occasional review - thorax.bmj.com · diators are, in many cases, exceedingly low, making detection...

Occasional review

Cysteinyl leukotrienes in asthma: current stateof therapeutic evaluation

Ian K Taylor

Department ofRespiratory Medicine,Royal InfirmarySunderland,Sunderland,Tyne and WearSR2 7JE, UKI K Taylor

Reprint requests to:Dr I K Taylor.Received 20 June 1994Returned to authors7 September 1994Revised version received29 March 1995Accepted for publication17 May 1995

Among the many inflammatory mediators im-plicated in asthma, the cysteinyl leukotrienes(LTC4, LTD4 and LTE4) - peptidolipid con-jugates formed following lipoxygenation ofarachidonic acid - have attracted much at-tention. 1 They are generated in vitro followingimmunological and non-immunological chal-lenge from lung tissue7 and purified mastcells,8 monocytes/macophages,5 and eosino-phils.9 The biological actions of the cysteinylleukotrienes have now been extensively char-acterised; within the lung they can impair mu-cociliary clearance, enhance mucus secretion,and facilitate changes in pulmonary vascularpermeability.' 6 Their potent spasmogenicproperties on human airway smooth muscleboth in vitro and in vivo have similarly beencomprehensively documented'11'4 and furtherevidence suggests that they increase bronchialhyperresponsiveness. 15-18 These properties,which reproduce some of the functional andhistological features of clinical asthma, havegenerated considerable interest in the quan-tification in vivo of cysteinyl leukotrienes inasthmatic subjects. In addition, the de-velopment and emergence of potent end organreceptor antagonists and synthesis inhibitorshave enabled an insight into the role of thesemediators in asthma.

Whilst a role for leukotrienes has been sug-gested in a wide variety of other diseases in-cluding hepatorenal syndromes, myocardialischaemia, and inflammatory conditions of thebowel, skin and joints,3 this article reviews theevidence of their involvement principally inasthma and, to a lesser extent, allergic rhinitis.Only clinical studies in asthmatic patients willbe considered, to the exclusion of animal andin vitro data, and will comprise three parts: (1)a review of those studies in which cysteinylleukotriene generation in vivo has been dem-onstrated either (a) following administrationto the airway of indirect bronchoconstrictorchallenges, (b) during clinical disease ex-acerbations, or (c) under basal conditions; (2)those studies in which there have been attemptspharmacologically to modulate cysteinyl leuko-triene generation or to attenuate their end organeffects in the airway under (a) unprovokedconditions, (b) following bronchoprovocativestimuli, or (c) in chronic persistent asthma;and (3) most importantly, given the current

available evidence, atherapeutic potentialasthma.

critical evaluation of theof these drugs in human

Evidence for cysteinyl leukotriene releasein asthmaIt is axiomatic that the most suitable place tomeasure inflammatory mediators is at theirputative site of action. The nose is readilyaccessible to evaluate mediator production andcysteinyl leukotrienes have been quantifiedin nasal secretions following local allergenchallenge.'920 The use of the fibreoptic bron-choscope coupled with bronchoalveolar lavage(BAL) now permits similar studies in the lowerrespiratory tract and abundant evidence existson cellular profiles, cellular activation status,and secretory products within the asthmaticairway. Whilst initial reservations over the safetyand tolerability of such procedures were ex-pressed, there is now general acceptance oftheir use in asthmatic subjects with a widespectrum of disease severity,2' although doubtsremain over interpretation ofBAL solute data.22Notwithstanding these reservations, increasedquantities of cysteinyl leukotrienes have beenrecovered from BAL fluid both in patients withchronic persistent asthma2324 and followingbronchoprovocation.2526 Plasma sampling andinterpretation of data are less problematic, butplasma concentrations ofproinflammatory me-diators are, in many cases, exceedingly low,making detection and quantification difficult.Furthermore, invasive sampling may result inex vivo generation of mediators secondary toactivation and repeated measurements are re-quired to give a time integrated insight of theirproduction.

Biochemical analysis of urine, however, cir-cumvents many of these problems. In the ab-sence of renal synthesis, urinary mediator (ormetabolite) levels will reflect plasma levels.Urine collections are easy to perform, are non-invasive and, because urine is essentially freeof cells, the potential problem of ex vivo pro-duction of mediators is minimised. In humans,LTE4 is the stable bioconversion product ofcysteinyl leukotriene metabolism in the lung,27and numerous studies2"'2 have now evaluatedthe metabolism, elimination, and pharmaco-dynamics of LTE4 excretion into the urine

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following either intravenous infusion ofLTC428 29 and LTE43" or inhalation of LTD4.31132Overall, these studies have demonstrated therapid excretion into urine of LTE4 - eitheras an intact molecule or following enzymaticconversion from LTC4 and LTD4 - within fourhours of either systemic administration or pul-monary inhalation. In the absence of eitherrenal or hepatic dysfunction, measurement ofurinary LTE4 excretion may be used to assessendogenous whole body cysteinyl leukotrieneproduction in vivo in man, and this has beenutilised in numerous studies both in the laborat-ory and in clinical asthma.

EVIDENCE OF CYSTEINYL LEUKOTRIENE RELEASEFOLLOWING INDIRECT CHALLENGEAllergen challengeActivation of mast cells classically by IgE-de-pendent mechanisms results in release of in-flammatory mediators such as histamine,prostaglandin D2 and the cysteinyl leukotrienes,and it is the end organ response to these me-diators that accounts for many of the featuresof the immediate bronchial response to inhaledallergen. Several studies have shown increasedlevels of urinary LTE4 excretion during earlyallergen-invoked bronchoconstriction.32 38 Thesedata complement those obtainedfromBALana-lysis following segmental allergen challenge tothe lung26 and also following nasal allergenprovocation.'9203940 By contrast, comparableelevations in urinary LTE4 excretion duringlater allergen-invoked bronchoconstrictor re-sponses are equivocal and have proved moredifficult to interpret despite the demonstrationof these products locally in the lung.25 It isnot clear from these observations during laterallergen-invoked bronchoconstriction whetherde novo cysteinyl leukotriene synthesis andrelease is occurring from cells such as eos-inophils recruited to the airway, or the end organresponse is consequent upon prior liberation ofcysteinyl leukotrienes from mast cells duringthe earlier stages ofallergen-provoked broncho-constriction. This issue has still not beenunequivocally clarified, even with the demon-stration of significant attenuation of late al-lergen-induced bronchoconstriction by potentcysteinyl leukotriene receptor antagonists,4'but is worthy of further critical analysis.

Exercise and cold air challengeExercise is a common stimulus of broncho-constriction in asthmatic subjects, although theexact pathogenic sequence of events under-lying its causation remains unclear. Severalmechanisms have been proposed, includingmast cell mediator release secondary to res-piratory water loss, and hyperosmolar pro-vocation and vascular phenomena provokingoedema formation within the airway wall. Dataconcerning the participation of inflammatorymediators, particularly cysteinyl leukotrienes,in either the maintenance or induction of theexercise-induced bronchoconstriction are con-flicting. A number of studies have shown noincrease in cysteinyl leukotriene concentrations

in either plasma,4' BAL fluid,43 or urine3644following exercise challenge. Similarly, in-halation of cold air is not associated with in-creased urinary eicosanoid production (GWTaylor, unpublished data). By contrast, a studyin children did show a modest increase inurinary LTE4 excretion45 and small but sig-nificant increases in cysteinyl leukotrienes havebeen demonstrated in BAL fluid after hyper-ventilation-induced bronchoconstriction.46However, the most compelling evidence for arole for the cysteinyl leukotrienes in exercise-induced asthma (and, indeed, the broncho-constriction invoked by hyperventilation ofcolddry air which is believed to share the samemechanism) are the numerous studies whichhave shown amelioration of airways limitationeither by selective blockade of the 5-lip-oxygenase enzyme47 or by selective end organreceptor blockade.4>5'

Platelet activating factor (PAF) challengeThe role of the ether-linked alkylphospholipidplatelet activating factor (PAF) in asthma hasattracted much attention although its preciserole in the pathogenesis of asthma is not clear.In common with other inflammatory me-diators, PAF is capable of reproducing manyof the functional and histological features seenin asthma both in vivo and in vitro, includingmicrovascular leakage, bronchoconstriction,and inflammatory cell activation. Despite caus-ing bronchoconstriction following inhalationin humans,52 54 PAF does not possess directcontractile effects on human airway smoothmuscle strips in cell-free media in vitro,55 sug-gesting that some of its function in vivo maybe mediated indirectly through the release ofsecondary mediators. In support of this, thegeneration of leukotrienes in response to PAFhas been described from a number of animalpreparations and purified human cells in vitro.Some of the acute bronchoconstriction in re-sponse to inhaled PAF in human subjects maybe mediated by cysteinyl leukotrienes.56 Sub-sequent support for a direct contributory rolefor cysteinyl leukotrienes in the airway responseto PAF in humans has been demonstrated bythe marked inhibitory effect of selective cy-steinyl leukotriene receptor antagonists, SKF104353 and ICI 204219 on PAF-invokedbronchoconstriction.5759 Furthermore, an oralPAF antagonist, UK 74505, significantly at-tenuated PAF-invoked rises in urinary LTE4levels.59

Aspirin challengeSome subjects with asthma are intolerant ofaspirin and other non-steroidal anti-inflam-matory drugs, but the aetiology of this phe-nomenon remains unclear. One hypothesis isthat inhibition of the cyclooxygenase enzymeprovokes bronchoconstriction by the "shunt-ing" of arachidonic acid towards metabolismby cellular lipoxygenases. In support of this,pretreatment of sensitised human bronchus invitro with indomethacin generates increasedLTC4 following immunological challenge.60

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Furthermore, systemic provocation with as-pirin in susceptible subjects results in the se-cretion of inflammatory mediators includingleukotrienes into nasal lavage fluid.6' Increasedurinary LTE4 excretion has now been observedin aspirin sensitive asthmatic subjects followingboth oral6263 and inhalational32 challenge. How-ever, pretreatment of subjects with indo-methacin in doses which were markedlyinhibitory towards cyclooxygenase35 did notfurther enhance allergen-invoked broncho-constriction or urinary LTE4 excretion, sug-gesting that the mechanism of aspirin-inducedasthma is not directly related to "shunting" ofarachidonate metabolism. Several studies havenow shown significantly increased basal ex-

cretion of urinary LTE4 in aspirin sensitiveasthmatic subjects compared with those whoare not aspirin intolerant and normal sub-jects,326264 but the significance of this is unclear.

EVIDENCE OF CYSTEINYL LEUKOTRIENE RELEASEDURING DISEASE EXACERBATIONSTaylor et aP3 initially observed increases inurinary LTE4 levels in 24 hour urine collectionsin patients admitted to hospital with acutesevere asthma, although there was a substantialoverlap of urinary LTE4 measurements intothe normal range. Furthermore, whilst urinaryLTE4 levels tended to decrease during diseaseremission, this did not reach statistical sig-nificance. Drazen et al5 further evaluated therole of cysteinyl leukotrienes in patients pre-senting with acute airways obstruction. UrinaryLTE4 excretion was significantly higher in thosepatients classified as "responders" (determinedon the basis ofairway reversibility to a nebulisedP2 agonist) compared with "non-responders"and normal volunteers. This provides strongsupport for a bronchoconstrictor role for cy-steinyl leukotrienes in acute severe asthma,particularly in those patients in whom broncho-constriction per se (and, by inference,heightened bronchodilator responsiveness) is a

major component of their airways obstruction.

EVIDENCE FOR CYSTEINYL LEUKOTRIENERELEASE UNDER BASAL CONDITIONSRecent evidence216-11 suggests that basal air-way tone in asthmatic subjects is influenced byendogenous cysteinyl leukotrienes and may beresponsible, at least in part, for persistent bron-choconstriction. For example, raised levels ofcysteinyl leukotrienes have been demonstratedin BAL fluid before endobronchial allergenchallenge in atopic asthmatic subjects com-

pared with control groups.26 Further, the cy-

steinyl leukotriene receptor antagonists, ICI204 219 and MK-571, and the hydroxyamicacid 5-lipoxygenase inhibitor, zileuton, haveshown significant acute bronchodilator effects

in asthmatics of moderate severity."" Whilstthese observations have been supported in pre-

liminary, albeit prolonged, dosing studies inchronic asthma,67-69 neither MK-571 nor ICI204219 significantly improved pulmonaryfunction prior to exercise challenge althoughthis may have been a reflection of the mild

airways obstruction in the population ofpatients studied.4849 Baseline observations ofurinary LTE4 excretion have also providedsome useful information. A recent study hasreported increased excretion of LTE4 in over-night urine samples in patients with nocturnalasthma which correlated with the magnitudeof the morning dip.70 By contrast, Westcottet al38 found no correlation between baselinemeasurements of FEV, and urinary LTE4levels, and others have found no difference inurinary LTE4 excretion between asthmatic andnon-asthmatic subjects under basal un-challenged conditions.3345

Therapeutic interventionIf cysteinyl leukotrienes play a significant partin the pathogenesis of asthma, then attempts tomodulate their pharmacological actions shouldbe of some therapeutic benefit. Clarification ofthe role of cysteinyl leukotrienes in asthma hasto date focused on three therapeutic strategies:(1) dietary provision of alternative fatty acidsubstrates within membrane phospholipidsthereby yielding products with less pro-inflammatory activity;7' this approach has beenlargely unsuccessful72 and will not be discussedfurther; (2) pharmacological inhibition ofspecific synthetic enzymes, particularly 5-lip-oxygenase, and (3) modulation of end organeffects with selective cysteinyl leukotriene re-ceptor antagonists. The remainder of this re-view will concentrate on these latter twoapproaches, with emphasis on the effect oftheseclasses of drugs on indirect bronchoconstrictorchallenges administered to the airway, and theireffect in chronic persistent asthma itself, ratherthan a discussion of those studies in whichantagonism of leukotrienes has been evaluated.

5-LIPOXYGENASE INHIBITIONEarly efforts to examine the efficacy of 5-lip-oxygenase inhibitors failed to show any thera-peutic benefit73"- or evidence of adequateenzyme blockade. Zileuton (A-64077), an oralhydroxamic acid 5-lipoxygenase inhibitor,76 hasproved more encouraging. Following nasal al-lergen challenge, symptoms ofnasal congestionand LTB4 concentrations in nasal lavage fluidwere significantly reduced although cysteinylleukotriene concentrations were not evalu-ated.40 In a separate study zileuton significantlyameliorated the bronchoconstriction invokedby cold dry air.47 In contrast, when ad-ministered three hours before inhaled allergenchallenge, zileuton did not significantlyattenuate either early or late allergen-invokedbronchoconstriction or the allergen-invokedairway hyperresponsiveness.77 Although urin-ary LTE4 excretion was reduced by almost50%, the lack of clinical effect in the airwaymay have been related to insufficient inhibitionof 5-lipoxygenase.77 However, zileuton hasshown significant acute bronchodilator effectsin moderately severe asthmatic patients and inpreliminary chronic dosing studies.68 A furthertherapeutic target has been to antagonise theregulatory protein 5-lipoxygenase activating

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protein (FLAP), since expression of both 5-lipoxygenase and FLAP are necessary for cellu-lar leukotriene synthesis.7879 To date only oneFLAP antagonist, MK-886, has progressed toclinical trials in laboratory-provoked airwaysobstruction. Whilst demonstrating marked at-tenuation of both early and late allergen-in-voked bronchoconstriction and urinary LTE4excretion,80 no effect was seen on the allergen-invoked increase in airways responsiveness al-though this may have been a reflection of thestudy design.

CYSTEINYL LEUKOTRIENE RECEPTORANTAGONISMAs with the early 5-lipoxygenase inhibitors,initial studies with cysteinyl leukotriene ant-agonists (L-649 923, LY-17 1 883, and L-648 051) administered orally8 82 or by in-halation83 in standard allergen provocationswere disappointing. The development of morepotent and selective second generation cy-steinyl leukotriene receptor antagonists (MK-571, ICI 204219, SK&F 104353, RG12525)administered either by inhalation, oral or intra-venous routes have proved more encouragingboth in laboratory-provoked airway narrowingand in clinical asthma itself. Numerous recentstudies have demonstrated their inhibitoryeffect against aspirin,84 PAF,5758 allergen, 418586and (despite the contradictory evidence fromdirect mediator measurements364344), exercisechallenge.415' For example, Manning et al,48using the highly potent and selective intra-venous LTD4 receptor antagonist, MK-571,showed significant attenuation of both themagnitude and duration of exercise-inducedbronchoconstriction, suggesting an importantrole for LTD4 in this condition. A similar ob-servation has been reported with the equallypotent LTD4 receptor antagonist ICI 204 219when administered orally before exercisechallenge.49 Furthermore, despite its modesteffect following allergen-induced broncho-constriction,8' LY 171 883 reduced the bron-chospastic response to hyperventilation ofisocapnic cold air, suggesting that cysteinylleukotrienes are involved in this response.50Administration of an oral dose of ICI 204 219two hours before allergen challenge sig-nificantly attenuated both allergen-inducedearly and late bronchoconstrictor responses andthe allergen-invoked increase in airways re-activity.4' A subsequent study with an inhaledpreparation of the same drug inhibited only theearly bronchoconstriction following allergenadministration;87 the discrepancy in effects ofthe different routes of administration werethought to reflect different pharmacokineticand pharmacodynamic profiles. Two furtherstudies of different design have shown that,following ingestion of ICI 204 219, increaseddoses of allergen were required to provokecomparable bronchoconstriction to those ob-served on the placebo limb.8586 Finally, intra-venous administration of MK-57 1 resulted ina dose-related inhibition of allergen-inducedbronchoconstriction,88 and inhalation ofSK&F104 353 significantly inhibited the broncho-

constriction invoked by PAF,57 exercise,5' andaspirin84 in susceptible subjects.As previously discussed, cysteinyl leuko-

trienes may contribute to resting bronchomotortone in asthmatic subjects. Both ICI 204 219and MK-57 1 have acute bronchodilator actionsadditive to those of inhaled salbutamol inpatients with moderately severe asthma.6667 Bycontrast, in subjects requiring only occasionaluse of 12 agonist bronchodilators and in whomthe airways limitation is minimal, these drugsappear to have little effect on basal airwaytone.48 49

Effects of cysteinyl leukotriene antagonistsin chronic asthma have also been reported.Dosing with LY 171 883 for six weeks resultedin a modest rise in airway calibre which wasassociated (in a subpopulation of patients) witha significant reduction in P2 agonist usage.89Similar data with more potent receptor ant-agonists (ICI 204 219,69 MK-571,67 and RG1252590), administered for up to six weeks,have also shown an improvement in airwayphysiology and symptom scores in patients withasthma.

ConclusionsThe clinical entity of asthma is now knownto comprise a combination of separate butintimately related pathophysiological processesincluding variable airways obstruction, bron-chial hyperresponsiveness, and inflammationof the airways. The initiation and propagationof inflammation of the airways results from thecoordinated collaboration of numerous in-flammatory cells (resident in, or recruited to,the airway) and their cellular products. Whilstmany would agree that no single inflammatorymediator is responsible for all the clinical andpathological events in bronchial asthma, thereis now substantial evidence that the cysteinylleukotrienes play an important part in thepathophysiology of the disease. Not only arethey capable of reproducing many of the func-tional and histological features of asthma, thereis now abundant literature on their release,both in acute severe asthma and followinglaboratory-provoked bronchoconstrictor chal-lenges, and on their contribution to the restingbronchomotor tone in asthmatic patients.Even when analytical approaches can be

trusted to generate good quality data, it isimportant to interpret data correctly, par-ticularly when invoking mechanistic roles forcysteinyl leukotrienes in mediating indirectbronchoconstriction. Such interpretation ofmechanistic events in vivo is important, giventhat apparently conflicting evidence may arisefrom either pharmacological modulation of aphysiological response when compared withdirect mediator measurements in biologicalmatrices (such as plasma, urine or broncho-alveolar lavage) during the response. Thetranslation from identification of a putativemechanism to a useful therapeutic role is oftennot conclusive and further corroborative evid-ence should, if possible, be sought.

Present therapeutic strategies in asthmahave two aims: (1) attenuation of airways in-

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Cysteinyl leukotrienes in asthma

flammation, and (2) promotion of broncho-dilation.9i In this context it seems appositeto examine the capabilities of pharmacologicalagents which potently inhibit cysteinyl leuko-triene synthesis or selectively antagonise theirend organ effects and to determine how thesemay be disease modifying in asthma. The Brit-ish Thoracic Society recently updated their

guidelines for the management of both acutesevere and chronic persistent asthma92 in which

they advocate the use of inhaled glucocorticoidsas first line anti-inflammatory therapy for allbut the mildest of asthmatic patients. Further,of the currently available bronchodilators in

clinical use, selective P2 adrenergic agonists are

by far the most effective. It is therefore againstthese therapies that mediator antagonists or

synthesis inhibitors must be evaluated.Whilst 5-lipoxygenase inhibitors and cysteinylleukotriene antagonists have demonstrableprotective effects against many broncho-

provocative insults and can promote broncho-

dilation, it is clear that further clinical studiesare required before they can be added to, or

replace, existing therapy for asthma. To date,there have been few clinical studies evaluatingthe putative anti-inflammatory properties of

these drugs, in contrast to the many clinical

and histological studies with glucocorticoids in

asthmatic patients across a wide spectrum of

disease severity.93 Furthermore, whether 5-lip-oxygenase inhibitors and cysteinyl leukotriene

receptor antagonists will induce changes of

sufficient magnitude in airways reactivity to

be considered disease modifying still remains

unanswered. Nevertheless, if further studies in

chronic persistent asthma confirm the current

promising evidence, then agents which phar-macologically modulate the in vivo actions of

cysteinyl leukotrienes should provide an ad-

ditional therapeutic approach for the treatment

of asthma.

This paper was commissioned and funded by Zeneca Phar-

maceuticals Ltd.

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