Regulation of platelet-activating factor (PAF) activity in human diseases by phospholipase A2inhibitors, PAF acetylhydrolases, PAF receptor antagonists and free radical scavengers

Prostaglandins, Leukotrienes and Essential Fatty Acids (1999) 61(2), 65–82 © 1999 Harcourt Publishers Ltd Article no. plef.1999.0038

Review

Regulation of platelet-activating factor (PAF) activity in human diseases by phospholipase A2 inhibitors, PAF acetylhydrolases, PAF receptor antagonists and free radical scavengers P. V. Peplow Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand

Summary The aim of this review is to present recent findings indicating the likely involvement of platelet-activating factor (PAF) in human diseases, and possible ways of alleviating its harmful effects. PAF is a potent proinflammatory mediator and promotes adhesive interactions between leukocytes and endothelial cells, leading to transendothelial migration of leukocytes, by a process of juxtacrine intercellular signalling. This process leads to activation of leukocytes and the release of reactive oxygen radicals, lipid mediators, cytokines and enzymes. These reaction products subsequently contribute to the pathological features of various inflammatory diseases. The reactive oxygen radicals cause low density lipoprotein (LDL) oxidation which mediates the development of atherosclerosis. Oxidized LDL may damage cellular and subcellular membranes, leading to tissue injury and cell death. Among the therapeutic approaches considered are agents that inhibit/degrade proinflammatory mediators and thereby have anti-inflammatory and/or anti-atherogenic potential. These include inhibitors of phospholipase A2 activity, PAF-acetylhydrolases, PAF antagonists and free radical scavengers/antioxidants, the latter protecting against oxidized LDL-induced cytotoxicity.

INTRODUCTION Platelet-activating factor (PAF) was originally found as a phospholipid mediator released by sensitized rabbit basophils. The ability of this mediator to aggregate platelets at very low concentration (10–10 M) led to numerous studies which demonstrated widespread, potent inflammatory activity. It was identified indendently as an endogenous polar glycerophospholipid from kidney, and on acute administration could result in hypotension and decreased cardiac output in experimental animals.1,2 The structure of PAF is 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. PAF is produced by a wide variety of human cells and tissues which includes granulocytes, macrophages, endothelial cells, lung tissue, uterus, brain and kidney. PAF has potent effects on platelets, leukocytes, and the microvasculature.3,4 PAF acts at very low concentrations

Correspondence to: P. V. Peplow

(10–12–10–9 M) and is proposed to have multiple physiological and pathological actions. It has been implicated as a mediator of inflammation, allergy, shock, thrombosis and atherosclerosis. In this review, attention is given to the mechanisms that control the activity of PAF under physiological conditions and, based on this, the possibility of regulating PAF activity in human diseases. Medline database (1993– 1998) was searched to identify clinical trial research of agents that regulate PAF activity, as well as animal studies suggesting that these agents could be of benefit in treating human ischemic and inflammatory diseases. REGULATION OF THE ACTIVITY OF PAF UNDER PHYSIOLOGICAL CONDITIONS There are several powerful mechanisms that individually or together can control the biological activity of PAF under physiological conditions. These include tightly 65

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controlled synthetic pathways, efficient degradative enzymes that are constitutively present and active, regulated expression and activity of the PAF receptor and spatial regulation regarding the presentation of PAF to target cells that bear the PAF receptor by a process of juxtacrine signalling. Synthetic pathways The biosynthesis of PAF shares a common precursor source with arachidonic acid and eicosanoids.5,6 The major phospholipids from which arachidonic acid is released by phospholipase A2 (PLA2) are the choline- and inositol-containing phosphoglycerides. The cholinecontaining glycerophospholipids may contain a high level of 1-O-alkyl-2-acyl-glycero-3-phosphocholine and a large proportion of the arachidonate in these glycerophospholipids is present as 1-O-alkyl-2-arachidonoylglycero-3-phosphocholine. For certain cells and tissues a high proportion of phosphatidylinositol may also be enriched with arachidonate in the sn-2 position. PAF is synthesized by two enzymic pathways: the remodelling and de novo pathways. They have been described previously.7 Included in the remodelling pathway 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine is converted to 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine (lyso-PAF) by PLA2, and this lyso intermediate is then acetylated by acetyl-CoA:lyso-PAF acetyltransferase (lysoPAF AcT) to form PAF. PAF is not produced constitutively via this pathway: synthesis is induced when the cells are stimulated by an appropriate agonist. The remodelling pathway appears to be the principal mechanism of synthesis of PAF in stimulated neutrophils, monocytes and endothelial cells. This is probably the main mechanism for synthesis of PAF in various inflammatory and allergic disorders. PAF synthesized via the remodelling pathway is secreted into the fluid phase by human monocytes and eosinophils. In contrast, PAF synthesized by endothelial cells via the remodelling pathway is translocated to the plasma membrane and retained on the cell surface. In this position it acts as an intracellular messenger and stimulates target PMNs as part of a juxtacrine system.8,9 The second mechanism for PAF synthesis is the de novo pathway and starts with 1-O-alkyl-sn-glycero-3phosphate which is acetylated, followed by removal of the phosphate and its replacement with phosphocholine. This last reaction is catalysed by PAF-synthesizing phosphocholine transferase (PAF-PCT). The de novo pathway is proposed to mediate constitutive synthesis of PAF in the brain and kidney. Thus, PAF produced by this mechanism may play a role in the homeostatic functions of these organs. The activities of the two enzymes directly responsible for PAF synthesis, lyso-PAF AcT and PAF-PCT, have been

assayed in rat brain areas. PAF-PCT activity was always more elevated than that of lyso-PAF AcT. The activity of PAF-synthesizing enzymes was also studied in gerbil brain during ischemia and reperfusion. After 6 min from bilateral occlusion of the carotid arteries, an increase of lyso-PAF AcT activity occurred in the hippocampus. This enzyme activity remained relatively high up to 3 days after reperfusion whereas in other brain areas it reached basal levels much earlier. It is known that the PAF levels increase in the brain of animals during ischemia, and the findings suggest that the remodelling pathway provides an important contribution to its synthesis particularly in the hippocampus.10 Degradation by PAF acetylhydrolase The actions of PAF are abolished by hydrolysis of the acetyl residue, a reaction catalyzed by PAF acetylhydrolase (PAF-AH). Inactivation of PAF is carried out by specific intra- and extra-cellular PAF-AHs, which comprise a subfamily of PLA2 that remove the sn-acetyl residue of PAF, but not phospholipids with long chain sn-2 residues, and are Ca2+ independent. PAF-AH hydrolyzes PAF and short-chain forms of oxidized phosphatidylcholine, transforming them into lyso-PAF and lysophosphatidylcholine, respectively. Mammalian brain contains at least three intracellular isoforms of PAF-AH, of which isoform Ib is the best characterized.11,12 PAF-AH from human plasma has been purified and characterized. In human plasma with no detectable lipoprotein (a) (Lp(a)) levels, PAF-AH is associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) with a distribution of 70 and 30%, respectively. By density gradient ultracentrifugation, Lp(a) was migrated as a broad band in the density region of d=1.050–1.100 g/ml. In plasma with Lp(a) levels 30–40 mg/dl or 80–100 mg/dl the PAF-AH activity migrated in this density region was 4 or 9% higher when compared to plasma having Lp(a) levels < 8 mg/dl.13,14 Assay of paired samples of Lp(a) and LDL for their PAF-AH activity showed that Lp(a) had markedly enhanced PAF-AH activity (approximately 7-fold based on equal particle concentrations) in comparison to LDL isolated from the same individual.15 The physicochemical properties of the Lp(a)-associated PAFAH activity were similar to those of the LDL-associated enzyme. Macrophages and liver cells secrete PAF-AH and the secreted enzyme is biochemically and immunologically identical to the human plasma PAF-AH: it is associated with LDL and HDL, and is sensitive to the same inhibitors.16,17 The source of the plasma PAF-AH is thought to be the liver, the macrophages or both. Synthesis and secretion of the plasma form of PAF-AH by macrophages is induced during differentiation with the accumulation of PAF decreasing by 90% and the activity of PAF-AH

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increasing 260-fold in stimulated human monocytes as they differentiated into macrophages.18 These changes during the maturation of monocytes to macrophages may serve to limit the acute inflammatory response. Human plasma PAF-AH degrades oxidized phospholipids.19 Approximately 4% of the population in Japan may have a deficiency in plasma PAF-AH activity,20 while in the USA and Europe no cases of deficiency have been reported. Human serum obtained from a group of women, in which the 17β-estradiol concentration was elevated in preparation for an in vitro fertilization procedure, showed an inverse relationship between the plasma estrogen concentration and the PAF-AH activity.21 Plasma PAF-AH activity decreased 5-fold on administering 17α-ethynyl estradiol to male and female rats (i.p. 2.5 mg/kg body wt, 5 days), while the administration of dexamethasone (i.p. 1.3 mg/kg body wt, 5 days) resulted in a 3-fold increase in plasma PAF-AH activity. The change in activity caused by estrogen and dexamethasone was associated with a change in the activity in the HDL fraction and not due to the presence of an inhibitor or activator in the plasma of the hormone-treated rats.21 PAF-AH activity in the rat is present in the HDL fraction, while in the human PAF-AH activity is principally associated with the Lp(a) and LDL fractions. Lipopolysaccharide (LPS) inhibited the PAF-AH secretion by macrophages, as did the cytokines IL-1α, IL-1β and TNF-α. LPS stimulates the monocyte-macrophage system to induce the release of cytokines such as IL-1α, IL-1β and TNF-α, and the LPS-induced inhibition of PAF-AH secretion was partially reversed by IL-1 receptor antagonist or by neutralizing antibodies against IL-1α, IL-1β or TNF-α. The failure to obtain a complete reversal of the LPS-induced inhibition with excess concentrations of these blocking agents suggested the presence of other LPS-induced mediators which might include other cytokines (e.g. IFN-γ), eicosanoids and PAF.22 PAF stimulated the production of PAF-AH by liver cells. Thus, the liver may be a major source of plasma PAF-AH, and PAF may induce the production of its inactivating enzyme by the liver.23 Regulation of PAF receptor PAF acts by binding to a specific receptor which has been indicated as belonging to the ‘serpentine’ family of receptors, with the receptor protein spanning the plasma membrane seven times (i.e. is a ‘7-membrane-spanning’ receptor). Binding of PAF to its receptor induces signalling mediated by G proteins, and through G proteins the PAF receptor is linked to additional intracellular signalling mechanisms which include turnover of phosphatidylinositol, increases in intracellular calcium and activation of protein kinase C (PKC) and other kinases. © 1999 Harcourt Publishers Ltd

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In addition, in endothelial cells and certain others, presentation of PAF to target cells that bear the PAF receptor (PMNs, monocytes, etc) is regulated spatially by a process of juxtacrine signalling. In juxtacrine intercellular signalling, the molecule that induces the functional changes in the target cell remains associated with the plasma membrane of the signalling cell, rather than acting in the fluid phase. An example of this is the interaction of PMNs with cultured human endothelium. The interaction of leukocytes with the endothelium involves regulated expression of molecules on both the endothelial cell and the leukocyte. This is true for each of the major classes of leukocytes, including lymphocytes, monocytes and granulocytes. One group of molecules binds or ‘tethers’ the PMN to the endothelial cell without requiring PMN activation: P-selectin and E-selectin are examples. A second group of molecules activates the PMN by binding to signal-transducing receptors: PAF is an example. PAF is translocated to the endothelial cell surface, where it mediates juxtacrine activation of PMNs by binding to a ‘7-membrane-spanning’ receptor. One consequence of juxtacrine activation of PMNs by PAF is functional upregulation of CD11/CD18 integrins on the PMN. These integrins bind to ligands (ICAM-1 and others) that are present on the endothelial cell. Thus, combinations of tethering and signalling molecules regulate PMN adhesive interactions with endothelial cells. Juxtacrine activation of PMNs by PAF also induces development of a polarized shape and priming for enhanced granular secretion.9,24–27 Human monocytes, neutrophils, platelets and B-lymphatic cell lines appear to constitutively express the same, or a similar, receptor for PAF.28 Various cytokines and eicosanoids regulate PAF-receptor gene expression.29 Treatment of human monocytes with IFN-γ caused an up-regulation of the PAF receptor at the mRNA and protein levels, and was associated with an increased response to PAF.30 In contrast, a transiently elevated intracellular concentration of cyclic AMP (cAMP) induced with prostaglandin E2 was a sufficient signal to inhibit PAF receptor expression in human monocytes at the mRNA and protein levels, and there was a diminished responsiveness to PAF. PAF receptor expression can be regulated at the transcriptional and possibly post-transcriptional levels by elevation of intracellular cAMP.29,31 Down-regulation of surface PAF receptor expression in human monocytes was also induced by phorbol myristate acetate (PMA), and was preceded by a rapid down-regulation of PAF receptor mRNA expression. It could be blocked by the protein kinase C inhibitors, H-7 and calphostin C. PAF receptor gene expression in human monocytes can be regulated through a PKC-dependent pathway and involves posttranscriptional destabilization of receptor mRNA.32 An enhanced expression of PAF receptor on human eosinophils was brought about by treatment with IL-3,

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IL-5 or GM-CSF, and suggests that these cytokines modulate the responsiveness of eosinophils to PAF through enhancement of PAF receptor expression on the cell surface.33 EFFECTS OF PAF ON CELLS IN REGARD TO EXPRESSION OF ADHESION MOLECULES AND FREE RADICAL GENERATION Adherence and extravasation of neutrophils and eosinophils across stimulated endothelial cells occurs in various inflammatory diseases. Local activation of these cells and release of reactive oxygen species, lipid mediators and granule constituents subsequently contributes to the pathological features of these disorders. Cell adhesion molecules (Table 1) Infiltration of granulocytes into tissues is governed by a number of receptors belonging to distinct families of adhesion molecules. During the initial step of adhesion and transendothelial migration, granulocytes roll on vascular endothelial cells. This step is mediated by reversible binding (i.e. weak interaction) of L-selectin (lectin adhesion molecule-1 [LECAM-1]) on the granulocyte to counter receptors on endothelial cells (E-selectin [LECAM-2]). This initial step is followed by a firmer adhesion, with Mac-1 (CD11β/CD18, CR3) being one of the molecules involved in this process. This molecule is a member of the beta-2 integrins and binds to ICAM-1 and ICAM-2 (intercellular adhesion molecule-1 and -2) on endothelial cells. Activation of the granulocyte by mediators bound to the endothelial cell surface causes a rapid shedding of L-selectin from the cell surface and Mac-1 is increased concomitantly by release from intracellular stores. PAF is one of the activating agents produced by endothelial cells34 and PAF (at 10–7 M) caused increases of CD11β expression of 35 and 43% in neutrophils and eosinophils, respectively;35 increases as high as 615% in neutrophils and 110% in eosinophils have also been reported.36 PAF (10–7 M) caused decreases of L-selectin expression of 14 and 37% in neutrophils and eosinophils.35 IL-5 affected selectively the surface expression of adhesion molecules in eosinophils but not neutrophils. IL-5 (10–9 M) caused an increase in CD11β expression of 44%

and a decrease in L-selectin expression of 50% in eosinophils. Eosinophil adhesion and degranulation, and superoxide production, induced by GM-CSF and PAF was markedly inhibited or abolished by treatment of the cells with anti-CD18 monoclonal antibody. This showed that Mac-1 (CD11 β/CD18)-dependent cellular adhesion plays an important role in the degranulation and superoxide production of eosinophils induced by GM-CSF and PAF.37 It has been observed that rolipram (an inhibitor of phosphodiesterase type IV, which hydrolyzes cAMP into the biologically inactive form 5′-AMP) inhibits PAFinduced CD11β increase and concomitant L-selectin decrease on human neutrophils and eosinophils, and also inhibits the respiratory burst in neutrophils and eosinophils.36 Several reports have shown that ligation and crosslinking of neutrophil L-selectin results in neutrophil activation, including intracellular calcium release, superoxide production, and induction of mRNA for IL-8 and TNF-α production.38 The process of adherence is a crucial step in the activation of leukocytes, and once activated leukocytes release a variety of humoral mediators that can damage any cell with which they are in contact. Among the various mediators released from leukocytes, particularly PMNs, are oxygen-derived free radicals (e.g. superoxide radicals, hydroxyl radicals), cytokines (e.g. IL-1β, TNF-α) and proteases (e.g. elastase). Activation stimuli which included IL-5, GM-CSF, IL-3, TNF-α, PAF, N-formyl-Met-Leu-Phen, phorbol myristate acetate (PMA) and ConA all induced adhesion of eosinophils to immobilized ICAM-1 and VCAM-1 in a dose and time dependent manner. IL-5 caused increased expression of CD11β molecules and decreased expression of L-selectin.39 Human monocytes adhered specifically to immobilized P-selectin (CD62P) or endothelial cells stimulated to express P-selectin on their cell surface. P-selectin primed monocytes for increased PAF synthesis and did not stimulate increased surface expression of integrin CD11β/ CD18.40 P-selectin expressed on endothelial cells or platelets may serve both to localize monocytes at sites of vascular inflammation or thrombosis and to prime the cells for subsequent responses that augment inflammation. Monocyte migration across unactivated endothelium in response to macrophage inflammatory protein-1α (MIP1α), RANTES, PAF or monocyte chemotactic protein-1

Table 1 Adhesive surface molecules involved in interactions between leukocytes and endothelial cells On surface of leukocyte

On surface of endothelial cell

Nature of binding

L-selectin (LECAM-1) PSGL-1 Mac-1 (CD11β/CD18)

E-selectin (LECAM-2) P-selectin (LECAM-3) ICAM-1 and ICAM-2

Weak (i.e. reversible) Weak Firm

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(MCP-1) was completely inhibited by monoclonal antibodies (mAbs) to CD18 of the CD11β/CD18 complex on the monocyte.41 Endothelial cells co-express E-selectin, P-selectin and PAF on their surfaces after activation by certain receptormediated agonists (see previous section). Together they mediate the adhesion of leukocytes to the endothelial cell surface. Binding of P-selectin on activated endothelial cells to P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils mediates the initial tethering and rolling of neutrophils on the vessel wall at inflammatory sites. P-selectin binding sites are uniformly distributed on the surface of quiescent neutrophils, but become redistributed to a segment of approximately 40% of the cell surface of activated, polarized neutrophils. The surface redistribution of PSGL-1 of activated neutrophils may facilitate transendothelial migration by a loosening or disruption of bonds between P-selectin and PSGL-1 at the leading edge of migrating cells.25,42 It has also been observed that adhesion of human monocytes to P-selectin increased the secretion of MCP-1 and TNF-α by the monocytes when they were stimulated with PAF. Increased cytokine secretion was specifically inhibited by G1, an anti-P-selectin mAb that prevents P-selectin from binding to PSGL-1 on the monocytes. Tethering of P-selectin specifically enhanced nuclear translocation of nuclear factor-kappa B (NF-kappa B), a transcription factor required for expression of MCP-1, TNF-α, and other immediate-early genes. Thus, P-selectin, through its ligand on monocytes, may locally regulate cytokine secretion in inflammed tissues.43 One mechanism suggested for the anti-inflammatory action of glucocorticoids is to induce dramatic downregulation of L-selectin and CD18 adhesion molecules on blood neutrophils.44

sion of L-selectin under the influence of oxygen radicals was not due to the histamine liberation. As histamine is known to induce a rapid up-regulation of the vascular adhesion molecule P-selectin in coexpression with PAF on endothelial cells, then the expression of the vascular and leukocyte selectins are both regulated by oxygen radicals but dependent on different mechanisms.46 Oxygen free radicals are involved in many pathological processes such as postischemic reperfusion injuries, hepatotoxicity of drugs and inflammatory processes. Postischemic reperfusion provokes inflammatory responses that contribute to tissue injury and necrosis. PMNs rapidly accumulate in ischemic tissue after the beginning of reperfusion, where they can form microvascular plugs and release proteolytic enzymes, reactive oxygen species and inflammatory mediators. These oxygen radicals induce damaging effects like lipid peroxidation, especially oxidative destruction of unsaturated fatty acids in the cell membrane inducing membrane leakage. Oxygen radicals further lead to a subsequent release of chemoattractants, leading to an accumulation of PMNs in the tissue. Oxygen radicals may act synergistically with PAF to potentiate tissue injury. Oxygen radicals induced > 50% loss of PAF-AH activity in human plasma and purified LDL within 60 s and almost complete inactivation by 10 min which was irreversible. Inactivation was prevented by the free radical scavengers superoxide dismutase (for superoxide radicals) or dimethylthiourea (for hydroxyl radicals) or by the iron chelator deferoxamine. Thus, superoxide-mediated, iron-catalyzed formation of hydroxyl radicals can rapidly and irreversibly inactivate PAF-AH. Inactivation of PAF-AH might represent one mechanism by which oxygen radicals may potentiate and prolong the proinflammatory effects of PAF.47

APPROACHES TO THE REGULATION OF PAF ACTIVITY IN HUMAN DISEASES

Production of oxygen free radicals PAF enhances superoxide (·O2–) production, CD11β expression and elastase release by PMNs, all essential components in the pathophysiology of multiple-organ failure. Lexipafant, a PAF receptor antagonist, inhibited PAF-enhanced superoxide production, CD11β expression and elastase release by PMNs.45 Eosinophils produced superoxide when stimulated with GM-CSF, PAF or PMA. The superoxide production induced by GM-CSF and PAF was abolished by treatment of cells with anti-CD18 mAb, indicating that CD11β/CD18 (Mac-1)-dependent cellular adhesion plays an important role in superoxide production of eosinophils induced by GM-CSF and PAF.37 Oxygen radicals induced the expression by endothelial cells of P-selectin and ICAM-1, and caused a shedding of the adhesion molecule L-selectin on leukocytes but did not alter the expression of CD18. The alteration in the expres© 1999 Harcourt Publishers Ltd

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Inhibition of PLA2 activation (Table 2) PLA2 is a key enzyme in the regulation of lipid mediators of the inflammatory process, providing the precursor for the eicosanoids when the cleaved fatty acid from membrane phospholipids is arachidonic acid, and for PAF when the sn-1 position of the phospholipid is an alkyl ether linkage (remodelling pathway). Therefore inhibition of this enzyme would be an important treatment in many inflammatory disease states. The secreted PLA2s are closely related proteins of low molecular weight (14 kDa) with calcium requirement in the mM range. Two types of secreted PLA2 have been identified in mammals: type I pancreatic PLA2 and type II inflammatory PLA2 which show 70% sequence homology. In contrast, the intracellular PLA2s have higher molecular weights (40–110 kDa)

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Table 2 Inhibition of PLA2 activation or its products Inhibitor

Model/species

Parameters affected

References

FPL 55712, a LTC4/D4 antagonist Nimesulide (CAS 51803-78-2) Cloricromene

PAF-induced intestinal injury; rat Activated neutrophils Activated neutrophils

Initial vasoconstriction, due to LTC4/D4 release, abolished PAF and LTB4 production PAF release, with activities of lyso-PAF AcT and PAF-PCT unaltered

52

and are either calcium independent or require microM amounts for activity.48 A multitude of structurally diverse compounds described in the literature have been reported to be inhibitors of PLA2 in vitro. Many of the PLA2 inhibitors have topical anti-inflammatory activity which may be due to their hydrophobic nature causing them to be more readily absorbed in the skin.49

Digestive disease and organ inflammation In vivo studies have shown that gut ischemia/reperfusion can provoke lung and liver injury by a mechanism that involves primed circulating neutrophils, and that PLA2 activation and its by-product, PAF, are implicated in this process. In vitro PAF-primed PMNs had an increased respiratory burst and increased adherence to endothelial cells.50 Cytokine stimulated endothelial cells have been shown to activate quiescent PMNs to disrupt the integrity of the endothelial cell monolayer by endothelial cell detachment rather than direct cytolysis.51 The disruption of endothelial integrity could explain the increased capillary permeability observed clinically and, in addition, may promote progressive organ inflammation by exposing thrombogenic surfaces leading to further accumulation of PMNs and other proinflammatory agents. PAF-induced injury in the rat intestine was attenuated by peptido-leukotriene antagonists, suggesting a role of PLA2.52 PAF at a dose below that causing intestinal injury rapidly up-regulated intestinal PLA2-II at both transcriptional and post-transcriptional levels, leading to a rapid increase in enzyme activity. This effect could not be blocked by PAF antagonist. However, depletion of circulating PMNs abolished the effect of PAF on PLA2-II gene expression and enzyme activation.53 Nimesulide (CAS 51803-78-2) exerts a marked antiinflammatory effect in several in vivo models of inflammation. Recent studies indicated that nimesulide not only inhibited PG synthesis in certain cell types, but also had pleiotropic effects on neutrophil functions, including the respiratory burst, integrin-mediated adherence and synthesis of PAF. Nimesulide dose-dependently inhibited PAF synthesis and the production of leukotriene B4 (LTB4) in stimulated neutrophils, indicating an inhibition by nimesulide of a common step in the release of these lipid

54

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mediators i.e. the activation of PLA2, possibly by elevating intracellular cAMP. The inhibitory effects of nimesulide on PAF and LTB4 production could largely be prevented by addition of H89, an inhibitor of cAMP-dependent protein kinase (PKA).54 Cloricromene is a coumarine derivative with antithrombotic and anti-ischemic properties which inhibits platelet and leukocyte function and suppresses arachidonic acid release by interfering with PLA2 activation. Cloricromene (50–500 microM) inhibited in a concentration-dependent manner the release of PAF by stimulated PMNs, but did not affect the activities of the enzymes involved in PAF-synthesis acetyltransferase or phosphocholine transferase. The inhibition of PAF release by activated leukocytes may contribute to the antithrombotic and anti-ischemic properties exerted by cloricromene.55 PAF-AH (Table 3)

Cardiovascular disease Animal studies have suggested that PAF may play a role in the pathophysiology of hypertension.56–58 An emerging concept in hypertension pathophysiology is the contribution of vascular structural changes (vascular remodelling). Vascular remodelling is usually an adaptive process in response to chronic changes in hemodynamic conditions and/or humoral factors. This process may contribute to the pathophysiology of vascular diseases and circulatory disorders. In hypertension, alterations in vascular structure are probably the consequence of increased pressure and flow, an imbalance of vasoactive substances, inflammatory mediators and endothelial dysfunction.59 An increase in plasma PAF-AH activity was found in patients with essential hypertension compared to control patients, and this increase was attributable to the higher PAF-AH activity in the LDL fraction. In patients with essential hypertension there was a tendency for plasma PAF-AH activity to increase with the length of the history of hypertension.60 PAF has been implicated as a major mediator involved in coronary artery constriction, modulation of myocardial contractility and the generation of arrhythmias which may bear on cardiac disorders such as ischemia, infarction and sudden cardiac death.61–64 Studies of European

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Table 3 Modifications of PAF-AH activity in various human diseases/disorders Disease/disorder

Change in PAF-AH activity of plasma (or serum) vs controls

References

Cardiovascular disease essential hypertension peripheral vascular disease myocardial infarction severe coronary artery disease ischemic stroke

↑ ↑ ↑ ↑ ↑

60

Respiratory disease bronchopulmonary dysplasia in newborn bronchial asthma

↑ days 3 to 5 ↓

73

Digestive disease Crohn’s disease severe chronic liver disease

↓ ↑ (serum)

76

Renal disease primary glomerulonephritis chronic renal failure

↑ (serum) ↓ HDL ↑ LDL and Lp(a)

80

Pancreatic disease insulin-dependent diabetes mellitus

↑ (serum)

89

Reproductive disease pregnancy-induced hypertension-preeclampsia

↑

92,93

Immunologically-related disorders systemic lupus erythematosus rheumatic disease

↓ (serum) ↑ (serum)

94

populations reported an increase in PAF-AH activity in patients with peripheral vascular disease and 1 year survivors of myocardial infarction.65,66 There was a correlation between PAF-AH activity and LDL- plus VLDL-cholesterol concentration in both patient and control groups, although correlations in the patient groups were variable with other lipid concentrations, and weak or non-existent with total cholesterol concentration. In the study after myocardial infarction, matching for individual lipid levels showed a higher PAF-AH activity in the patient group.66 A study in Australia reported that the average PAF-AH activity tended to be higher in patients with severe coronary artery disease. There were correlations between total cholesterol and LDL-cholesterol concentrations and PAF-AH activity in both patient and control groups, but PAF-AH activity was higher for a given cholesterol level in the patients with coronary artery disease.67 A missense mutation (G- →T transversion at nucleotide 994) in exon 9 of the plasma PAF-AH gene results in a Val- →Phe substitution at amino acid 279 of the mature protein and a consequent loss of catalytic activity in the degradation of PAF and oxidised phospholipids.68,69 The role of a deficiency or low activity of PAF-AH caused by the missense mutation in the etiology of coronary artery disease has been determined in the Japanese population. The genotype of plasma PAF-AH (MM, normal; Mm, heterozygote; mm, deficient homozygote) was determined by a polymerase chain reaction for 454 patients with myocardial infarction and 602 control subjects. The © 1999 Harcourt Publishers Ltd

65 66 67 70

74,20

79

87

96

frequency of the m allele was higher in male patients with myocardial infarction than in controls. In contrast, the m allele was not associated with myocardial infarction in women.69

Cerebrovascular disease Ischemic tissue injury is known to be associated with the release of PAF and in addition, tissue injury can cause impairment of blood cell rheological properties which may be due in part to the generation of oxidized membrane phospholipids. Any change that leads to a lower activity of PAF-AH in the erythrocyte membrane could lead to the accumulation of oxidized membrane phospholipids. The erythrocyte membrane activity of PAF-AH tended to be lower in stroke patients than in healthy control subjects. The erythrocyte cytosol activity was lower in the patients, while the plasma PAF-AH activity was higher in the patients with ischemic stroke than in the control subjects. There was a positive correlation between PAF-AH activity in erythrocyte membranes and the erythrocyte filterability in the stroke patients.70 It was reported that erythrocyte deformability is lower in stroke patients than in control subjects,71 but in a later study erythrocyte deformability was not altered in patients with acute cerebral ischemia compared to controls.72 Respiratory disease PAF is a mediator produced in human airways during

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acute and chronic inflammatory lung diseases. Inhaled PAF causes bronchoconstriction and increased airway responsiveness in human subjects. Infants developing chronic lung disease were smaller and of younger gestational age. In infants with bronchopulmonary dysplasia, higher PAF levels in blood were found on days 3 to 5, along with increased tracheal lavage PAF-AH activities on days 1 to 2, compared with infants without the disease over the first 7 days of life. Increased levels of PAF in tracheal lavage on days 3 to 5 were associated with increasing severity of bronchopulmonary dysplasia.73 The plasma PAF level was higher and the serum PAF-AH activity lower in adults with bronchial asthma, both in remission and at the time of asthmatic attack, than in healthy volunteers.74 A study in Japan showed that among healthy adults, healthy children, and asthmatic children, who were grouped into five classes on the basis of respiratory symptoms (remission, wheezy, mild, moderate, and severe groups), the probability of PAF-AH deficiency was higher in groups with severe symptoms (moderate and severe). It was suggested that deficiency of serum PAF-AH might be one of the factors leading to severe respiratory symptoms in asthmatic children.20 Acetylhydrolase activity (AH) has been measured in bronchoalveolar lavage (BAL) fluid obtained from normal donors and from adult patients with mild bronchial asthma or with lung fibrosis. BAL-AH is an enzyme different from secretory PLA2 and from plasma AH and erythrocyte AH and is correlated with the number of BAL macrophages. BAL-AH activity in patients with bronchial asthma was lower than that in normal donors, while BAL-AH activity in patients with lung fibrosis was higher than that in normal donors. The secretion and inactivation of BAL-AH may influence the levels of this enzyme in BAL fluid during acute and chronic inflammatory lung diseases and regulate the proinflammatory activities of PAF in these disorders.75

Digestive disease The PAF-AH activity in mucosal biopsy specimens from the distal ileum was lower in patients with Crohn’s disease than in control patients, and there was no difference in PAF-AH activity of colonic or jejunal mucosal specimens between Crohn patients and controls. The plasma PAF-AH activity of Crohn patients was decreased as compared to healthy subjects. Crohn patients with high disease activity had a lower plasma PAF-AH activity as compared to patients in clinical remission, and as compared to healthy subjects. The plasma PAF-AH activity increased within 4 months after bowel resection.76 By continuous perfusion of a colonic segment, PAF and lyso-PAF production were higher in patients with active ulcerative colitis compared to control patients. There

was a correlation between colonic PAF output and respectively, macroscopic mucosal lesions and myeloperoxidase colonic output.77 Myeloperoxidase is a marker enzyme for PMNs. PAF (0.35 µg) caused ischemic intestinal necrosis when administered intraaortically in rats, with extensive hemorrhagic damage in all regions of the small bowel and a marked hemoconcentration. Pretreatment of rats with dexamethasone or medroxyprogesterone increased plasma PAF-AH activity, and prevented the gross and histological features of ischemic intestinal necrosis. In contrast, when decreased activities of plasma PAF-AH were induced by 17α-ethynyl estradiol or 4-aminopyrazolopyrimidine administration, lower amounts of PAF were sufficient to cause bowel necrosis and hemoconcentration. PAF-AH is present in human milk: for newborn infants who are being breast-fed, the presence of this enzyme of milk origin in the lumen of the small bowel may be beneficial in the prevention of ischemic bowel necrosis.78 The PAF-AH activity in patients with severe chronic liver disease has been found to be altered in comparison to normal subjects. Liver patients with chronic cholestasis had elevated serum PAF-AH activity especially in stage III or IV primary biliary cirrhosis, as well as in a patient with secondary biliary cirrhosis and one with cholangiocarcinoma. Normalization of liver function following liver transplantation was accompanied by a reduction to normal or near normal PAF-AH activity, and it is likely that the liver can play an important role in regulating serum PAF-AH activity.79

Renal disease Increased PAF levels in the plasma and urine as well as increased PAF-AH activity in serum in patients with primary glomerulonephritis were found in comparison to normal volunteers. The PAF-AH activity in renal cortex of those patients was reduced compared to normal kidney tissue.80 Patients with chronic renal failure are at a greatly increased risk of developing cardiovascular disease, and this is only partly attributable to an increased prevalence of conventional risk factors.81,82 Increased susceptibility of LDL to oxidation was reported in chronic renal failure83,84 but other studies failed to confirm this.85,86 A recent study showed that serum PAF-AH activity was similar in patients with chronic renal failure compared to control subjects. Serum paraoxonase (aryldialkylphosphatase) and arylesterase activities were reduced in patients with chronic renal failure. HDL cholesterol was decreased in the patient group, whereas Lp(a) was increased. This suggested that PAF-AH activity associated with HDL is decreased because of the reduced concentrations of HDL cholesterol in renal failure, while increased activity in LDL

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or Lp(a) resulted in normal activity overall.87 Paraoxonase and PAF-AH are associated with HDL and have been shown to inhibit the oxidative modification of LDL. Oxidation of LDL is recognized as a key early event in the development of atherosclerosis (see free radical scavengers, Table 5). Oxidized LDL shows enhanced uptake in macrophages and can lead to cholesteryl ester accumulation and foam cell formation.88 Thus, reduced paraoxonase activity may contribute to decreased HDL antioxidant capacity in chronic renal failure and would be expected to contribute to the increased risk of atherosclerosis found in chronic renal failure.87

Pancreatic disease The PAF-degrading capacity as well as triglycerides and total and VLDL and LDL cholesterol in serum were increased in patients with insulin-dependent diabetes mellitus compared to control subjects, whereas no significant difference was observed in HDL cholesterol. These findings confirm the parallel changes of lipoproteins and PAF-degrading capacity found in serum from atherosclerotic patients.89 A 50-fold increase in blood levels of PAF was reported in patients with type 1 insulin-dependent diabetes mellitus without micro or macrovascular complications as compared with healthy subjects. By contrast, PAF was not significantly increased in patients with type 2 non-insulin-dependent diabetes mellitus with lipid abnormalities and micro or macrovascular complications. Similar levels of PAF precursors and PAFAH activity were noted in the three groups.90 Platelets from patients with type 1 diabetes exhibited more sensitivity to aggregation when compared with platelets from controls without diabetes after challenge with PAF. The increased aggregation observed in the platelets from patients with type 1 diabetes in response to PAF was due in part to their increased production of TxA2.91 Reproductive disease Pregnant women with normotension may be refractory to pressor agents such as angiotensin II in part because of the decrease in PAF-AH activity, which results in an increase in PAF. In contrast, plasma PAF-AH activity is not decreased in pregnant women with pregnancy-induced hypertension-preeclampsia, who have increased sensitivity to various pressor agents.92,93 Such a modulation also did not occur in the fetuses of pregnant women with pregnancy-induced hypertension.93 Immunologically-related diseases PAF was released in detectable amounts in the plasma of eight out of 10 patients with systemic lupus erythematosus (SLE) during the most active phases of the disease. PAF was never detectable in the plasma of patients with inactive SLE or of healthy subjects. PAF-AH activity was © 1999 Harcourt Publishers Ltd

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reduced in sera of 10 patients with active SLE as compared to seven patients with inactive SLE, 16 patients with rheumatoid arthritis (RA), five patients with nephrotic syndrome (NS) and 15 healthy subjects. The PAF-AH activity in sera of patients with active SLE had an association to LDL. The protein concentration of LDL was reduced in patients with active SLE as compared to patients with inactive SLE, RA and NS and to healthy subjects. This suggested that the decrease of PAF-AH activity in active SLE might be due in part to a change in LDL related to the activity of the disease.94 The levels of PAF bound to lipoproteins have been reported to be higher in the serum from patients with rheumatic diseases compared to that of control subjects.95 The PAF-AH activity in sera of patients with rheumatic diseases was increased when compared with that in the control group. The PAF-AH activity was enhanced to a lesser degree in RA than in non inflammatory arthritides (osteoarthritis and chondrocalcinosis). 96

Systemic inflammatory response syndrome After operations with cardiopulmonary bypass, patients often show early symptoms of the systemic inflammatory response syndrome (SIRS). Potential mediators of SIRS include PAF, which has been linked to septic shock and multiple organ dysfunction (see PAF receptor antagonists, Table 4). Plasma PAF-AH activity decreased by 38% after instituting cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery because of plasma dilution and returned to near-preoperative levels within 6 h postsurgery. After that, enzyme activity decreased again, resulting in a 24% reduction until at least 3 days postsurgery. Patients in poor postoperative condition had a lower preoperative PAF-AH activity than did normal patients. Moreover, patients who developed postoperative SIRS had a lower preoperative PAF-AH activity than did patients without SIRS.97 PAF receptor antagonists (Table 4) Antagonists for the PAF receptor are structural analogues that competitively inhibit the binding of PAF to the receptor, and also there are several antagonists with structures that are not obviously similar to PAF, but nevertheless act as competitive inhibitors.98 PAF receptor antagonists may also influence the activity of PAF by modulating the activity and/or secretion of PAF-AH. For example, the structurally related PAF receptor antagonist CV-3988 markedly inhibited the activity of PAF-AH and also reduced its release by rat hepatocytes. In contrast, BN 50739 and WEB 2170, thienotriazolodiazepine PAF receptor antagonists, did not affect the activity of PAF-AH, but increased its secretion by rat hepatocytes.99 PAF receptor antagonists inhibited PMN migration across cytokine-

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Table 4 Treatment with PAF receptor antagonists in various disease/disorders Disease/disorder

Model/species

Antagonist

Parameters affected

References

Cigarette-smoke exposure; hamster

WEB 2170

Inhibition of leukocyte adhesion to vascular wall and formation of leukocyte-platelet aggregates

102

Human

SR-27417A

103

asthma

Human

WEB 2086

mild and moderate asthma

Human

WEB 2086

Attenuated the late asthmatic response; no effects on early asthmatic response, allergen-induced airway responsiveness, or baseline lung measurements Reduction in inhaled corticosteroid dosage during treatment phase Higher clinical improvement than after treatment with placebo

Isolated left colon perfusion, intra-colonic administration of TNB; rabbit

WEB 2170

Inhibition of PAF release

106

Experimental interruption of blood flow to both kidneys; rat

Ro 24-4736

107

4 h cold renal ischemia/ reperfusion in presence of neutrophils; rat

BN 52021

Renal function less impaired and histological abnormalities less pronounced compared with postischemic kidneys from vehicle-treated animals Increased plasma flow rate, GFR and Na+ reabsorption compared to kidneys reperfused without antagonist

Human

Lexipafant

109

Pancreatitis induced by microvascular ischemia; male rat Alloxan-induced diabetes; mouse

BB 882

Reduced incidence of organ failure and total organ failure at the end of treatment Reduced the rise in serum amylase acitivity compared with controls and improved pancreatic histology score Antagonist protected against alloxan-induced diabetes

BN 50730

Improvement of clinical indicators when antagonist given at 40 mg × 2/day for 28 days; no improvement in clinical and biological indicators when antahonist given at 40 mg × 2/day for 84 days

112,113

CV-3988

Antagonist had protective effect

114

SM-12502

Antagonist prevented endotoxin-induced increases in pulmonary vascular permeability and histological changes Antagonist provided complete protection against endotoxin-induced lethality Antagonist reduced the mortality

116

Cardiovascular disease vascular disease Respiratory disease asthma

Digestive disease TNB-induced colitis Renal disease renal ischemia

Pancreatic disease acute pancreatitis acute pancreatitis diabetes

Immunologically-related disease rheumatoid arthritis Human

Systemic inflammatory response syndrome lung injury Postperfusion lung injury following cardiopulmonary bypass; dog sepsis Endotoxin-induced sepsis; rat sepsis gram-negative sepsis

Endotoxin-induced sepsis; mouse Human

SR-27388

SR-27388 BN 52021

activated endothelium. PMN migration across activated endothelium in response to exogenous PAF was also markedly inhibited following exposure of PMNs to 15(S)HETE. 15(S)-HETE was rapidly esterified into PMN phospholipids and 15(S)-HETE-remodelled PMNs displayed impaired cytoskeletal and adhesion responses when stimulated by exogenous PAF. The remodelling of PMN phospholipids with 15(S)-HETE was associated with a 6-fold reduction in the affinity of specific high-affinity PAF receptors for their ligand and impaired PAF-induced IP3 production.100

104

105

108

110

111

111

117,118

Cardiovascular disease Platelet aggregability to PAF at rest and after exercise was studied in 44 patients with coronary artery disease. The PAF EC50 values (the concentration which induces 50% of maximal aggregation) in 21 patients with positive exercise test results were decreased at rest compared with 21 normal subjects and the maximal percentage of aggregation to 50 nM PAF was increased. In contrast, the PAF EC50 values and the maximal percentage of aggregation in 23 patients with negative exercise test results were not different from the control group. In patients with positive

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exercise test results, the serum PAF-AH activity at rest was higher than for the control group, whereas the enzyme activity did not differ in patients with negative exercise test results compared to controls, and there was no change in PAF-AH activity during exercise in any group. Thus, in patients with exercise-induced myocardial ischemia, the platelet response to the aggregatory effect of PAF was increased at rest, in contrast to coronary artery disease patients without exercise-induced ischemia who responded like the controls. It was suggested that the platelets of patients with positive exercise tests expressed a high density of PAF receptors or a higher affinity of the receptors to the agonist.101 PAF receptor antagonists inhibited leukocyte adhesion to the vascular wall and formation of intravascular leukocyte-platelet aggregates which are induced within minutes by cigarette smoking. This correlated with the accumulation of PAF-like mediators in the blood of cigarette smoke-exposed hamsters. These mediators were PAF-like lipids, formed by nonenzymatic oxidative modification of existing phospholipids, that were distinct from biosynthetic PAF.102

Respiratory disease Treatment of asthmatic subjects with SR 27417A, a potent PAF receptor antagonist, attenuated the late asthmatic response. There were no effects on early asthmatic responses, allergen-induced airway responsiveness, or baseline lung measurements.103 The effect of an orally active PAF antagonist, WEB 2086 (40 mg × 3/day for 12 weeks), on the inhaled corticosteroid requirements of symptomatic atopic asthmatics was studied, and while a reduction in inhaled corticosteroid dosage was possible during the treatment phase, this was almost identical in the WEB 2086 and placebo treated groups.104 In a later study in which patients with mild and moderate asthma were treated with WEB 2086 (80 mg × 3/day for 8 weeks) there was a higher clinical improvement than after treatment with an inactive placebo.105 Digestive disease Using an ex vivo isolated left colon rabbit perfusion model, intracolonic administration of trinitrobenzene (TNB, 30 mg) induced colonic inflammation. During TNB infusion there was an increase in tissue levels of PAF compared to controls. Pretreating the colons with the PAF antagonist WEB 2170 prior to TNB infusion blocked PAF release, suggesting that PAF may play a role in TNB-induced colitis and mediate tissue injury.106 Renal disease An oral PAF antagonist, Ro 24-4736, was administered to rats prior to or after the interruption of blood flow to both kidneys for 30 min. In animals treated with the PAF © 1999 Harcourt Publishers Ltd

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antagonist prior to ischemia, renal function was less impaired and histological abnormalities were less pronounced when compared with postischemic kidneys from vehicle-treated animals. The PAF antagonist was also protective when administered 30 min but not 2 h following ischemic insult.107 The presence of PMNs during reperfusion of nonischemic rat kidneys produced no alteration of functional parameters or PAF production. After 4 hour cold ischemia, the presence of PMNs during reperfusion produced a worsening of plasma flow rate, glomerular filtration rate and Na+ reabsorption in comparison with kidneys reperfused without PMNs. Also, higher production of PAF occurred in the kidneys reperfused with PMNs than in the kidneys reperfused without PMNs. After 4 hour cold ischemia, addition of the PAF antagonist BN 52021 during reperfusion in the presence of PMNs increased the plasma flow rate, glomerular filtration rate and Na+ reabsorption in comparison with kidneys reperfused without this PAF antagonist. After 4 hour cold ischemia, addition of BN 52021 during reperfusion in the absence of PMNs had no effect on functional parameters in comparison with kidneys reperfused without the PAF antagonist.108

Pancreatic disease Trials of the PAF antagonist Lexipafant have been performed to see whether it could alter the clinical course and suppress the inflammatory response of human acute pancreatitis. There was a reduction in the incidence of organ failure and in total organ failure score at the end of medication (72 h). During this time seven of 12 patients with severe acute pancreatitis who had Lexipafant recovered from an organ failure; only two of 11 patients with severe acute pancreatitis who had placebo recovered from an organ failure and two others developed new organ failure.109 The effect of the PAF antagonist BB 882 on an experimental model of acute pancreatitis induced in male rats by a technique of microvascular ischemia was studied. A single intraperitoneal injection of BB 882 (5 mg/kg) given 30 min after induction of the disease in 12 animals reduced the rise in serum amylase activity compared with that in control animals and improved the pancreatic histology score.110 An i.v. administration of the dual PAF antagonist and anti-oxidant SR-27388 (10 mg/kg) in mice protected against alloxan-induced diabetes.111 Immunologically-related diseases Ten patients with an active rheumatoid arthritis were treated for 4 weeks with a PAF receptor antagonist, BN 50730, given orally (40 mg × 2/day). Clinical indicators of disease activity improved during the treatment period.112 However, in a later study in which 56 patients with active RA received either BN 50730 (40 mg × 2/day orally) or

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placebo for 84 days, treatment with BN 50730 resulted in no improvement in clinical and biological indices of RA activity.113

Systemic inflammatory response syndrome The PAF antagonist CV-3988 had preventive effects on postperfusion lung injury following cardiopulmonary bypass (CPB) in dogs. The PAF activity increased twice 5 min after the start of CPB, then it was progressively increased to a level 4.5 times at the end of CPB. Circulating numbers of leukocytes and platelets depleted sharply after the CPB, and then decreased gradually. Such depletion was not modified by CV-3988. Accumulation of leukocytes at the pulmonary circulation, and evidence of leukocyte sequestration in pulmonary capillary beds were found in dogs without CV-3988.114 Sepsis from gram-negative infections is attributed to the release of endotoxin (lipopolysaccharide, LPS) from cell walls of lyzed bacteria. LPS triggers a complex cascade of events including the activation of leukocytes and the concomitant release of inflammatory mediators such as PAF, cytokines, activated complement fragments and eicosanoids. These mediators in turn attract and activate additional leukocytes. Degradative enzymes and reactive oxygen radicals are released, organ and vascular damage and hemodynamic collapse occur, ultimately resulting in death. Serum concentrations of nitrite/nitrate (NOx), type PLA2, LTB4 and PAF-AH were higher in patients with septic shock compared to patients without septic shock.115 The effect of the PAF antagonist SM-12502 was studied in rats with endotoxin-induced sepsis. SM-12502 prevented endotoxin-induced increases in pulmonary vascular permeability and endotoxin-induced histological changes, such as leukocyte infiltration and pulmonary interstitial edema, 6 h following the administration of endotoxin.116 In mice, i.v. or oral doses of SR-27388, which is a dual PAF receptor antagonist and antioxidant, afforded complete protection against endotoxin-induced lethality.111 The antioxidant potency of SR-27388 is due to an efficient free radical scavenging activity.

Numerous PAF antagonists have been used in clinical trials for sepsis. BN 52021 (120 mg i.v. given every 12 h for 4 days) reduced the mortality of a subset of patients with gram-negative sepsis.117,118 Free radical scavengers (Table 5)

Cardiovascular disease Atherosclerosis is explained as a chronic inflammatory response to injury of the endothelium. Inflammatory and other stimuli trigger an overproduction of free radicals, which promote peroxidation of LDL in the subendothelial layer of the arterial wall. Products of LDL oxidation are bioactive, and induce endothelial expression and secretion of cytokines, growth factors and several cell adhesion molecules. The latter are capable of recruiting circulating monocytes and T lymphocytes into the intima where monocytes are differentiated into macrophages, the precursor of foam cells. In response to the growth factors and cytokines, smooth muscle cells proliferate in the intima, resulting in a narrowing of the lumen. Oxidized LDL can inhibit production of prostacyclin and nitric oxide, which are two potent autacoids that are vasodilators and inhibitors of platelet aggregation. Furthermore, oxidized LDL is toxic to cells of the arterial wall and increases atherogenesis.119,120 Vitamin E was shown to be protective against the development of atherosclerosis by retarding LDL oxidation.121,122 There is substantial evidence for a role of dietary antioxidants in the prevention of cardiovascular disease. Two recent reports add to the supporting evidence for a protective effect of vitamin C.123 One of these studies, a 5 year prospective population study of Finnish men, suggests that vitamin C-deficient men may be at increased risk of myocardial infarction. The other study suggests that vitamin C may play a role in preventing manifestations of existing coronary artery disease, rather than limiting disease progression. Dietary supplementation with vitamin C prevented the accumulation of PAF-like lipids in the blood of hamsters induced by cigarette smoke, and it prevented cigarette smoke-induced

Table 5 Treatment with antioxidants in various diseases/disorders Disease/disorder

Model/species

Antioxidant

Parameters affected

References

Cardiovascular disease atherosclerosis coronary artery disease

Rabbit, human Human

Vitamin E Vitamin C

Protective by retarding LDL oxidation Prevents manifestations of existing coronary artery disease

121,122

SOD

Inhibition of increases in PAF and myeloperoxidase activity and hemorrhagic changes in gastric mucosa

127

Reduction of pain

129

Digestive disease gastric mucosal injury

Electrical stimuli to gastric artery; rat Immunologically-related disease rheumatic diseases Human

Vitamin E

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leukocyte adhesion to the vascular wall and formation of leukocyte-platelet aggregates.102 Increased dietary intake of fruits and vegetables for 2 weeks providing 30 mg carotenoids/day in two matched groups of human subjects who were smokers or non smokers resulted in increased resistance of LDL to oxidation of 14 and 28% respectively. Blood reduced glutathione (GSH) level was higher in smokers at entry but returned to a concentration similar to non smokers at the end of the study.124 An increased plasma antioxidant capacity was shown to be associated with the development of new lesions in men with carotid atherosclerosis during a 5 year period. As scavenging of oxygen free radicals is considered to protect from atherogenesis, increased antioxidative capacity may represent an adaptive response.125 In studies using the thoracic aortas of control rabbits and from 1.5% cholesterol-fed rabbits, all of which had visible advanced atheromatous surface changes on the aortas, the superoxide dismutase (SOD) activity was lower in atherosclerotic aortas than in control aortas.126

Digestive disease Continuous infusion of SOD inhibited the increases in PAF and myeloperoxidase activity and the hemorrhagic changes in gastric mucosa brought about by electrical stimuli to the gastric artery in rats. This suggested that oxygen radicals derived from PAF-activated granulocytes induce oxidative stress, and that oxidative changes are implicated in the pathogenesis of gastric mucosal injury.127 Pancreatic disease Glycosylation increased LDL oxidation due to superoxide radicals, and also reduced PAF-AH activity. These changes may contribute to enhance and/or accelerate the progression of atherosclerosis in diabetic patients.128 Immunologically-related diseases Beneficial effects of vitamin E in the therapy of osteoarthritis were described some 30 years ago. Recent studies have also shown a beneficial effect of vitamin E in rheumatic diseases, mainly in the reduction of pain.129 Systemic inflammatory response syndrome A study of PMNs isolated from patients undergoing cardiopulmonary bypass (CPB) demonstrated that CPB not only directly primed PMNs, but also potentiated priming of PMNs by PAF. PMA-activated PMN superoxide production was raised at 6 h post-CPB compared to preCPB levels. When PMNs were primed in vitro with PAF and then activated, superoxide production at 6 h postCPB was higher than pre-CPB levels.130 © 1999 Harcourt Publishers Ltd

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THERAPEUTIC POTENTIAL OF AGENTS REGULATING PAF ACTIVITY Endothelial dysfunction, which is an important earlyrecurring phenomenon in ischemic injury and an important initial step in the development of atherosclerosis, appears to be triggered within 2.5 min of the endothelial production of a large burst of superoxide radicals. The initial dysfunction may be amplified by neutrophilgenerated factors, including oxygen-derived free radicals, cytokines, proteases and lipid mediators (e.g. PAF, LTB4). In addition adhesion molecules on the surface of the PMN, along with their ligands on the endothelial cell membrane, promote endothelial dysfunction through juxtacrine cell signalling. Pharmacological agents that exert endothelial protective effects can be grouped into three broad categories: (1) substances replacing endogenous cytoprotective agents of endothelial origin including prostacyclin (PGI2) and endothelium-derived relaxing factor (EDRF): the endothelium protecting agents include these agents as well as stable analogues of PGI2, and nitric oxide donors; (2) substances that inhibit/degrade proinflammatory mediators of endothelial origin: the proinflammatory agents are primarily PAF and oxygen-derived free radicals (e.g. superoxide radicals); and (3) substances that inhibit neutrophils or neutrophil-derived mediators such as oxygen-derived free radicals, cytokines (e.g. TNFα and IL-1β), proteases (e.g. elastase) and lipid mediators (e.g. PAF, LTB4).131 Therapeutic agents in category (2) that have antiinflammatory and/or anti-atherogenic potential are: PLA2 inhibitors. Although there are many PLA2 inhibitors with anti-inflammatory activity, very few have been clinically evaluated. To date, manoalide has been clinically evaluated and a retenoid derivative, BMS 181162, may enter clinical trials for psoriasis. The concept of regulating eicosanoid and PAF production by PLA2 inhibition still remains a viable therapeutic approach for the treatment of inflammatory disease. PAF-AH. In animal studies, administration of supplemental, exogenous PAF-AH has been shown to suppress inflammation.132 Thus, in diseases where there is a deficiency of enzyme activity, and PAF or related compounds might accumulate, supplemental PAF-AH may reverse the pathological response. Paraoxonase and PAF-AH work in concert to inhibit LDL oxidation and may therefore have anti-atherogenic properties. PAF anatagonists. In animals, antagonizing PAF, as adjunct treatment with currently used reperfusion therapies, improved cardiovascular function and survival, and should be introduced into clinical trials to determine whether similar protective effects can be provided in humans.133 Several PAF antagonists have passed safety and efficacy testing in humans; however, to date, no

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clinical trials have investigated the protective effects of PAF antagonists against regional myocardial ischemiareperfusion injury. Also in animals, antagonizing PAF provided protection against ischemic renal injury, and the coincident use of anti-ICAM-1 monoclonal antibody did not confer additional protection over that provided by PAF antagonist alone. Moreover after 4 hour cold ischemia, the addition of a PAF antagonist during reperfusion of kidneys protected against a decline of functional parameters that occurred during reperfusion in the presence of PMN. From the results of studies in experimental pancreatitis there exists a rationale for the use of PAF antagonists in the treatment of acute pancreatitis. Two pilot studies have demonstrated a beneficial effect of the PAF antagonist Lexipafant on acute pancreatitis. A multicentre, phase III study is currently underway in the UK. The PAF antagonist WEB 2086 has proved to be useful in the treatment of mild and moderate asthma, while the antagonist BN 52021 has reduced the mortality of patients with gram-negative sepsis. Furthermore, PAF antagonists may have clinical applications in reducing the inflammatory process in human allograft recipients, for example in the transplantation of ischemically injured kidneys or liver. Treatment of rats with kidney allografts with the PAF antagonist BN 52021 resulted in an improvement in renal allograft function and decreased thromboxane production by homogenates prepared from kidney allografts.134 Also the PAF antagonist TCV-309 improved posttransplant function of rat kidneys that had been subjected to a period of warm ischemia prior to cold storage and there was decreased PMN infiltration in the renal grafts.135 The PAF antagonist E5880 together with the immunosuppressant FK506 improved the function of porcine hepatic allografts subjected to prolonged warm ischemia in non-heart-beating donors.136 Free radical scavengers. Animal studies have shown that free radical scavengers (e.g. superoxide dismutase) and antioxidants (including vitamin C, vitamin E) can inhibit oxidative stress brought about by oxygen radicals derived from PAF-activated granulocytes. SR-27388, which is a dual PAF antagonist and efficient free radical scavenger, protected against endotoxin-induced lethality and alloxaninduced diabetes in mice. Therapeutic agents in category (3) are: free radical scavengers, antibodies to proinflammatory cytokines, antiinflammatory cytokines, elastase inhibitors, LTB4 receptor antagonists. Agents which inhibit the juxtacrine signalling pathways are monoclonal antibodies to cell adhesion proteins (e.g. anti-CD11β, anti-CD18, anti-ICAM-1). New effective treatments of tissue injury may require the coincident use of several of these agents, and indicates a need for the physiological and pathophysiological interactions between these agents to be investigated. A variety of anti-cytokine therapy and anti-mediator therapy

has been tested in an attempt to prevent or reduce multiple organ dysfunction syndrome developing in patients under overwhelming surgical insults such as major surgery, severe trauma, extensive burn and systemic sepsis.137 Also to prevent a recurrence of atrial arrthymia, type la or lb antiarrhythmics which have been shown to be effective may be used in association with each other or with other treatments (e.g. anti-PAF).138

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