Journal oj Cutaneous Pathology 1974: 1: 27.S-290

Prostaglandins in Normal andPathological Skin

J0RGr,N S0ND1;RGAM!D

University of Copenhagen Department of Dermatology, Rigshospital, Copenhagen,Denmark

(Received jor pithlicatioti Deeember 2, 1974)

T h e skin has served as a focus for miilti-diseiplinary research on prostaglandins forthe past 5 years and several review articles(Fulghum 1970, Kumar & Solomon 1972,S0ndergaard 1973, Ziboh 1973b) have al-ready coveted some dermatologieal aspectsof the prostaglandins. The almost geometri-eally increasing studies on prostaglandinshave thrown so much new light on normalskill function and pathological skin condi-tions that it seems pertinent to review thesubject.

The aim of the present review is to surveythe recent research developments in theprostaglandins related to dermatology. Formore comprehensive reviews on prostaghin-ditis providing a key to non-dermatologicalareas the reader is referred to monographsby von Euler & Eliasson (1967), Ramwcll& Shaw (1970) and Ramwell (1973). It iseonvenient to divide this review into twomain sections, dealing with experiments onnormal and pathological skin. It is desirableto recall briefly some important teatures ofstructure, biosynthesis, metabolism, adenyleyclase relationships and antagonists of theprostaglandins.

I. Prostaglandins

A. Structure, Biosytitlicsis and MetabolismT h e prostaglandins (PG) are a group of

biologically highly active fatty acids widelydistributed within the tissues. Kurzrok &Lieb (1930) originally found that humansemen contained a substance which con-tracted or relaxed the human uterus, andthis observation was independently confirm-ed and extended by von Euler (1934) andGoldblatt (1933, 1935). Von Euler (1936)termed the substance, which was lipid-sol-uble, "prostaglandin". The original ob-servations were almost forgotten, or at least,disregarded until 1957, when Bergstrom &Sjovall succeded in isolating and, later on(Bergstrom et al. 1963), elucidating thechemical structure of several naturally oc-curring prostaglandins.

The prostaglandins are fatly acids con-taining 20 carbon atoms with C8 to C12closed to form a five-membered ring (Fig.1). Among the 14 currently naturally oc-curring prostaglandins four groups, i.e. E,F, A, and B, have been described. PGE,,PGEo, and PGE;j are dihydioxy derivativeswith one, two or three double bonds, re-spectively. The PGF-series ate triliydfoxyderivatives. The structural formulae of theE, F, A and B prostaglandins are shown inFig. 1. Further details on structure andnomenclature were presented by Andersen(1971).

Prostaglandins have beeti detected in al-most any mammalian tissue, where they

276 S0NDERGAARD

OH

COOH

PGF, a

COOH

PGA, PGB|Fig. I. Siruetural formulae of E, E, A and B pi'oslaglaiidins.

COOH

have been sought (for review see Bergstromet al. (1968)) including human skin (Greaves& McDonald-Gibson 1972, jonsson & Ang-gard 1972, Ziboh 1973a). The current con-eept is that the prostaglandins are not storedwithin the tissues but are enzymatically syn-thesized from essential fatty acids as a re-sponse to certain stimuli (Lands & Samuels-son 1968, Vonkeman & van Dorp 1968).Dihomo-y-linolenic acid (8, 11, 14-eicosa-trienoic acid) is tbe precursor of PGE| andPGE],,; while arachidonic acid (5, 8, 11, 14-eico.saletraenoic acid) is the precursor ofPGEo and PGF.,,,. The enzyme activityseems associated with tbe cellular micro-somal fraction.

In human epidermis, Ziboh (1973a) foundprostaglandin synthetase activity in the par-ticulate fraction indicating the presence ofan active prostaglandin syntbetase systemassoeiated with membranes. An unstableand biologically very active cyclic endo-peroxide intermediate may be closely re-lated to rabbit aorta contracting stibstance(RCS) deseribed by Piper & Vane (1969)and Gryglewski & Vane (1972).

The prosUiglandins are rapidly metabo-lized to biologically inactive compounds inlissties (Nakano et al. 1969, Anggard &Larsson 1971) mainly mediated via the 15-hydroxy proslaglandin dehydrogenase andprostaglandin , l'''-rcductase (Anggard &.Sainuelsson 1964, 1965). Using radioiin-munological lechniqties and mtiltiple-ionanalysis with detileralcd carriers, quantita-tive determinations of plasma and urinarymetabolites may be performed (Granstrom& Samuel.sson 1972, Beguin el al. 1972,Hamberg 1973). Simultaneous delermina-lion of prostaglandins and prostaglandinmetabolites in plasma of patients sufferingfrom localized dermatoses and in plasmaand urine from patients with generalizeddermatoses migbt yield valuable informa-tion. However, less complicated and time-consuming lecbniques are probably requiredbelore such data are available.

B. Adenyl Cyclase RelationshipsMany of the effects attributed lo lhe pro-staglandins are manifest through changesin the intraeellular concentration of the

PROSTAGLANDINS 277

nucleotide cyclic adenosine 3', .S'-mono-phosphate or cyclic AMP (c-AMP). c-AMP,discovered by Sutherland et al. in 1938 isa product of enzymic activity. The enzymeadenyl cyclase eatalyses the conversion ofadenosine triphosphate to c-AMP whichthen mediates the intraeellular effects ofseveral hormones (Fig. 2). The tiiodifyingeffects of the prostaglandins, while probablymanifest at the level of the plasma mem-hrane throtigh closely associated specificreceptors, is probably not exerted direetlyon the adenyl cyclase enzyme.

Recent evidcnee also implicates phospho-diesterase, adenylate kinase and ATPase.Possible mechanisms of prostaglandin ae-tion on membranes have been described byShaw et al. (1972) and Johnson & Ramwell(1973). In tnost tissues the E-series of pro-staglandins stimulate the production of c-AMP. The E-series of prostaglatidins hasrecently been found to stimulate cyclic gua-nosin 3', 5'-monophosphate (cGMP) in cer-tain tissues (Kuehl 1974). Cyelic AMP isinactivated by c-AMP phosphodicstcraseenzymes. All components of the c-AMPsystem have been demonstrated in human

epidermis (Mier & Urselmann 1970a, 1972,Kumar ct al. 1971, Hsia et al. 1972, Voor-hees et al. 1974), where they may influencenortnal and pathological epidermal cell divi-sion. This subject has been extensively re-viewed by Voorhees et al. (1974) and ap-pears in further detail in section III. Thetnessenger function of c-AMP was initiallythought of primarily as a "turn on" switchwhereby hormones, including the prosta-glandins, could stimulate certain target tis-sues. However, it has recently been shownthat c-AMP can inhibit or "turn off" severalcell functions of considerable importancefor the modulation of inflamtnation andimmunity (Bourne et al., 1974). This willbe further discussed in seetion 111.

C. A)itagotiistsEfforts have been made to develop anta-gonists which counteract PG-induced ac-tivities or inhibit PG synthesis. The mostintensely studied group of inhibitors are thenon-steroidal anti-inflammatory agents. Re-cognition that these compounds potentlyblock PG action or inhibit their synthesiscame as recently as 1971, when experi-

Hormones

. ^ ^ Adenyl cyclase , PhosphodiesteraseATP — •cyclic AMP •AMP

" t u r n o n " a n d " t u r n o f f "mechani sms

Fig. 2. The adenyl cyclase enzyme system.

278 S0NDERGAARD

tnental evidence was offered to support theconcept that tbe tberapcutic effects of as-pirin-like drugs could be ascribed to suchproperties (Vane 1971), Prostaglandin bio-synthesis by human skin is similarly inhi-bited by aspirin-like drugs (Greaves & Mc-Donald-Gibson 1972). Although corlicosle-roids do not inhibit prostaglandin biosyn-thesis in several tissues (Vane 1971), atleast part of tbc anti-inflammatory proper-ties of topically applied corticosteroids bavebeen claimed to be due to inbibition of pro-slaghmdin biosynthesis in human skin(Greaves & McDonald-Gibson 1972). Asretrospectively expected, pretreatment with1 g of aspirin four times daily did not in-hibit tbe cutaneous reaction to intradermallyinjected PGE, (Micbaelsson 1970). Furtbcr-inore, PG syntbesis can be inbibited by.several fatty acid sub.strates, PG analogues(McDonald-Gibson ct al. 1973), and a bi-cyclo (2:2:1) heptenc derivative (Wlodawerct al. I97f). Polyphloiclin phosphate (PPP)was originally tbought to be a competitiveantagonist but the locus of action is stillunresolved. PPP may act at tbe level of Ibecyclic AMP dependent kinases (Kuchl ct al.1971). PPP .significaiilly reduces the ery-tbema caused by intradermal injection ofPGEj in normal buinan skin (S0ndcrgaard& Paulli J0igensen 1973).

II. The Normal Skin

Tbe presence of prostaglandins in skin wasdemonstrated as early as 1970. In ether ex-tracts of acidified aqueous homogenates offrog skin, Ramwell & Sbaw (1970) detectedpharmacological activity equivalent to 4.2X 10-'^ M PGE| per g of tissue, and bytbin-layer chromatograpby these smoothmuscle stimulating prostaglandins wereidentified as PGEj and PGEo. Similarly, ex-tracted human skin homogenates contain68-1325 ng PGE , (tnean of nine biopsies386 ng) per g dry tissue when tested on an

ovariectomizcd rat uterus (S0ndergaard &Sbaw, unpublished data). Proslaglandin bio-syntbesis by skin was demonstrated //; vilroby Jouvenaz et al. (1970) and Jessup et al.(1970), and later confirmed by Van Dorp(197!) and Greaves & McDonald-Gibson(1972). In a study on tbe biosyntbcsis andmetabolism of prostaglandins in human skinobtained by excision, Jonsson & Anggard(1972) found tbat PGEo was tbc majorprostaglandin tbougb small amounts ofPGF2,,-like material were found in someexperiments. Tbe content of PGEo in tbeirskin bomogenates was 15 ng/g rising to250-300 ng/g upon incubation. PGE^ wasfound to be rapidly metabolized via tbc 15-bydroxy prostaglandin debydrogenase andprostaglandin /|'-'-reductase,

A, The FpiilermisFbcre is increasing evidence tbat prosta-glandins influence the development and ma-turation of epidermis. Ki.scher (1967), usingcbick embryo skin in tissue culture, incu-bated epidermal cells in the presence ofPGE, and PGB,, After 4 days of incuba-tion, tbere was a well-defined epitbelial pro-liferation and precocious keratinization intreated cultures, and developtnent of tbedown featber organ was completely suppres-sed. In a subsequent election niicioscopicalstudy (Kischer & Keeter 1970), the culturedtissues revealed numerous gaps in the der-mo-epidermal junction when PGBi was pre-sent in the culture niediutn, Tbis was foundas early as tbc second day and raised tbequestion of wbetber these breaks migbt beanalogous to skin lesions involving ulcera-tions. If these results can be repeated onepidermis of other species, including man,tbcy may bave iniportani implications in thepathogenesis of abnormalities of hair growthand of ulcerative skin conditions.

Work on (be interrclationsbips bclweenepidertnal prostaglandins and the adenylcyclasc system, although in tbe earliest

PRO.STAGLANDINS 279

stages, have already provided enough datato suggest that prostaglandins may have arole in the control of mitotic activity inepidermis and structures derived frotn it(for review see Voorhees et al. 1974). Fur-ther studies on the inter-relationship be-tween essential fatty acids, prostaglandinsand cyclic nuclcotides may provide informa-tion on the factors controlling keratiniza-tion and replieation of epidermal cells. Thecutaneous epithelium was used for extensivestudies on the mode of action of prostaglan-dins on membranes by Ramwell & Shaw(1970). These authors suggested that theeffects of prostaglandins may result fromtheir ability to displace membrane calcium.

Another important obsei-vation is the frogskin darkening effect of PGEi, Eo, and E a(Peaslee 1971). In black goldfish, the dark-ening effect of prostaglandins was due tomelanosome dispersion (Abramowitz &Chavin 1973). If these results ean be ex-tended arvd repeated iti hurnau. skit\ prosta-glandins may play a pathogenetic role inpigmentary skin disorders.

B. The Epidermal AppendagesThe sebaeeous glands are the main soureeof lipid miUevia\ in ihe biologicaUy impov-tant surface film. Sebum contains a rnixturcof lipids, including fatty acids, alcohols andhydrocarbons. The production is regulatedby hormones. Glucagon, epinephrine andadrenocorticotropic hormone, intracellularlymediated via c-AMP stimulate Vipolysis re-sulting in the liberation of free fatty acidsand glycerol. Ziboh & Hsia (1972) demon-strated that PGEo inhibits sterol ester bio-synthesis in the skin of rats made defieientin essential fatty acids.

The question of whether or not the sttongantilipolytic action of E-proslaglandins maybe relevant in inhibiting the liberation offree fatty acids from normal and dysfunc-tioning human sebaceous glands is still un-answered.

The eccrine glands are true secretoryglands, producing the clear aqueous sweatresponsible for heat regulation. Althoughthese organs respond to direct applicationof heat, sweating is almost exclusively theresult of nervous impulses. As demonstratedby Dale & Eeldberg (1934), acetylcholineis liberated at sweat nerve endings. Epine-phrine causes profuse sweating in a nutn-ber of .speeies sueh as horse, sheep and cat,but not in man. Prostaglandins are knownto tnarkedly influence adrenergic neuro-transmission (for review see Hedqvist 1970)and the results of Hahn & Patil (1972) sug-gest that salivation induced by PGEo,, maybe due, at least in part, to release of aeetyl-choline from cholinergic nerve termitials.No studies on the action of prostaglandinson animals' sweating after epinephrine stim-ulation have beetT canied out. In tnan, iti-tradermal itijection of prostaglandins doesnot produee any inerease in sweating. Juh-\\\\ & Michaelssoti (1969) injected PGE,,PGEo, PGE,n and PGFo,, in the skin of theback of 22 subjects and compared the num-ber of functioning sweat pores after stainingwith o-phthaldialdehyde to the number ofpores in a saline-injected control area. Noneof these pvoslaglandins caused any increaseiti sweating.

C. The DermisThe cutaneous vascular reaction. have beenstudied by several authors (Horton 1963,Kaley & Weiner 1968, 1971, Solomon et al.J968, Crunkhorn & Willis 1971a, b. S0nder-gaard & Gteaves 1971a). Horton (1963)found that PGBi increased capillary per-meability as shown by intradennal injectionin guinea pigs pretreatcd with pontaminesky blue. Eurthermore, he noticed thatPGE| did not cause pain when applied tohuman blister bases. Application of PGEjto normal untreated or shaved rabbit orguinea pig skin produced no tiotieeable ef-fect (Solotnon et al. 1968). Application of

280 S0NDERGAARD

' • ' \ J

Fig. 3. Response to intradermal injection of proslaglandin E| in the human forearm. A dose of1 fig PGE| dissolved in 0.1 ml 0.154 M NaCI was injected and the photograph was obtained 20min later.

PGEj after removal of the stratum corneumby stripping with tape induced a cutaneousvascular reaction similar to, only weakerthan, the reaction which occurred after in-tradermal injection. On a weight basis, Ka-ley & Weiner (1968) found that the averageincrease in vascular permeability caused byPGEi in rat skin was similar to that ofbradykinin, serotonin and histamine. Afterintradermal injection, PGEj caused a per-sisting dusky erythema and a well-definedweal (S0ndergaard & Greaves 1971a) (Fig,3), The erythema occurring alter injectionof 1 /(g PGE| persisted for up to 12 h, theweal only 1-2 h. In human skin, a reactionis noticeable with as little as 1 ng PGEj,whereas the erythema and weal caused byPGFi^ are considerably smaller. The rela-tionship of the erythema and weal to dosageof PGE] in human skin is shown in Fig, 4,Part of the cutaneous inflammatory rcac-

6 700- -

01PG EI

I/

Fig. 4. Erythema ( ^ %) und weal (A • )produced by four different concentrations ofPGE|, Tbe areas of erytbetna and weal mea-sured planinictrically 20 min after the intra-dermal injections.

PRO.STAGLANDINS 281

tion to PGEj is probably due lo endogenoushistamine release (Crunkhoin & Willis1971a), Intradermal injection of 1 pg PGE|redueed skin histamine in 10 human sub-jects by approximately 24 %, and the weal,but not tbe erythema, eould be reduced byprelreatinent with antihistamine (S0nder-gaard & Greaves 1971a).

The in vitro effects of prostaglandin Eoon human cutaneous vaseular smooth mus-cle have been studied by Goldyne & Win-kelmann (1973). Their results indieate thatP G E J may mediate eulaneous vaseular ac-tivity nol only Ihiough its own effect butalso by modifying responses to catechola-mines.

Collagen is the major component of skin,making up about 70 % of the weight of dryfat-free human skin. The fibroblasts syn-thesize and release into the extracellularspace the collagen precursor tropocollagen.On the outer surface of cultivated fibro-blasts the polymerization of eollagen fibrilsby aggregation of tropocollagen particlescan be observed (Zeliekson 1963). Kiseher(1967) has reported that PGE, and PGB,stimtilate eollagen morphogenesis in organcultures of developing chick skin. Further-more, by electron microscopy, Kiseher(1973) observed reduction of chick embryoskin explants upon incubation witb PGB|,PGB^, and PGE,, whereas PGF,,, causedn o sueh reduction.

This interesting aspect of prostaglandinaction, of potential significance for woundhealing and tissue repair has been furtherstudied by Blumenkranlz & S0ndergaard(1973). Prostaglandin E| and F|,, was foundto stimulate eollagen biosynthesis as evalu-ated by hydroxylation of proline and lysine,speeifie indieators of collagen biosynthesis,and glyeosylation of hydroxylysine in 10-day-old chiek embryo tibiae, glyeosylationbeing a lerininal step of eollagen biosyn-thesis related lo the normal process of col-lagen extrusion from (he fibroblasts. This

work has eonfirmed the findings of Aroraet al. (1970), who found that eotton pelletplus PGE] led to a greatly enhanced granu-loma formation.

D. The Subctitaneous TisstteUnder basal eonditions, prostaglandin-sen-sitive lipolytic systems seem to be more ac-tive in human subeutaneous tissue than inhuman omental tissue (Carlson & Hallberg19(-)8). Whether or not this observation eanbe related to the high affinity to PGEi ofstibcutaneous connective tissue is unknown.After administration of •'H-labelled prosta-glandin E| lo mice, in an autoradiographicstudy, Hansson & Samuelsson (1965) founda striking uptake of radioactive tracer insubcutaneous tissue. This was confined tomaterial whieh was stained pink by thevan Gieson connective-tissue stain. Obvi-ously, the fat cells of the subeutaneous layerdid not bind ^H, and no or very little uptakewas detected in adipose tissue elsewhere inthe mouse.

Fredholm et al. (1970), studying lhe ef-fects of PGEj in canine subcutaneous adi-pose tissue in sittt, found that PGEj signifi-cantly increased glucose uptake whereas therelease of free fatty aeids and glyeerol inunstimtilated tissue was inconsistent. Lipo-lysis induced by nerve stimulation was in-hibited by PGEj.

Ill, The Pathological Skin

The pathologieal skin eonditions havingbeen the subject of prostaglandin studies in-clude several inflamntatory skin conditions,i.e. eulaneous inflammation due to ultra-violet radiation (S0ndergaard & Greaves1970b, Mathur & Gandhi 1972, Snyder &Eaglstein 1974a, b), primary irritant derma-titis (Goldyne et al, 1973, S0ndergaard etal. 1974), burn lesions (Anggard et al. 1970,Hamberg & Jonsson 1973, Arturson et al.1973) imntttnological skin disorders, i.e.

282 S0NDERGAARD

atopic dermatitis and urticaria (Solomonet al. 1968, Juhlin & Michaiiilsson 1969), al-lergic contact dermatitis (S0ndergaard &Greaves 1970a, Greaves et al. 1971, Gol-dyne et al. 1973), vascttlar disorders (Em-mons et al, 1967), proliferative derntatoses(Ziboh & Hsia 1973, Aso et al. 1974), skintutnors (Bhana et al. 1971, Sykes & Maddox1972, Apps & Cater 1973) and itch (Horton1963, Solomon et al. 1968, Juhlin & Mi-chaelsson 1969, Willis & Cornelsen 1973,Ferreira 1972, Greaves & McDonald-Gib-son 1973),

A. InflatnmationThere is now abundant evidence to supportthe view that prostaglandins, mainly the E-series, play an important role in inflamma-tion (for review see Vane 1972, Willoughbyet al, 1973) including sustained cutaneousinflammation (reviewed by S0ndergaard1974). The release of mediators of inflam-mation seems to be sequential starting withhistamine and 5-hydroxytryptamine in somespecies, followed by kinins and then prosta-glandins and probably slow reacting sub-stance-A (Willis 1969, S0ndergaard & Grea-ves I97()b, Di Rosa et al. 1971).

For prostaglandins to be important me-diators of inflammation they must be ableto produce the cardinal signs. Intradermalinjection of prostaglandin E| in concentra-tion as low as 10 ng/ml caused pronouncederythema of a strikingly sustained quality(S0ndergaard & Greaves 1971a, Fig. 1).Repeated injections of PGE| at the samesite of the skin produced an inflammatoryreaction, clinically characterized by redness,edema and tenderness with biochemicalchanges of the glycosaminoglycans similarto those seen in the inflammatory reactionfollowing tissue injury (S0ndergaard et al.1973), Furthermore, PGE, does not causecutaneous vascular tachyphylaxis (PaulliJ0rgensen & S0ndergaard 1973), The mor-phology and cellular sequence in the PGEj-

induced reaetion, studied by a skin-windowtechnique, were similar to those of non-spe-cific inflammation (S0ndergaard & Wolf-Kirgensen 1972), The antagonism that existsbetween different tnembers of the prosta-glandin family is of interest in this respect.Thus PGFo,, which blocked the vascular re-sponse to known chcmotactic substances itivivo failed to modify leucocyte migration(Willoughby 1968), Furthermore, in fattyacid deficient rats the prostaglandin-phaseof the inflammatory response has recentlybeen found to be significantly reduced (Bon-ta et al, 1974),

Recognition Ihat the prostaglandins mayparticipate in tbe pathogenesis of inflam-mation induced by ultraviolet radiation, assuggested by S0ndei"gaard & Greaves(I97()b) and Mathur & Gandhi (1972), hasnow led to studies on the therapeutical ef-fect of prostaglandin antagonists, Snydcr &Eaglstein (1974b) have reported that indo-methacin and aspirin, injected intradertnal-ly, delayed and decreased ultraviolet ery-thema, and the same authors have alsoshown (Snyder & Eaglstein 1974a) that asingle application of a 2,5 % solution ofindomethacin decreased the redness, wartnthand tenderness of sunburned skin for 24 hor longer. Similar therapeutical approachesshould be applied to other inflammatoryskin conditions where prostaglandins are in-volved, i,e, burn lesions (Arturson et al,1973) and primary irritant dermatitis (Gol-dyne et al, 1973, S0ndergaard et al, 1974),

B, ImtnunityThe immediate hypersensitivity reaction(type 1 reaction of Gell & Coombs 1968)as well as the delayed hypersensitivity re-action (type IV reaction) have been thesubject for prostaglandin research relatedto dermatology,

Szentivanyi (1968) has theorized thai thefundamental abnormality in atopy may bedue lo a deficiency in adenyl cyclase. How-

PROSTAGLANDINS 283

ever, in Mier & Urselmann's studies (1970a,b), no decrease in the level of adenyl eyclaseactivity was detected in biopsy specimensfrom lesions of atopic dermatitis.

Whereas the role of hislamine in imme-diate-type weal-and-flare reactions is wellestablished (Katz 1942, S0ndergaard &Greaves 1971b), there is so far no ditectevidence for release of prostaglanditis inskin. In other tissues, e.g. guinea pig lungs,prostaglandins may be involved in the ana-phylaclic reaction (Piper & Vane 1968),and certainly the pharmacological proper-ties of the prostaglandins fully justify stud-ies on their role in the skin in this con-text.

One type of wealing reaction in the skinwhieh might be due in part to prostaglan-dins is the edema following bee stings, con-sidering that bee venom contains phospholi-pase A (Hogberg & Uvnas 1957), whichstimulates prostaglandin formation (Bartelset al. 1968).

In patients suffering from atopic derma-titis, proslaglandins cause an erythemalous

U J

HUMANOLLERGICCONTACT

DERMATI T IS

Fig. 5. Concentration of prostaglandins (ex-pressed as PGE) equivalents) in perfusates ofseven patients with allergic contact dermatitisand normal skin of four eontrol subjeets.

reaction when intradermally injected (Solo-tnon et al. 1968, .luhlin & Michaelsson1969). This reaction, which is identical tothat seen in nortnal subjects, is curiouslydifferent from the paradoxical blanchingproduced by other potent vasodilators suchas histamine, serotonin, and bradykinin.

Flutnati allergic contact dermatitis hasbeen studied by S0ndei'gaai'd & Greaves(197()c). Originally a smooth-muscle con-tracting substance with prostaglandin-likeproperties was detected by S0ndergaard &Greaves (197()a). In a subsequent study(Greaves ct al. 1971), this activity, presentin skin perfusates from 35 out of 45 pa-tients suffering from allergic contact ecze-ma, was found to be due to a mixture ofprostaglandins E and F. By contrast, noprostaglandins or trace amounts could bedetected in perfusates from 22 control sub-jects (Fig. 5). These studies have recentlybeen confirmed by Goldyne et al. (1973).

Receptors for vasoactive hormones andmediators of inflammation including theptoslaglandins seem to regulate several im-munological leucocyte functions, probablyvia the adenyl eyclase system (for reviewsee Bourne et al. 1974), including histaminerelease frotn hutnan basophils, release oflysosomal enzymes from human neutrophils,itntnune cytolysis, interferon production byT-lyniphocytes, and plaque fortnation onsheep red blood cells by B-lymphocytes.These results represent early attetnpts at in-vestigating potetitially itnportanf mecha-nisms for regulation of immunity whichmay open up entirely new therapeutic ap-proaches to treatment of immunologic hu-man skin disorders.

C. Vascular DisordersPlatelet aggregation and adhesion influencethe cutaneous microcirculatioii and areclosely related to vascular stasis and throm-bosis (Ryan & Gopeman 1969). The prosta-glandins influence the stickiness of platelets.

284 S0NDERGAARD

Klocze (1967) has shown that PGEj specifi-cally inhibits ADP-induced platelet clump-ing, whereas PGEo stimulates platelet ad-hesiveness in certain animal species. Thework of Emmons et al. (1967) is of interestin this respeet, since, by use of topically orintravenously administered PGE|, they wereable to completely inhibit thrombus forma-tion which readily followed vascular injuryin rabbits.

The chetnical trigger for the plateletthrombus formation in arterial thrombosis,the "labile aggregation stimulating factor"(LASS), may be closely related to the endo-peroxide intermediate of prostaglandin syn-thesis and "rabbit aorta contracting sub-stance" (Willis 1974).

When prostaglandins were intra-arteriallyinjected severe attacks of flushing followed(Bergstrom et al, 1959), It has been claimedthat prostaglandins lnight be involved incertain conditions accompanied by flushing,since prostaglandins were present in highconcentiations in tumor tissue and bloodfrom patients with medullary carcinoma ofthe thyroid and other types of tumors inwhich flushing was a prominent feature(Williams et al, 1968, Sandier et al, 1968),

D, Proliferative DermatosesProliferative skin lesions in essential fattyacid-deficient laboratory animals have beenassoeiated with a reduction in prostaglandinconcentrations in skin. Burr & Burr (1929,1930), Hansen et al, (1954) and Menton(1968) observed that rats, dogs and micefed essential fatty acid-deficient diets devel-oped thickening of the epidermis, hyper-keratosis, increase in epidermal mitoticactivity, hair loss and increased seba-ceous gland activity. These cutaneouschanges preceded any other manifestationsof essential fatty acid deficiency and theskin abnormalities were reversed by feedingthe animals arachidonic acid and linolenicacid, the essential fatty acid precursors of

prostaglandins, Ziboh & Hsia (1972) havereported that topical application of prosta-glandin Eo in a vehicle of propylenglycol-ethanol 3:7 (v/v), 100 /(g/day to the scalylesions of essential fatty acid deficient ratsresulted in clearance of the lesions, Intra-peritoneal injection of PGE-; had no ob-servable effect on the skin lesions, probablydue to the rapid systemic metabolism ofP G E J , Clearly, these results indicate con-nections between arachidonic acid, PGEoand keratinization.

Among the proliferative dermatoses, pso-riasis has been the loeus for extensive stud-ies on cyclic AMP for 4-5 years (for reviewsee Voorhees ef al, 1974), but so far onlyfew attempts have been made to tie resultsobtained in prostaglandin and e-AMP re-search together. Recently, however, Aso etal, (1974) have reported reduced levels ofE-type prostaglandins in involved psoriatieepidermis. Furthermore, PGE) stimulationof c-AMP accumulation was significantlyreduced in involved psoriatie epidermis ascompared to uninvolved epidermis. Topicalapplication of e-AMP proved unsuccessfulin the treattnent of seven patients with pso-riasis (Auerbaeh 1974). This could be dueto wrong dosage or wrong route of adminis-tration and should iiot discourage other at-tempts to use various proslaglandins thera-peutically in psoriasis,

E. Skitt TttmorsThe presence of small quantities of PGEjand PGFo,, has been demonstrated in Ka-posi's sarcoma (Bhana ct al. 1971), and theabdominal complaints such as diarrhoea andpain that the diffusely involved patient mayexperience have been related to release ofthese substances, Sykes & Maddox (1972)found it unlikely that prostaglandins wereessential for tumor growth. In sarcomassubcutaneously implanted in the mouse,estimations of prostaglandin were low,whereas similar tumors Irom a different

PROSTAGLANDINS 285

source contained very high levels. Hainmer-strom et al. (1973) found that polyoma virustransformation of libroblasts led to a con-siderable inerease in PGEo produetion.However, further studies, including studieson eulaneous benign and malignant tumors,are needed to further establish the relation-ship of tbe proslaglandins to growth con-trol and oncogenesis.

F . ItchItch and pain are closely related .sensations.Prostaglandins are known to cause hyper-algesia in skin (Solomon et al. 1968, Fer-reira 1972). Ferreira (1972) also noted thatthe effects of intradermal infusion of verylow concentrations of Ei and E^ prosta-glandins, mimicking endogenous release,were cumulative, depending not only onconcentration but also on time of exposure.The results of simultaneous infusion of pro-staglandins and histamine and bradykiiiinshowed that prostaglandins of the E type in-creased pain sensitivity to these substanees.Using a different model system Greaves &McDonald-Gibson (1973) eonfirmed theseresults. They found that PGE, lowered thethreshold of htiman skin lo bistamine-evok-ed itehing. They suggest that regulation ofthreshold responses (vascular permeability,leucotaxis) may be an important generalrole of prostaglandins in inflammation. Ac-cording to Greaves & MeDonald-Gibson(1973), the aniiprurilic effects of cortico-steroids topically applied lo inflamed skinmight be due lo the inhibitory action ofthese substanees on prostaglandin synthesispreviotisly observed (Gleaves & McDonald-Gibson 1972),

Concluding Remarks

Interest in Ibe dermatologieal aspects ofthe prostaglandins has increased rapidlyover the past 4-5 years. Prostaglandins andprostaglandin forming and degrading en-

zymes are present in skin. In the normalskin the prostaglandins may play a role inthe control of epithelial growth, hair growthand keratinization. The antilipolytic actionof the proslaglandins is well established,whereas the influence on tbe metabolism ofsebaeeous gland lipids remains almost un-explored. The stimulating effect of certainproslaglandins on eollagen biosynthesis isan aspect of prostaglandin action of poten-tial significance for wound healing and tis-sue repair. Agents counteracting prosta-glandin-induced aetivities or inhibiting pro-staglandin biosynthesis have proved usefuliri experimental work. The therapeutical ef-fects of aspirin-like drtigs may be ascribedlo such properties.

In pathological skin eonditions prosta-glandins of the E-series seem to play a roleas mediators of sustained cutaneous inflam-mation which may lead to entirely newtherapeutical approaches in this field. Theregulatory role of eertain prostaglandins inseveral immunologieal leucocyte functionsmay represent early mechanisms for regula-tion of immunologieal human skin dis-orders. The studies on cyclic AMP andother cyclic nucleotides in proliferative der-matoses are already abundant. However,more work is needed to tie results obtainedin prostaglandin and cyclic nucleotide re-search together. Elucidation of these inter-relationships seems important from an ex-perimental point of view and may have im-portant therapeutieal implications.

Acknowledgments

This work was supported in part by grantsfrom the Danish Slate Researeh Founda-tion. Miss Helen Heiligstiidl is acknowledgedfor her skilful technical assistance in mostof the author's experimental work.

286 S0NDERGAARD

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Address:Jfirgen S^ndergaardDept. of DertiutlologyUniversity oj CopenhagenRigshospitalDK 2100 Copetihagen ODenmark