Leukotrienes in respiratory disease.

Arachidonic acid metabolism via 5-lipoxygenase gives rise to a group of biologically active lipids known as leukotrienes: leukotriene B(4), which is a potent activator of leukocyte chemotaxis, and cysteinyl leukotrienes (leukotriene C(4), D(4)and E(4)) which account for the spasmogenic activity previously described as slow-reacting substance of anaphylaxis. The biological actions of leukotrienes and the observations that leukotrienes are synthesised in the lung following antigen provocation and are elevated in asthma, stimulated considerable activity in the pharmaceutical industry to find drugs that modulate the synthesis or actions of leukotrienes. Three cysteinyl leukotriene antagonists (zafirlukast [Accolate], montelukast [Singulair] and pranlukast) and one 5-lipoxygenase inhibitor (zileuton) have received regulatory approval for the treatment of asthma. The clinical data obtained from using these drugs are generally consistent and complimentary. As a class the leukotriene modulators produce a rapid improvement in lung function after the first oral dose. Lung function improvements are maintained on chronic administration and are associated with reductions in a variety of asthma symptom scores. All of the available data are consistent with the hypothesis that all the leukotriene modulators exert their clinical benefit primarily through interference with cysteinyl leukotrienes. There are no compelling clinical data for an additional contribution by leukotriene B(4)in human asthma. In other respiratory conditions such as COPD, which are characterised by pronounced neutrophil infiltration, it may be that the chemotactic properties of leukotriene B(4)are more important and therefore evaluation of 5-lipoxygenase inhibitors in this condition is warranted. The introduction of the leukotriene modulators into clinical practice is the culmination of over 60 years of research since the initial discovery of the slow-reacting substances. The leukotriene modulators, and in particular the cysteinyl leukotriene antagonists, provide respiratory physicians with an oral therapeutic option and have set an efficacy standard which new oral anti-inflammatory approaches will have to beat.

Structure and activity relationships leading to the discovery of ICI D2138, a selective, potent and orally active inhibitor of 5-lipoxygenase.

Structure and activity relationships of (methoxyalkyl)thiazole and 4-methoxytetrahydropyran series of 5-lipoxygenase inhibitors are reviewed. One member of the 4-methoxytetrahydropyran series, 6-([fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]methyl) -1- methylquinol-2-one (ICI D2138), is undergoing clinical evaluation.

Stimulation of human polymorphonuclear leukocytes by leukotriene B4 and platelet-activating factor: an ultrastructural and pharmacological study.

Human polymorphonuclear leukocytes (PMNs) stimulated by N-formylmethionyl-leucylphenylalanine (fMLP), leukotriene B4 (LTB4) and platelet-activating factor (PAF) showed a similar sequence of ultrastructural changes. Exposure of unstirred PMNs to these soluble stimuli induced a rapid (within 10 s) plasma membrane ruffling followed by polarization of cells associated with formation of broad agranular lamellipodia (maximal by 30 s). Similar changes were observed in stirred PMN suspensions except that the polarized cells formed multicellular aggregates with the agranular lamellipodia extending outward from the clumps. In addition, these receptor-directed agonists induced concentration-dependent PMN aggregation that was rapid and reversible, and in cells pretreated with cytochalasin B the agonists induced a degranulatory response. The calcium ionophore ionomycin also activated PMNs but, in contrast to the other stimuli, ionomycin produced irreversible aggregation and evoked enzyme release in the absence of cytochalasin B. Ionomycin stimulated LTB4 release, whereas the response induced by PAF or fMLP was barely detectable. The possible role of LTB4 and PAF in mediating responses to other agonists was investigated pharmacologically using the 5-lipoxygenase inhibitor PF 5901 and a specific PAF antagonist, kadsurenone. PF 5901 blocked ionomycin-induced LTB4 release but did not inhibit aggregation or degranulation induced by ionomycin, PAF, fMLP, or LTB4. Kadsurenone blocked PAF-induced aggregation and degranulation but not responses to LTB4, ionomycin, or fMLP. We conclude that LTB4 and PAF are potent activators of human PMNs that act independently of one another and that these lipids appear not to be involved in the responses to the other agonists studied.

Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase.

1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site. Zileuton was approximately 40 times less potent.7. Oral anti-inflammatory activity was assessed in an arachidonic acid-induced mouse ear oedema model in animals treated with indomethacin to block pro-inflammatory prostanoids. ICI D2138, given orally, caused dose-dependent inhibition of oedema with an approximate ID50 of 1.8 mg kg'. Zileuton was approximately 10 times less potent.8. ICI D2138 caused a dose-dependent inhibition of antigen-induced broncho-constriction in guineapigs with an approximate ID50 of 0.1 mg kg-', i.v. Zileuton was approximately 10 times less potent.9. In view of the pharmacological profile described here, ICI D2138 has the potential to provide improved clinical efficacy compared to existing lipoxygenase inhibitors such as zileuton.

Designing therapeutically effective 5-lipoxygenase inhibitors.

Metabolism of arachidonic acid by the enzyme 5-lipoxygenase leads to the formation of a group of biologically active lipids known as leukotrienes. Peptidoleukotrienes are powerful bronchoconstrictor agents while leukotriene B4 is a potent chemotactic agent for a variety of leukocytes. In view of these properties, leukotrienes have been proposed as important mediators in allergic and inflammatory disorders, and inhibitors of 5-lipoxygenase, by blocking leukotriene synthesis, have therapeutic potential in a range of diseases including arthritis and asthma. This review by Rodger McMillan and Ed Walker summarizes the biology of leukotrienes and the current knowledge of the mechanism of 5-lipoxygenase, providing a framework for consideration of the discovery, development and clinical status of drugs in the three major classes of 5-lipoxygenase inhibitors: 'redox' inhibitors, iron ligand inhibitors and 'non-redox' inhibitors.

Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors.

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth-2-ylmethoxy)phenyl]-1-thiazol-2-ylprop yl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2-ylmethoxy)phenyl]-4- methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 microM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 microM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 microM in human blood, a selectivity for 5-LPO over CO of greater than 20,000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.

Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase.

Methoxyalkyl thiazoles are novel 5-lipoxygenase inhibitors which are neither redox agents nor iron chelators and are exemplified by ICI211965 [1-(3-(naphth-2-ylmethoxy)phenyl)-1-(thiazol-2-yl)prop yl methyl ether]. ICI211965 potently inhibits LTC4 synthesis in murine macrophages (IC50 = 0.0085 microM) and its selectivity with respect to cyclo-oxygenase (greater than 5800) is greater than any previously reported lipoxygenase inhibitor. ICI211965 also selectively inhibits LTB4 synthesis by human blood in vitro (IC50 = 0.45 microM) and rat blood ex vivo (ED50 = 10 mg/Kg, p.o.). Methoxyalkyl thiazoles exhibit a tight structure activity relationship and resolution of a chiral member of the series demonstrates that 5-lipoxygenase inhibition resides largely in one enantiomer. Methoxyalkyl thiazoles represent the first class of agents for which 5-lipoxygenase inhibition is mediated by specific, enantioselective interaction with the enzyme.

Are tolfenamic acid and tenidap dual inhibitors of 5-lipoxygenase and cyclo-oxygenase?

Tolfenamic acid and tenidap have been reported to be dual inhibitors of cyclo-oxygenase and 5-lipoxygenase. In this study inhibition of 5-lipoxygenase by tenidap and tolfenamic acid in plasma-free leukocyte suspensions (IC50 values = 10 microM) required concentrations more than 100 fold higher than those which inhibited cyclo-oxygenase (IC50 values = 0.05 and 0.02 microM respectively). The potencies of tolfenamic acid and tenidap as cyclo-oxygenase inhibitors were markedly reduced in blood (IC50 = 6.5 and 10 microM respectively) and neither significantly inhibited 5-lipoxygenase. Since both drugs also failed to inhibit 5-lipoxygenase in rat blood ex vivo, we conclude that, at physiological levels of plasma proteins, tolfenamic acid and tenidap are selective cyclo-oxygenase inhibitors.

(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity.

(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.

Identification, characterization, and quantitation of soluble HLA antigens in the circulation and peritoneal dialysate of renal patients.

Human lymphocyte antigen (HLA) class I and class II antigens and beta 2 microglobulin (B2M) were identified in peritoneal dialysate (PD) and serum from patients with end-stage renal disease (ESRD) using monoclonal antibodies in an enzyme-linked immunoassay. The HLA class I and class II antigens each exhibited approximate molecular weights of 50,000 to 60,000 daltons by chromatography on Sepharose CL 6B. Class I antigens in serum and PD fluid were associated with B2M. Free B2M (Mr 11,500) also was detected in both sera and PD fluids. Unlike class I antigens, class II antigens were not found to have attached B2M. Class I and class II antigens eluted from 2-diethylaminoethanol ion exchange gradient columns at 0.07 mol/L (molar) phosphate buffer pH 7.2 and migrated with alpha 2-beta 1 mobility in agarose electrophoresis. Class I antigens were purified from ESRD patients' PD fluid by solid-phase immunoaffinity chromatography. Enzyme-linked immunoassay demonstrated that this purified protein was composed of a class I heavy chain and B2M. Class I allospecificity was confirmed by neutralization on known HLA typing antisera in a microcytotoxicity assay. Soluble HLA class I antigen preparations specifically inhibited blast transformation of responder lymphocytes in mixed lymphocyte culture reactions. Inhibition was dose dependent and ranged from 0% to 95%. The presence of soluble HLA antigens in body fluids may play an important part in the immunologic tolerance to self. This study demonstrates a ready source of large quantities of soluble HLA for detailed analysis.

Indazolinones, a new series of redox-active 5-lipoxygenase inhibitors with built-in selectivity and oral activity.

Since the hypothetical mechanisms of hydroperoxydation of arachidonic acid by, respectively, 5-lipoxygenase (5-LPO) and cyclooxygenase (CO) involve a redox cycle, a compound which reduces 5-LPO and CO to their inactive state would give a nonselective inhibitor of both enzymes. Structural modifications of such a compound could be expected to give improved potency and selectivity for 5-LPO and oral activity. Such an approach has led to the discovery of 1,2-dihydroindazol-3-ones which are potent 5-LPO inhibitors with various degrees of selectivity. Structure-activity relationship studies indicated that while N-1,N-2-unsubstituted and N-1-substituted derivatives are orally inactive, N-2-alkyl derivatives are orally active and inhibit both 5-LPO and CO. In contrast, N-2-benzyl derivatives are selective for 5-LPO but possess only weak oral activity. Further structural modifications have identified ICI 207968 [1,2-dihydro-2-(3-pyridylmethyl)-3H-indazol-3-one, 21a] which combines potent oral activity and high selectivity. Methemoglobin (MHb) induction by 21a in dog blood precluded its development for clinical use. Attempts at dissociating 5-LPO inhibitory properties and MHb formation showed that MHb formation in vitro seemed to be related to the redox potential of the compounds whereas 5-LPO inhibition was not. This study led to a series of 4-(N-n-pentylcarbamoyl)indazolinones which maintained in vitro 5-LPO potency but did not induce MHb.

Selective chiral inhibitors of 5-lipoxygenase with anti-inflammatory activity.

The studies described here, using enantiomers of an optically-active methoxy alkyl thiazole ICI216800 (1-methoxy-6-(naphth-2-yl-methoxyl)-1- (thiazol-2-yl)indane), provide unequivocal evidence for a specific, chiral interaction with 5-lipoxygenase. In accordance with their biochemical efficacy these compounds also demonstrate enantio-specific anti-inflammatory activity in a leukotriene-mediated model of inflammation. This is the first class of compounds for which 5-lipoxygenase inhibition and anti-inflammatory activity have been shown to be mediated via a specific chiral interaction.

2-substituted indazolinones: orally active and selective 5-lipoxygenase inhibitors with anti-inflammatory activity.

1. This paper describes the pharmacological profile of ICI207968, a novel, orally-active and selective inhibitor of 5-lipoxygenase. 2. Inhibition of leukotriene B4 (LTB4) synthesis by 2-substituted indazolinones was not directly related to redox potential but was critically dependent on the nature of the N2 substituent. 2-(3-Pyridylmethyl)-indazolinone (ICI207968) combined selectivity and oral potency. 3. In several in vitro systems ICI207968 exhibited similar lipoxygenase inhibitory potency (IC50 values from 1.5 microM to 6.0 microM) and was approximately 300 times less potent against cyclo-oxygenase, as measured by inhibition of prostaglandin E2 (PGE2) synthesis. 4. ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED50 values of 2.5, 10 and 25 mg kg-1 p.o. for inhibition of LTB4 release from A23187-stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE2 synthesis at oral doses up to 300 mg kg-1. 5. Co-administration of ICI207968 with arachidonic acid, into rabbit dermis, potently inhibited both plasma extravasation and polymorphonuclear leucocyte (PMNL) infiltration induced by this inflammatory fatty acid. The anti-inflammatory potency of a number of intradermally administered indazolinones, with similar redox potentials, was related to their inhibitory potency against leukotriene generation in blood. Oral administration of ICI207968 (100 mg kg-1) in the rabbit inhibited ex vivo leukotriene generation in blood and arachidonic acid-induced skin inflammation. 6. These data demonstrate that ICI207968 is an orally active and selective inhibitor of 5-lipoxygenase which has anti-inflammatory properties. IC1207968 will be a valuable agent for clarifying the biological roles of leukotrienes and the therapeutic potential of 5-lipoxygenase inhibitors.

Metabolism of unsaturated fatty acids by RBL-1 5-lipoxygenase: influence of substrate solubility and product inactivation.

Several alternative fatty acid substrates have been employed to characterise the kinetics of rat basophilic leukaemia cell (RBL-1) 5-lipoxygenase. Using arachidonic acid (AA) as substrate, enzymes rates declined at high substrate concentrations (greater than 25 microM) and were associated with pronounced lag phases. The concentrations of AA at which apparent substrate inhibition and lag phases were observed were comparable with those at which AA induced emulsion formation in aqueous media. No evidence for substrate inhibition or lag phases was observed using eicosapentaenoic acid (EPA), a more soluble substrate which did not induce emulsion formation at concentrations up to 100 microM. Reactions catalysed by RBL-1 5-lipoxygenase terminated before exhaustion of substrate. AA and EPA induced time-dependent enzyme inactivation at concentrations 100-fold lower than their apparent Km values for the enzyme. The ability of several fatty acids to induce time-dependent inactivation was directly proportional to their substrate potency. We conclude that apparent substrate inhibition is a consequence of a change from monomeric to micellar substrate which has a lower affinity for the enzyme and that premature termination of the enzyme reactions is a consequence of product-induced enzyme inactivation.

Agonist-induced calcium flux, phosphoinositide metabolism, aggregation and enzyme secretion in human neutrophils.

Formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF) and leukotriene B4 (LTB4) are potent activators of human neutrophils. Using human neutrophils prelabelled with the fluorescent indicator dye, Quin 2, or with [32P]-orthophosphate, we examined the effects of these stimuli on intracellular free calcium concentration, [Ca2+]i, and on various indices of phosphoinositide metabolism, including [32P]-phosphatidic acid (PtdA) formation. The concentration-dependence of the observed changed in [Ca2+]i or [32P]-PtdA were then compared to stimulus-induced aggregation and enzyme release (beta-N-acetylglucosaminidase (NAG) and lysozyme). FMLP, PAF and LTB4 caused a concentration-dependent elevation of [Ca2+]i, aggregation and enzyme release. However, unlike FMLP and PAF, LTB4 (less than or equal to 2.5 microM) did not cause significant formation of [32P]-PtdA. The concentration response curves for agonist-induced elevation of [Ca2+]i lie to the left of those for aggregation and enzyme release. FMLP and PAF also caused an elevation of [Ca2+]i at concentrations lower than those required to elicit [32P]-PtdA formation. These observations suggest that [Ca2+]i elevation per se cannot mediate human neutrophil functional responses to FMLP, PAF and LTB4. Consequently there may exist other mediator(s) that act in concert with [Ca2+]i or are triggered by [Ca2+]i elevation to promote human neutrophil activation. Both the elevation of [Ca2+]i and the formation of these putative mediator(s) in response to LTB4 apparently occur independently of inositol phospholipid hydrolysis.

Leukotriene B4 and inflammatory disease.

Polymorphonuclear leukocytes (PMNL) are prominent at sites of acute inflammation. Their infiltration is stimulated under pathological conditions by a variety of agents which include bacteria, immune complexes and complement derived chemotactic peptides. Recently attention was focussed on the 5-lipoxygenase product leukotriene B4 (LTB4) which has been demonstrated to induce the key features associated with an acute inflammatory reaction. However, evidence supporting a pro-inflammatory role for LTB4, and therefore the anti-inflammatory efficacy of 5-lipoxygenase inhibitors, is largely circumstantial. Moreover, there are concerns that other chemotactic factors, notably C5a, may compensate for the absence of LTB4. Here we challenge this view and, on the basis of recent experimental and clinical data suggest that LTB4 does not simply duplicate the activity of C5a. Instead we propose that their predominant site(s) of action differ in such a way that they may synergise in mediating PMNL recruitment.

Leukotriene B4 metabolism in human leukocytes: fact or artefact?

The object of this study was to investigate the importance of omega oxidation in regulating leukotriene B4 (LTB4) levels in man. In human polymorphonuclear leukocytes metabolism of LTB4 was rapid but was critically dependent on PMN number: greater than 1.5 X 10(6) PMN/ml were required. Metabolism of LTB4 was blocked in the presence of plasma. In whole blood and in PMN-rich rheumatoid synovial fluids no significant metabolism of LTB4 was detected within 30 min at 37 degrees C. We conclude that LTB4 metabolism at inflamed sites will be regulated both by cellular content and the degree of plasma exudation. In most pathological conditions rapid exchange with the micro-vasculature will be more important than metabolism in limiting LTB4 levels.

Interactions of murine macrophages with monosodium urate crystals: stimulation of lysosomal enzyme release and prostaglandin synthesis.

Exposure of murine peritoneal macrophages to crystals of monosodium urate monohydrate (MSUM) stimulated release of inflammatory mediators from the cells. There was an early, rapid burst of prostaglandin E2 (PGE2) synthesis which was complete by 2 h. Release of N-acetyl glucosaminidase (NAG), a lysosomal enzyme, was evident within 1 h and was maximal by 8 h. Early release of lysosomal enzymes (1-2 h) was not accompanied by leakage of cytoplasmic enzymes; however, treatment with high concentrations of MSUM, or prolonged exposure to crystals, provoked release of the cytoplasmic enzyme lactate dehydrogenase, presumably as a result os cell lysis. Responses of macrophages to MSUM occurred in the absence of serum but were modified by serum proteins. Prior exposure of crystals to IgG potentiated release of NAG and PGE2. Exposure to albumin slightly enhanced release of PGE2 induced by MSUM but did not affect NAG release. However, albumin prevented enhancement of NAG release by IgG. The interaction of MSUM with macrophages, and subsequent release of inflammatory mediators, may contribute to the inflammation association with both acute and chronic gouty arthritis.