium, activa­ tion of protein kinase C, and synthesis of eicosanoids (Shukla, 1992). The known receptor is clearly linked to a G-protein, although which one is not yet known. Additionally, there is phosphorylation on tyrosine residues in unknown proteins in response to PAF (Dhar et al., 1990; Sha'afi et al, 1991; Chao et al., 1992; Tripathi et al., 1992). Although there are pharmacological data to support the existence of two receptors (Hwang, 1988), the molecular studies so far have revealed only one (see cloning references above). PAF receptors in intracellular membranes have been described, but it is not known whether these are spare receptors, or surface receptors in a stage of cycling, or whether they have a specific intracellular function. Stewart et al. concluded that PAF fiinctions as an intracellular messenger since they found that antagonists of the receptor blocked the synthesis of prostaglandins in response to agonists other than PAF (Stewart et al., 1989, 1990).

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IV. SYNTHESIS OF PAF A.

Enzymatic Mechanisms

The actions of PAF are dictated by its concentration in blood and tissues. In general, the concentration is very low—^usually unmeasurable—^and the reason for this is thought to be that cells do not make PAF, or at least not much, constitutively. PAF can be synthesized by two pathways (Figure 1). The first pathway, termed remodeling, begins with the hydrolysis of arachidonate from the sn-2 position of a membrane phospholipid. This reaction probably is catalyzed by an arachidonatespecific phospholipase A2 (PLA2) since several groups have found that PAF synthesis and arachidonic acid release are closely coupled. Wykle and colleagues proposed that the PLA2 hydrolyzes arachidonate from 1-(9-alkyl-2-arachidonoyl5«-glycero-3-phosphocholine generating 1 -6)-alkyl-2-lyso-5A2-glycero-3-phosphocholine (lyso-PAF) and free arachidonic acid (Chilton et al., 1984). An alternative mechanism for the generation of lyso-PAF has come from recent studies in which it appears that the first step is hydrolysis of arachidonate-containing plasmalogen phosphatidylethanolamine (PE) by a PLA2 (Nieto et al., 1991; Snyder et al., 1991; Venable et al., 1991). The lyso-PE product stimulates the transfer of arachidonate from the PAF precursor to the lyso-PE, simultaneously forming lyso-PAF. The latter reaction is catalyzed by a coenzyme A-independent transacylase, the activity of which does not seem to change upon cell stimulation (Venable et al, 1993b). Once lyso-PAF has been produced via one or the other mechanism it then is acetylated in a reaction catalyzed by acetyl coenzyme A:lyso-PAF acetyltransferase, using acetyl coenzyme A as a donor, to form PAF. This enzyme is activated, probably by phosphorylation, when the cell is stimulated (Alonso et al., 1982; Lee et al., 1982; Nieto et al., 1988; Holland et al., 1992). The second route to PAF synthesis, the de novo pathway, begins with l-0-alkyl-5«-glycero-3-phosphate followed by incor­ poration of an acetate, and then by removal of the phosphate and its replacement with a phosphorylcholine. The enzymes in this pathway appear to be constitutively active, and it has been proposed that there is continuous production of a small amount of PAF via this route (Lee et al., 1986; Blank et al., 1988). B. Formation of Oxidatively Fragmented Phospholipids That Are Structurally Similar to PAF

The polyunsaturated fatty acids in membrane phospholipids are susceptible to free-radical oxidation, which has been shown to occur in some pathologic condi­ tions. These include reperfusion following ischemia, the adult respiratory distress syndrome, and chronic inflammation. We found that oxidation of synthetic phos­ pholipids could fragment the unsaturated fatty acid while it was still esterified. This results in structural analogs of PAF (Figure 2), and we and others have shown that they can act through its receptor to reproduce the effects of PAF (Smiley et al, 1991). Tokumura and co-workers have identified such compounds in extracts of

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TADA-ATSU IMAIZUMI ETAL. Remodeling

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I

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H2C-O-CH2R O H3C-C-O-CH H2C-(g)-chollne

Cholinephosphotransferase

H2C-O-CH2R H3C-C-O-CH H2C-OH

Figure 1. Synthesis of PAF can occur via two pathways. Remodeling pathway (on left). Most PAF is thought to be made by this route, particularly in cells participating in the inflammatory response. This pathway begins with a PLA2 reaction, which may act on 1-0-aIkyl-2-arachidonoyl glycerophosphocholine (right side of left panel) to yield lyso-PAF and free arachidonic acid. The lyso-PAF is converted to PAF by transfer of acetate acetyl coenzyme A by a specific acetyltransferase. Alternatively, the PLA2 may act on plasmalogen phosphatidylethanolamine, and the lyso-phosphatidylethanolamine then serves as an acceptor for arachidonate in a transacylation reaction from the PAF precursor, which yields lyso-PAF (left hand side of left panel). This mechanism fits with many observations on the flux of arachidonic acid. Irrespec­ tive of the subsequent steps, the PLA2 step is absolutely required for initiation of PAF synthesis by this pathway—a situation we have termed conditional. Once the lyso-PAF is generated the acetyltransferase reaction becomes limiting, and we have termed this a modulating step. De novo pathway (right side). In this pathway 1 -O-alkyl-sn-glycero3-phosphate is acetylated by a different acetyltransferase, and then l-O-alkyl-2-acetyl-SA7-glycero-3-phosphate phosphohydrolase acts to yield 1-0-alkyl-2-acetyl-sn-glycerol. This Is a substrate that can be converted to PAF by a dithiothreitol-insensitive CDP-cholinephosphotransferase. This pathway seems to act constitutively, being regulated only by the availability of substrate, and may continu­ ously produce a small amount of PAF for some physiological role(s). (Reprinted by permission from J. Lipid Res. 14, 691-702, 1993.)

Metabolism of Platelet-Activating

i

L i-

147

Factor

PC Free Radical ► Oxidation

rr =0

^ 0

1 O-PC

+Fragments

0 Synthetic

6-PC

>=0

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Figure 2, Generation of PAF-like oxidized phospholipids contrasted with the synthe­ sis of PAR Phospholipids with bioactivity like that of PAF can result from the oxidation of polyunsaturated fatty acids at the sn-2 position of choline phosphoglycerides (upper panel). Fragmentation of the acyl chain yields compounds that are sufficiently similar in structure to PAF to allow them to bind to the PAF receptor. This response has been observed in model phospholipids, cultured cells, and brain tissue, and may represent an important mechanism by which PAF-like bioactivity can be generated in an unregulated fashion.

brain (Tokumura et al., 1989), and have carried out detailed structural studies (Tanaka et al., 1993). We found that similar compounds are produced when endothelial cells are exposed to oxidants, and that they are released as vesicles (or blebs) from the plasma membrane (Patel et al., 1992). We have show^n that these bioactive lipids are generated v^hen lov^ density lipoprotein particles are exposed to oxidants, and that one of their effects is to stimulate the growth of vascular muscle cells (Heery et al., 1995). This may be particularly relevant since it is thought that oxidation of the lipids in LDL is a crucial step in atherosclerosis (Steinberg et al., 1989a; Witztum and Steinberg, 1991). Since these compounds are made by a free-radical reaction, rather than by regulated enzymatic steps, they could be

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generated in much larger amounts than PAF and at inappropriate times and places. If they escape the usual regulatory controls that govern PAF synthesis and are produced in excess, then degradation via the PAF acetylhydrolase might be crucial in protecting against pathological effects.

V. DEGRADATION OF PAF AND OXIDIZED PHOSPHOLIPIDS BY THE PAF ACETYLHYDROLASE Regardless of the pathway by which PAF is synthesized or the mechanism by which analogs such as the oxidized phospholipids are generated, both are degraded to inactive products by a phospholipase that is specific for PAF and closely related lipids, PAF acetylhydrolase (Figure 3). There are at least two forms of this enzyme: a secreted form present in mammalian plasma (Wardlow et al., 1986; Stafforini et al., 1987a,b), and an intracellular form that is found in various blood cells and tissues (Blank et al, 1981; Stafforini et al, 1993). Although they catalyze the same reaction and have the same substrate specificity, the plasma and intracellular forms of the PAF acetylhydrolase are different proteins as judged by a variety of criteria (see below). The degradation of PAF and related phospholipids by these isoenzymes may be a crucial step that regulates inflammation. A.

Biochemical Characteristics of the PAF Acietylhydrolase(s)

The defining characteristics of this enzyme's activity are that it does not require calcium and is specific for short acyl groups at the sn-2 position of the substrate phospholipid (Blank et al., 1981; Stafforini et al, 1987b). There is no measurable activity when the acyl chain is longer than six carbons. For the plasma enzyme, this trait is essential if the enzyme is to circulate in an active form—^if typical phos­ pholipids were substrates the enzyme would continuously hydrolyze the phos­ pholipids of lipoproteins and cell membranes. The 1 -0-acyl and 3-phosphoethanolamine analogs of PAF, and phospholipids containing oxidatively-fragmented resi­ dues at sn-2 also are substrates (Stafforini et al., 1987b; Stremler et al., 1991). It is possible that the enzymatic activity evolved to catalyze the hydrolysis of this last group of compounds which, in addition to receptor-mediated actions, might have a variety of toxic effects on cells. Nonetheless, the recent findings that phos­ pholipids other than PAF are substrates makes the traditional name incorrect, but we have retained it here for consistency with previous work. The PAF acetylhydro­ lase is a PLA2 with specificity for short acyl chains. The activities in plasma and in cells have identical substrate specificity, but studies of the molecular weight, chemical inhibition, protease inactivation, and antibody recognition have shown them to be distinct proteins (Stafforini et al., 1991, 1993). The plasma protein is resistant to proteolysis, and is unaffected by reagents that derivatize sulfhydryl or histidyl residues, and sodium fluoride. In contrast, the enzyme in spleen, liver and leukocytes all are inhibited, at least partially, by these treatments. Also, the enzyme

Metabolism of Platelet-Activating

Factor

149

A. r-AlkyI

Alkyl

PAF Acetyihydrolase

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OH

•— Phosphocholine

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PAF

Lyso PAF + Acetate

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PAF Acetyihydrolase

0-C0-[CHj3.,CH0 I

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Oxidized Phospholipids

►

I— Acyl LoH I

+

0-C0-[CHj3^CH0

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Lyso Phospholipids -1Oxldized Fatty Acids

Figure 3. Degradation of PAF and oxidized phospholipids. Panel A: The degradation of PAF occurs by hydrolysis of the acetyl residue in a reaction catalyzed by a specific phospholipase (PAF acetyihydrolase) which does not require calcium and is specific for short residues at sn-2. In particular, phospholipids with the usual fatty acids are not utilized as substrates. This enzyme also catalyzes the hydrolysis of phospholipids with oxidatively fragmented fatty acids (panel B), an action that may protect against oxidation of low density lipoprotein. Related enzymes with the same substrate specificity are present in tissues.

from erythrocytes, which is inhibited by histidine and cysteine modification, is sensitive to proteolysis and NaF (Stafforini et al, 1993). There may be two or more intracellular enzymes; for example, the neutrophil and erythrocyte enzymes mi­ grated at the same rate during electrophoresis in polyacrylamide gels, while the liver enzyme displayed a higher mass/charge ratio (Stafforini et al., 1991). B.

Properties of the Plasma Form of the PAF Acetyihydrolase

The plasma PAF acetyihydrolase has an apparent mass of 43,500 Da and is tightly associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) (Stafforini et al., 1987a,b). Under optimal conditions the enzyme exhibits identical catalytic properties irrespective of which particle it is associated with. However, in plasma that contains concentrations of PAF described in vivo (10"^ M or lower), the HDL-associated enzyme does not degrade PAF at appreciable rates, while the LDL-associated enzyme does (Stafforini et al., 1989). It is not yet clear why the activity differs in the two types of particles when substrate is limiting, but it may be that the PAF partitions into the particles at a different rate, and that this step limits the access of the enzyme to the substrate. The plasma PAF acetyihydrolase is synthesized and secreted by both macrophages (Stafforini et al., 1990; Narahara et

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TADA-ATSU IMAIZUMI ET AL.

al., 1993) and hepatocytes (Carter et al., 1988; Satoh et al, 1991b). In each case, it appears that secretion of the enzyme occurs independently of the secretion of lipoprotein particles, and that the acetylhydrolase then associates with either nascent lipoproteins secreted by the cells (in the absence of serum) or with mature lipoproteins if serum is included in the culture medium. Macrophages also may play a role in the local regulation of PAF levels since the precursor monocytes do not produce the enzyme. However, upon differentiation to macrophages they begin to produce and secrete PAF acetylhydrolase (Elstad et al., 1989). Secretion of the PAF acetylhydrolase by hepatocytes is suppressed by estrogen (Carter et al., 1988; Satoh et al., 1993), which may account for the dramatic fall in the plasma activity that has been observed late in gestation, and which has been proposed to be important in the initiation of labor (see chapter 9, "The Role of PAF in Reproductive Biology"). C. The PAF Acetylhydrolase From Human Plasma Prevents Oxidative Modification of LDL

Modification of LDL is an early event in atherogenesis, and the modified LDL particles are thought to be produced from native particles by oxidation that is somehow carried out by cells in the arterial wall, including endothelial cells, monocyte and macrophages, and smooth muscle cells (Steinberg et al, 1989; Witztum and Steinberg, 1991). Blood monocytes invade the vascular wall and become macrophages, which take up modified LDL through their scavenger receptor to become foam cells (Brown and Goldstein, 1983; Witztum and Steinberg, 1991). This results in the accumulation of cells loaded with cholesterol esters, which is recognized histologically as a fatty streak. The molecular events that result in oxidation of LDL by vascular cells have not been determined. However, a number of biochemical changes have been identified in LDL particles that have been oxidized. One of the most important is the modification of apolipoprotein B-lOO, since this is what results in recognition by the scavenger receptor. The modified particles have an increased electrophoretic mobility due to a change in the charge of the protein (Mahley et al., 1979; Fogelman et al., 1980; Brown and Goldstein, 1983; Gonen et al, 1983), and there is peroxi­ dation of their lipids (Parthasarathy et al, 1989; Steinberg et al., 1989; Lenz et al., 1990; McNally et al., 1990; Rankin et al., 1991). A central role for the latter change is suggested by experiments in which oxidized lipids were added in vitro and shown to directly derivatize apolipoprotein B-100 (Steinbrecher, 1987). Also, antioxidants such as butylated hydroxytoluene and probucol slow atherogenesis in animal models (Parthasarathy et al., 1986; Kita et al, 1987; Carew et al., 1987; Bjorkhem et al., 1991; Reaven et al., 1992). Thus, generation of lipid peroxides may be important in the modification of LDL and the subsequent development of atherosclerosis.

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We showed that the PAF acetylhydrolase catalyzes the hydrolysis of oxidativelyfragmented phospholipids (Stremler et al., 1991). During modification of LDL, polyunsaturated fatty acids in phospholipids (predominantly choline phosphoglycerides) are oxidized, and then are hydrolyzed to yield lysophospholipid and the oxidized fatty acid and/or their fragmentation products (Steinbrecher et al., 1984). The fragments of lipids that have undergone peroxidation are thought to covalently bind to apolipoprotein B-lOO, which causes increased electrophoretic mobility and changes receptor recognition (Steinbrecher, 1987). In this model, the hydrolysis of oxidized phospholipid is required for LDL to be modified. However, we found that hydrolysis of the oxidized phospholipids resulted in the release of water-soluble products, presumably reactive fragments, and that the net effect was to protect apolipoprotein B-lOO from modification (Stafforini et al., 1992). Thus, catalysis of the degradation of oxidatively-fragmented phospholipids by the PAF acetylhydro­ lase prevents modification of LDL. If this also occurs in vivo, it would indicate that this enzyme is a crucial defense against atherosclerosis. D.

Population Studies of PAF Acetylhydrolase Activity in the Plasma of Normal Human Subjects and Animals

The PAF acetylhydrolase activity in serum is low in human newborns, and it increases linearly with respect to the natural logarithm of the age from birth to 6 weeks (Caplan et al., 1990). In adults, plasma PAF acetylhydrolase activity in­ creases gradually with advancing age (Satoh et al., 199la). It is lower in pre-menopausal women than in men (Farr et al., 1986; Satoh et al., 1991a), however, over 50 years of age the difference between men and women lessens (Satoh et al., 1991 a). In women, the PAF acetylhydrolase activity changes during the menstrual cycle and it is negatively correlated with plasma estrogen level (Miyaura et al., 1991). PAF acetylhydrolase activity decreases in maternal plasma during the latter stages of pregnancy in humans (Johnston, 1989) and rabbits (Maki et al., 1988), and administration of estrogen to rats decreases the plasma activity (Pritchard, 1987; Miyaura et al., 1991). These observations taken together suggest that estrogen decreases the activity in plasma, and that the closer values in older men and women are due to a loss of the suppressive effect of estrogen. Estrogen probably acts by decreasing the secretion of PAF acetylhydrolase by the liver cells, as described above. In an experiment reported by Miyaura et al. (1991), administration of glucocorticoids increased the level of the PAF acetylhydrolase in the plasma of rabbits and reversed the suppressive actions of estrogen. This suggests that a portion of the antiinflammatory actions of steroids may be due to an increase in this enzyme that catalyzes the removal of inflammatory lipids. It will be interesting to elucidate the mechanism for the effects of estrogen and glucocorticoids on the synthesis of PAF acetylhydrolase by hepatocytes once a cDNA probe and antibodies are available.

1 52

TADA-ATSU IMAIZUMI ET AL. E. Genetics of the Plasma PAF Acetylhydrolase

Based on measurement of the enzymatic activity in plasma samples from a population of subjects, Miwa et al. (1988) reported that about 4% of Japanese children and adults are markedly deficient in the plasma PAF acetylhydrolase. These investigators also were able to study five families, and concluded that the mode of transmission was autosomal recessive. They found that deficiency of the PAF acetylhydrolase occurred more frequently in asthmatic children with severe symptoms than in normal children, suggesting that it plays a role in limiting inflammatory and allergic responses. However, there were subjects with low activity of plasma PAF acetylhydrolase who did not have a defined phenotype. There have been no reports of deficiency of this enzyme in other ethnic and racial groups, although the prevalence of 4% in Japan has been confirmed by another group in the northern part of the country (Imaizumi and Satoh, unpublished observation). Importantly, these workers found that deficient subjects examined serially were always low, a result that excludes some trivial causes for the obser­ vation. We have tested plasma samples from over 1,000 subjects in the United States and have not found a case of marked deficiency (unpublished results). The molecu­ lar basis for the deficiency observed in Japan is unknown since the gene has not yet been identified. However, the possibility of an inhibitor was excluded by mixing studies. If true deficiency is common in some populations, it will provide an experiment of nature to assess the function, if any, of this enzyme in human physiology and disease. F. The Plasma PAF Acetylhydrolase In Disease

The activity of PAF acetylhydrolase in plasma has been reported to be increased in patients with atherosclerotic diseases such as peripheral vascular disease (Ostermann et al., 1987), ischemic stroke (Satoh et al., 1988), and familial HDL deficiency (Tangier disease) (Pritchard et al., 1985). Based on the analogy to inflammatory conditions, we propose that this represents a protective response to some signal generated during atherogenesis. Conversely, it is possible that the increased activity contributes to the onset or progression of atherosclerosis. We conclude that this is less likely because the activity of plasma PAF acetylhydrolase is also increased in insulin-dependent diabetes mellitus (Hofmann et al., 1989), and habitual cigarette smokers (Imaizumi et al., 1990), implying that the increased activity is a result rather than cause in these disorders. However, the observations that the enzyme activity is increased in patients with atherosclerosis, while it is decreased by estrogen, which is associated with a decreased risk of atherosclerosis, are consistent with the counterhypothesis that the enzyme is atherogenic rather than protective. Further experimentation will be necessary to resolve this point. It is also reported that PAF acetylhydrolase activity is increased in plasma from patients with essential hypertension (Satoh et al., 1989) and spontaneously hypertensive rats (Blank et al..

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Table 1. Changes of PAF Acetylhydrolase Activity in Physiological and Pathological Conditions Plasma type PAF-AH activity

I. Plasma Human physiological newborn aging sex pregnancy pathological peripheral vascular disease ischemic stroke myocardial infarction familial HDL deficiency (Tangier Disease) essential hypertension insulin-dependent diabetes mellitus chronic cholestasis

Reference

low Caplanetal., 1990 Satohetal., 1991a increase premenopausal women < men Farretal., 1986; Satohetal., 1991a Johnston, 1989 decrease

primary glomerulonephritis rheumatoid arthritis noninflammatory arthritides habitual cigarette smokers systemic lupus erythematosus septic shock neonatal necrotizing enterocolitis coronary bypass operation child asthma cigarette smoke extract LDL oxidation by Cu Experimental animal models estrogen administration (rat) pregnancy (rabbit) dexamethasone administration (rat) corticosterone implantation (lizard) chronic stress (lizard) gastric ulcer by water-immersion stress (rat) necrotizing enterocolitis (rat) spontaneous hypertensive rat (rat) lupus mouse (mouse) lupus mouse, moribund (mouse) peritoneal LPS administration (guinea pig)

increased increased increased increased increased increased increased normalized after liver transplantation increased increased increased increased decreased decreased decreased decrease increased incidence of deficiency decrease decrease decrease decrease increase increase increase increase decreased increased decreased increased increased in peritoneal supernatant

Ostermann et al., 1987 Satohetal., 1988 Ostermann et al., 1988 Pritchard et al., 1985 Satohetal., 1989 Hofmann et al., 1989 Meade etal., 1991 Latrouetal., 1992 Dulioust et al., 1992 Dulioust et al., 1992 Imaizumi etal., 1990 Tettaetal., 1990 Taylor etal., 1992 Caplanetal., 1990 Stephens et al., 1992 Miwaetal., 1988 Miyaura et al., 1992 Stafforini et al., 1992 Pritchard, 1987; Miyaura et al., 1991 Makietal., 1988 Miyaura et al., 1991 Lenihan et al., 1985 Lenihan et al., 1985 Fujimura et al, 1989 Caplanetal, 1988 Blank etal, 1983 Zhao etal, 1992 Zhao etal, 1992 Karasawa et al, 1992

{continued)

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TADA-ATSU IMAIZUMI ETAL.

Table 1. (Continued) II. Cell Human in vivo RBC aging ischemic stroke (RBC) Experimental animal models lupus mouse, moribund (liver, kidney, lung, spleen)

Intracellular type PAF-AH activity

Reference

decrease decreased

Yoshida et al., 1994 Yoshidaetal., 1992; Yoshida et al., 1993

increased

Zhao etal., 1992

1983). PAF has a hypotensive activity, and there is a possibility that excessive levels of PAF acetylhydrolase could increase blood pressure by removing the hypotensive signal. We believe this is unlikely for two reasons. First there is normally a great excess of PAF acetylhydrolase activity in plasma, and there are no data to suggest that the Tj/2 of PAF would be shorter with increased levels. In fact, we have found that this is not the case (unpublished data). Second, Satoh et al. (1989) found increased levels of PAF acetylhydrolase activity in the plasma of patients with hypertension, but the level increased with the length of time that the patient had hypertension; again suggesting that it was a result rather than a cause. In related experiments, investigators have examined the role of cigarette smoking on the accumulation of PAF or PAF-like lipids in blood and on the enzyme activity. Imaizumi et al. (1991) showed that PAF-like lipids accumulate in the plasma upon acute inhalation of cigarette smoke. Miyaura et al. (1992) found a substance in cigarette smoke extract that inhibits the PAF acetylhydrolase, and we have found that the activity in plasma LDL is lost upon artificial oxidation with Cu^"^ (Stafforini et al., 1992). We postulate that the unidentified compound from cigarette smoke inhibits the PAF acetylhydrolase, which then may lead to the increased levels of PAF or related compounds due to a decreased rate of hydrolysis. This could accelerate vascular damage by the proinflammatory actions of PAF, and could account for some of the deleterious effects of smoking. Alterations of the plasma PAF acetylhydrolase activity have been described in various inflammatory conditions. The enzyme activity in serum is increased in patients with primary glomerulonephritis (Latrou et al., 1992), while that in plasma from patients with systemic lupus erythematosis {Tetta et al., 1990) is decreased. The activity in plasma from lupus mice is also decreased, but when they are moribund, activity increases (Zhao et al., 1992). The PAF acetylhydrolase activity is high in serum from patients with cholestasis caused by liver diseases such as sclerosing cholangitis, advanced primary biliary cirrhosis, or cholangiocarcinoma, but was shown to normalize after successful liver transplantation (Meade et al., 1991). PAF acetylhydrolase activity is decreased in plasma from patients with septic

Metabolism of Platelet-Activating Factor

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shock (Taylor et al., 1992), but it is increased in the exudate in the peritoneal cavity of guinea pigs with experimental endotoxic shock following intraperitoneal ad­ ministration of lipopolysaccharide (Karasawa et al., 1992). The level of PAF acetylhydrolase activity has been implicated in gastrointestinal disorders as it is decreased in patients with neonatal necrotizing enterocolitis (Caplan et al., 1990) and rats with experimental necrotizing enterocolitis (Caplan et al., 1988). Serum PAF acetylhydrolase activity is increased in patients with rheumatoid and other forms of arthritis (Dulioust et al., 1992). Thus, both increased and decreased enzyme activity have been reported in plasma from patients or animals with various inflammatory conditions (Table 1). This suggests that PAF acetylhydrolase activity may be affected by multiple factors which mediate the inflammatory response, and the response may be complex, perhaps increased during some stages and decreased during others. In support of this, some work suggests that PAF itself, after being generated in pathological inflammation, induces increased synthesis and secretion of the plasma PAF acetylhydrolase activity by the liver. Moreover, we have shown that the secretion of plasma type PAF acetylhydrolase from normal macrophages increases during differentiation (Elstad et al., 1989), and the same has been shown in HL-60 cells (Narahara et al., 1993). We have shown that interferon decreases this response (unpublished observations) and Narahara et al. (1993) found that endotoxin inhib­ ited the secretion of PAF acetylhydrolase by HL-60 cells. Administration of dexamethasone, a potent antiinflammatory steroid hormone, to rats increases the activity in plasma (Miyaura et al., 1991), and this response can be mimicked by treatment of cultured HL-60 cells with dexamethasone. Implantation of corticosterone or chronic stress also increases the activity in the plasma of lizards (Lenihan et al., 1985). These findings may partially account for the mechanisms by which plasma PAF acetylhydrolase activity is altered in pathologic situations such as inflammation. G.

Intracellular PAF Acetylhydrolase

We recently reported the purification and characterization of a PAF acetylhydro­ lase from human erythrocytes, which is clearly a distinct protein from the plasma form (Stafforini et al., 1993). This should rapidly lead to reagents that will allow us and others to test the role of this enzyme. For example, it is puzzling that erythrocytes have such high levels of this enzyme since they do not synthesize PAF, nor do they take up and hydrolyze exogenous PAF at an appreciable rate (Stafforini et al., 1993). We have proposed that the enzyme is present in these cells predomi­ nantly as a an antioxidant defense since erythrocytes are particularly prone to oxidative damage as they have high concentrations of oxygen and iron. Conversely, the PAF acetylhydrolase in erythrocytes might contribute to the hydrolysis of PAF if the cells were lysed at the site of inflammation and released their PAF acetylhy­ drolase. Yoshida et al. (1992a, 1993) showed that PAF acetylhydrolase activity in

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red blood cell cytosol and membrane are decreased in patients with cerebral thrombosis and that the activity was correlated with erythrocytes deformability. They also found that the activity decreases with aging of erythrocytes in vivo (Yoshida et al., 1994). The PAF acetylhydrolase activities in kidney, liver, lung, and spleen have reported to be increased in moribund lupus mice (Zhao et al., 1992). There currently is no other information on changes of the intracellular form of PAF acetylhydrolase activity that have been correlated with physiologic or pathologic events. It will be intriguing to determine if it plays a role in defense against oxidative damage, or has other actions. Since the acceptance of this manuscript, the cDNA for human PAF acetylhydro­ lase was cloned (Tjoelker, L.W., et al. (1995). Nature 374, 549-553.). The recom­ binant plasma PAF acetylhydrolase inhibits the inflammatory effects of PAF in in vivo and in vitro experimental models. The cDNAs for three subunits of bovine brain PAF acetylhydrolase were also cloned, and the cDNA for one of the subunits is the bovine homolog of human gene which is causative for Miller-Dieker lissencephaly, a human cerebral malformation (Hattori, M., et al. (1994). Nature 370, 216-218; (1994) J. Biol. Chem. 269, 23150-23155; (1995) J. Biol. Chem. 270,31345-31352.).

ACKNOWLEDGMENTS We are grateful for the technical assistance of Susan Cowley, Donnelle Benson, Bart Tarbett, and Linda Wilcox in the projects from our laboratories. Drs. Kay Stremler and Mark Elstad made important contributions to these studies. The work has been supported by the Nora Eccles Treadwell Foundation and the George and Dolores Dore Eccles Foundation, and by grants from the National Institutes of Health and the American Heart Association. Dr. Stafforini is the recipient of a Minority Scientist Development Award from the American Heart Association and Drs. Prescott and Zimmerman were Established Investigators during much of the work reviewed here.

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