leukotrienes their possible role in pulpal and periapical diseases

8/3/2019 Leukotrienes Their Possible Role in Pulpal and Periapical Diseases

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R e v i e w a r t i c

e u k o t r i e n e s : t h e i r p o s s i b le r o le in p u l p a l a n d

7: 233-241 .M a h m o u d T o r a b i n e j a d ' ,E i i s a b e t t a C o t t i ^ G e o r g e L e s s a r d ^Departments of ^Conservative Dentistry, Univeof Cagliari, Italy, ^Endodontics, ^Biochemistry, LLinda University, California, USA.

Key words: leukotrienes; pulp; inflammation; peapical diseaseAccepted June 11, 1991

m ber of local messengers implicated in the control

, 2). This current pape r

pulp al a nd periapica l disease.

of LTs came from an experiment by Harkavy wapplied aqueous solutions of ethanolic extractsthe sputum of asthmatic patients to smooth muspreparations from cat jejunu m and rab bit dudenum. Application of the extracts to the muscaused contraction of the muscle strips when extracts were collected during an asthmatic attaHowever, sputum extracts obtained prior to an asmatic attack failed to produce the same effects (Feldberg & Kellaway (8) and later Kellaway Trethe wie (9) repo rted that perfusion of the lunof ovalb um in-im mu nized guinea pigs with solutiocontaining the same antigen resulted in the releaof a substance capable of causing contraction jejunum. Because of the slow onset of this reactithe substance was named slow-reacting substan(SRS) by the cited investigators. In 1960, Brockhurst obtained the term "slow reacting substanceanaphylaxis" or SRS-A to describe a substanwhich caused a slow and long-lasting contractionthe guinea pig ileum and resisted the antihistamidrugs (10). The term SRS-A refers to any slreacting substance released during an antigen-anbody reaction. The biochemical and pharmacolocal characteristics of SRS-A and the mechanisinvolved have been studied by Orange et (11 1 5 ) . The discovery by Orange & Chang pre-incubation of human lung fragments with cteine resulted in a dose-dependent release of SRA suggested that cysteine might be a precursor


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et a l .

PROSTAGIANOINSP G I 2

P G F 2 aP G E 2

THROM BOX ANET x A 2T x B 2

L E U K O T R I E N E SL T A 4 L T D 4L T B 4 L T E 4L T C 4 L T F 4

L I P O X I N SLP AL P B

Pathway s of formation of various ara chido nic acid meta-

NL ) (18). They incubated rabbit PM NL s with

LTs, the long chemical names (table) are custom-

(e.g. LTA4,) following the letter designations indi -

derived from dihom o-5-linolenic acid ca r-pt " 3 " , while substances formed fromucts of eicosapentaenoic acid 2 0 :5

and m e t a b o i i s m

cell stimulation and activation

and a b r e v i a t i o n s for v a r i o u s l e u k o t r i e n e s

ase, the enzyme which specifically acts on aradonic acid to produce prostaglandins, the lipoxenases can oxidize othe r fatty acids such as eicosenoic and eicosapentaenoic acids as well. Almall mammalian cells (except erythrocytes) concyclooxygenases. However, the 5-lipoxygenase pears to be present only in inflammatory cells sas neutrophils, eosinophils, mast cells, basopmacrophages, and monocytes (2124). Goetzlsuggested lymphocytes as another source of (25).

Lipoxygenases are dioxygenases which catathe insertion of molecular oxygen into the 1,4-tadiene stru cture of polyu nsaturated fatty acids (Cells which possess a 5-lipoxygenase also concyclooxygenase as well. Therefore, the activatedzymes are in competition for the arachidonic according to both their Kms (affinity constant) their catalytic activity (27).When the 5-lipoxygenase acts on arachidacid, it produces 5-hydroperoxyeicosatetraeacid (5 -H PF TE ) throu gh loss of water and formsunstable epoxide intermediate, 5,6-oxido-7,9,l 1eicosatetraenoic acid (LTA4) (27). LTA4 is the cursor for the formation of other LTs. It can ebe hydrolyzed by the epoxide hydrolase, Lhydrolase, to form 5(S), 12R-dihydroxy-6,148,10-trans-eicosatetraenoic acid (LTB4), or canaltered by addition of glutathione to 5-hydroxglutathionyl derivative (LTC4) via LTC4 syntheStudies have shown that various cells produce dient LTs. Human pulmonary mast cells (28) eosinophils (29) produce mainly LTC4. In conthuman pulmonary macrophages (30) and PMgenerate mainly LTB4. It appears that the humonocyte is capable of producing both LTB4 sulfidopeptide LTs such as LTC4 and LTD4 (31

Further metabolism of LTC4 occurs via two dient pathways: an oxidative pathway and peptidtic pathway. The peptidolytic pathway leads to


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the 6-Glutam yl-transp eptidase (32). LTD4 is

eptid ase (33 ). LT C4, D4,E4 are the substance s which w ere referred to

Inactivation of LTC4, LTD4 and LTE4, occurs

More detailed descriptions on the chemical

of l e u k o t r i e n e s

L T s , it appears thatcific LT rec eptors m ust occur in different organ s

These studies clearly show specific binding on

LTs have a wide range of biological activities and

P o s s i b i e r o l e i n p u i p a i a n d p e r i a p i c a i d i s e ations of the many other functions of LTs readers referred to comprehensive reviews by Piper (57) aothers (30, 41).R o i e of i e u k o t r i e n e s i n i n f i a m m a t i o nTissue injury results in release of a group of sustances which affect the host microcirculation adevelopm ent of infiammation. Gells such platelets, leukocytes and endothehal cells can mobize arachidonic acid and metabohze it to form sstances such as the PGs and LTs, each with specific biological activity. The first indication tlipoxygenase products play a role in infiammatcame from the observation that 12-HETE was prent in the epidermis of patients with psoriasis (5The 15-HPETE and 15-HETE found in the tishad no effect on human PMNLs (59). 5,12 diHE(LTB4) was the most potent lipoxygenase prodamong the three types of LT studied. LTB4 ispotent chemotactic and degranulating agent PMNLs and causes the accumulation of PMNLsthe site of infiam m ation (60, 61 ). LTB4 has bealso detected in rheumatoid arthritis, gout and priasis (62, 63).LTB4 plays a significant role in the infiammatprocess. It affects the leukocyte functions and presence has been demonstrated in infiammatexudates experimentally induced by implantatof sponges containing 1 % uric acid, zymosancarrageenin (64). Turner et al. incubated the solufraction of hu m an blood platelets which containthe lipoxygenase activity with pure arachidonic aand found that HETE (12-L-Hydroxy-5,8,10,eicosatetraenoic acid) is a potent me diator of neu tphil chemotaxis (65). LTB4 is considered as onethe most potent chemotactic agents for PMNLs.Palmer and co-workers investigated the chemtactic potency of some 5-lipoxygenases products human, rat and rabbit PMNLs. They showed tin all three species, LTB4 was 100-fold more pottha n any other co m poun d studied. (59). In 19Goetzl & Pickett (66) evaluated the in vitro effecthe 5-lipoxygenase metabolites on human PMNThey found that LTB4 was by far the most potagent. LTB4 evoked a chemotactic response in ntrophils at a concentration as low as 3 ng/ml whother lipoxygenase products such as LTC4 did nelicit any response until higher concentrations wrendered. At 30 ng/ml, an intense chemotaxis wobserved, which was similar to that evoked by opmal concentrations of G5a (66). Follow up studhave confirmed the validity of these findings, (


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e t a i .

LTB4 caused a profoundder m al injection of LTB4 caused accum ulation

LTB4 over abrasions of humanIn vivo leukocytes accumulation subsequent to in-

Recently, chemotactic effects of LTB4 and G5a on

Although LTB4 has its primary effect on PMNLs,

4 and its metabolites have a greater ch emot-LTB4 does not appear to possess vasodilator activ-

Throughout the infiammatory process, when

LTB4 witho ut affecting PG -induce d pain. T hethors suggested a possible relationship betwhyperalgesia and presence of LTB4 and its relfrom PMNLs (81).The vascular response to cysteinyl-LTs (LLTD4 LTE4) is more complex and varies in diffespecies. Although the administration of synthcysteinyl-LTs causes vasoconstriction in guineaskin, (82) in human skin they cause vasodilatIntradermal injections of LTG4, LTD4, and LTEman produce increased blood fiow as well as thema and wheal formation (83-85).Ghan and associates have shown vasodilatoryfects in human and pig skins following the apcation of these LTs (79). The vasodilatory respin the pig occurred at considerably lower doses that seen in humans. When even higher doseLTG4 and LTD4, similar to those used in humwere tested in the pigs, vasoconstrictor respowere observed.Based on the results of these studies, it appthat at low concentrations cysteinyl-LTs are vdilators in pigs and humans; while they cause vconstriction at very high doses (79). The dilaaction of LTs in skin is in marked contrast tocontraction seen in the coronary artery (86). cysteinyl-LTs increase microvascular permeabin airways and other tissues. They are thoughact specifically on the endothelial lining of the pcapillary venule. The leakage of plasma inducedLTG4 and its metabolites is generally precededan arteriolar constriction (30). The cysteinyl-are potent bronchoconstrictors, they increase valar permeability in postcapillary venules and stilate mucus secretion (19).In b i b i t o r s a n d a n t a g o n i s t s o f l e u k o t r ie n e sA great deal of interest has been focused on agwhich can inhibit or antagonize the action of L T s . There are two reasons for this interest; fLTs appear to be involved in lymphocytic chetaxis as well as vasodilation and second, the specrole of them in many infiammatory events is known.

Three general classes of substances have butilized to explore LT metabolism and action 8 7 ) . The first group consists of agents which blarachidonic acid availability. The second groupthe inhibitors of 5-lipoxygenase, the enzym e respsible for the synthesis of 5-HPETE and thus all ( 8 7 ) . (Figure 1) The third group are substanwhich antagonize LT receptor binding.


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P o s s i b l e r o i e i n p u l p a l a n d p e r i a p i c a i d i s e a

of 5 - i i p o x y g e n a s e in l e u k o t r i e n e s y n t h e s i s

infiam ma tion (89). The synthesized LTA4

LTB4 in PM NL s (41 , 90). Th us inh ibition

A number of pharmacological agents have been

ugh t to be specific include: D iethylcar-(L-651,(92). These ha ve been shown in various systems

applications (93). These findings emphasizein vitro and in vivo

than systematic names. However, they appear fall in the limited number of categories.Gertain agents have been shown to affect bthe cyclooxygenase and lipoxygenases, for this rson they are classified as du al in hib itors. In vitro dinhibitors include: timegadine and GBS-1108 (9One of the few compounds which has been shoto be an in-vivo inhibitor of eicosanoid synthesisthe phenylpyrazoline, BW755G. This compoundknown to be an inhibitor of both the cyclooxygenand the 5-, 12- and 15-lipoxygenases. BecauBW755G is a multiple inhibitor, it has similar anedema, analgesic and antipyrietic activity to inmethacin, but is more effective in reducing leukcyte accumulation when used in therapeutic dosThe difficulty with such a multiple inhibitor is tit is difficult to isolate the role of the inhibitor the 5-lipoxygenase.

The fact that the 5-lipoxygenase is an iron-ctaining enzyme led to the development of a serof acetohydroxamic acid derivatives. Phenoxyciamyl-, benzyoxybenzyl-, and tetrahydronapthyropenyl acetohydroxamic acids (BWA4G, A13and BWA797G) inhibit calcium -me diated LTB4 sthesis both in vitro a n d in vivo.Piriprost (U60,275), a PGI,, derivative is an hibitor of sulfoleukotriene or cysteinyl-LT synthebut has also been reported to be an inhibitor of 5-lipoxygenase (95). Another class of inhibitors the Azodisalicylates such as Sulfasalazine aL651392. Both of these drugs act via their commmetabolite, 5-aminosalicylate to inhibit the prodtion of LTB4 and 5-H ET E, both ch em otactic infiamatory mediators (96, 97).MK886, a translocational inhibitor of the 5-lipygenase has been found to be effective in the inbition of LTB4, synthesis (97).R e c e p t o r a n t a g o n i s t s in i n f l a m m a t i o nGellular receptors for leukotrienes have been chacterized in a number of cell types. Receptors LTB4 have been detected in hum an PM NL s (9 0 ) . Th e tim e course of uptake of LTB4 in to PMNparallels the time frame for physiologic effects, sgesting the involvement of an LTB4 receptor. Oone study on LTB4 antagonists has been reportFretland utilized an antagonist, SG41930 to angonize LTB4 uptake (98). Most studies on LT rectors have focused on the cysteinyl-LT receptors. Atagonists of LTD4 binding alter cellular and tiscontraction without affecting the LTB4-induPMNL-chemotactic responses. Early studies w


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i n e j a d e t a l .

of l e u k o t r i e n e s i n p u i p a i a n d p e r i a p i c a i d i s e a s e s

The 5-lipoxygenase metabolites of arachidonicatory. LTB4 causes chem otaxisin vitro (59, 67) and in vivo (69). It107) stimulates aggregation, degranulationneration of superoxide in PM N L (67, 108,In addition, LTB4 has been implicated for

Despite the presence of numerous reports on thef lipoxygenase m etabolites of arachid onic acid

ber of investigators by using various techn iques

Lessard et al. (100) examined the metabolism of

PGFj^ as compared to levels foundIn 1984 Matejka et al. reported presence of PGE2

processes by stimu lating the synthesis ofOkiji et al. induced infiammation by application

in infiamed pulps. When a dual inhibitor of cycoxygenase and lipoxygenase was administered prto the application of LPS, the production of LTand the number of PMNLs were significantly dcreased. Adm inistration of indom ethacin had effect on the production of this metabolite (121)In a recent study, we determined the concetrations of LTB4 and LTG4 in human periradiculesions (122). Periapicai specimens from asymptoatic and symptomatic patients and pulpal tissufrom unerupted third molars as well as chronicainfiamed gingival tissues were obtained and frozThe concentrations of LTB4 and LTG4 were detmined by reverse phase high pressure liquid chroatography. Representative samples from each growere also examined microscopically. Low levels LTB4 and LTG4 were detected in the uninfiampulpal samples in contrast to the elevated levfound in chronically infiamed gingival tissues as was asymptomatic and symptomatic periradiculesions. A significant statistical difference was notbetween the concentration of LTB4 in symptomalesions compared to those found in asymptomalesions and chronically infiamed gingival tissu(P


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7 2 : 9 1 - 9 3 .7 7 . CZARNETZKI B, ROSENBACH T Chemotaxis of hum an trophils and eosinophils towards leukotriene B4 and itw-oxidation products in vitro. Prostaglandins 1986;851-58.78. BRAY MA, CUNNINGHAM F M , FORD-HUTCH INSON AW, Leukotriene B4: a mediator of vascular permeability.Pharmacol 1981; 72 : 483-86 .7 9 . CHAN CC , FORD-HUTCHINSON AW. Effects of synthetickotrienes on local blood flow and vascular permeabiliporcine skin. J Invest Dermatol 1985; 84: 154-57.8 0 . RACKHAM A, FORD-HUTCHINSON AW. Inflammation pain sensitivity: effects of leukotriene s D4, B4 and prolandin E, in the rat paw. Prostaglandins 1983; 25: 1938 1 . LEVINE J D , L A U W , K W I A T G . Leukotriene B4 prodhyperalgesia that is dependen t on polymo rphonucleukocytes. Science 1984; 225: 743-45 .8 2 . P E C K M J , P I P E R PJ, W I LL IA M S T J . The effect of leukotrC4 and D4 on the microvasculature of the guinea-pig Prostaglandins 1981; 2/.- 315-21 .8 3 . D R A Z E N J M , A U S TE N K F, LEWIS RA, et al . Compara

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leukotrienes their possible role in pulpal and periapical diseases

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