Arch Dermatol Res (1992) 284 [Suppl]: $12-S17

9 Springer-Verlag1992

Leukotriene

B4

and platelet-activating factor in human skin

L. Michel and L. Dubertret Department of Dermatology, INSERM U312, H6pital Saint-Louis, 1 Avenue Claude Vellefaux, F-75010 Paris, France

Summary. Acute inflammatory reactions are characterized by leukocyte infiltration associated with increases in vascular permeability and in local blood flow. Leukocyte infiltration can be induced by chemotactic factors such as leukotriene U 4 (LTB4) and paf-acether (formely known as platelet-activating factor) that can be generated within inflammatory lesions. Vascular permeability and increase in blood flow are also affected by LTB 4 and paf-acether, as well as by several other substances, including histamine and prostaglandins. Derived from arachidonic acid via the 5 lipo-oxygenase pathway, LTB 4 is one of the most potent leukocyte chemotactic substances known. Intradermal injections of LTB 4 induce dermal neutrophil infiltration in animal models and in humans. Topical application of LTB 4 to human skin induces intraepidermal micro-abscesses containing numerous intact neutrophils. LTB 4 has been found to be increased in psoriatic lesions, but its synthesis by epidermal cells remains undecided. Like other leukotrienes, LTB 4 can stimulate DNA synthesis in cultured human epidermal keratinocytes. However, receptors for LTC 4 but not for LTB 4 have been found on human keratinocytes in culture. Paf-acether is an ether-linked phospholipid identified as 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine and is considered to be one of the most potent mediators of acute allergic and inflammatory reactions. For instance, intradermal injection of pafacether induces inflammatory events such as neutrophil infiltration and increase in vascular permeability. Recent data suggest that cutaneous cells, such as fibroblasts and keratinocytes, are capable of producing paf and that paf is released during the development of allergic cutaneous reactions. Paf is also increased in psoriatic lesions, and it is tempting to speculate that paf may contribute to the development of various skin disorders with acute and chronic skin inflammation. In the future, LTB 4 and paf antagonists might help in providing an answer to the hypothesis that these two mediators may have a key role in many chronic inflammatory skin diseases and may offer new prospects for topical and systemic treatments.

Correspondence to." L. Michel, Department of Dermatology, INSERM U 312, H6pital Henri Mondor, F-94010 Creteil, France

Key words: Leukotriene B4 - Platelet-activating factor - Cutaneous inflammation - Eicosanoids

The initiation of inflammatory reaction in human skin is characterized by the production of soluble factors and by the mobilization of various cell populations including polymorphonuclear neutrophils. Among the soluble mediators which participate in the inflammatory reaction, and which may also modulate the subsequent more specific immune response, two classes of molecules have emerged as the principal protagonists: cytokines and lipid mediators derived from cell membrane phospholipids. Lipid mediators include arachidonic acid metabolites (eicosanoids) such as prostaglandins and leukotrienes, and platelet-activating factor (paf). They are produced by the activation of phospholipase A 2 that cleaves the membrane phospholipid 1-O-alkyl-2-arachidonyl-snglycero-3-phosphocholine into arachidonic acid and the 1-alkyl-2-1yso-glycerophosphocholine (lyso-paf) molecule. Subsequent oxidative metabolism of the free arachidonic acid leads to the production of eicosanoids. Acetylation of the remaining lyso-paf by acetyl-coenzyme A: lyso-paf acetyl-transferase yields the paf molecule. Potential sources of eicosanoids and paf in the normal and inflammed skin are both the constituent cells (keratinocytes, fibroblasts, mast cells, vascular endothelium) and the blood cells infiltrating the skin (neutrophils, eosinophils, monocytes, lymphocytes, and platelets), as detailed below. These lipid mediators exhibit a wide range of biological activities, acting on a variety of cell populations and often including the cells which produced them. Their biological activity is thought to be mediated by cell membrane receptors. Recently, a pal receptor from guinea pig lung has been cloned [34] and its proposed structure suggests that it is associated with a G protein. Functional studies had previously suggested that this may be also the case with leukotriene B4 (LTB4) receptors [511, The present review focuses on the two potent lipid mediators, LTB 4 and paf, on their origin and role in

S13 the development of cutaneous inflammation and in the pathogenesis of chronic inflammatory dermatoses. Pal, first described as platelet-activating factor [4] and later identified as 1-O-alkyl-2-O-acetyl-sn-glycero-3phosphocholine [5, 20], is one of the most potent mediators of acute allergic and inflammatory reactions [3, 6, 56, 71]. Pal is synthesized by a wide variety of human inflammatory cells including neutrophils, monocytes, alveolar macrophages, platelets, eosinophils, and vascular endothelial cells (reviewed in [59]); pal synthesis occurs rapidly after appropriate stimuli. For example, phagocytosis or tumor necrosis factor (TNF) promotes synthesis and release of paf in neutrophils and macrophages within 10 min. Specific receptors for paf have been identified on many target cells, and after the cloning of paf receptor from guinea pig lung [34], a recent characterization of the cloned human pal receptor revealed that it is a new member of the rhodopsin type of receptor family [75]. Paf interaction with its specific cell surface receptors stimulates phosphoinositide metabolism and the subsequent mobilization of intracellular calcium via a G protein [54]. Apart from its well-known effects on platelets [20], paf activates many functional responses in various target cells. For instance, pal is a potent chemotactic agent for neutrophils [2] and is the most potent chemotactic factor for eosinophils in vitro so far described [67, 72]. paf also induces aggregation of both neutrophils and monocytes as well as production of superoxide anions in the latter cell type [59]. Interestingly, pal stimulates the synthesis of 5-1ipoxygenase products in neutrophils [18, 42]. Human neutrophils stimulated with pal in the range of 10-s-10 -7 M for 15 min release detectable amounts of LTB 4 and its co-oxidation products, 20-OH and 20-COOH-LTB 4 [45]. Preincubation of neutrophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances stimulatory effects of paf and other inflammatory mediators towards neutrophils [73], and, in particular, GM-CSF enhances the synthesis of the 5-1ipoxygenase products in response to paf stimulation in a time- and dose-dependent manner [45]. Similarly to pal', the 5-1ipoxygenase metabolites of arachidonic acid are potent lipid mediators that play a major role in inflammatory and allergic reactions [12, 26, 36, 55, 65]. LTB 4 is the major product of arachidonic acid metabolism produced by the 5-1ipoxygenase pathway in human polymorphonuclear neutrophils [7]. As shown recently, both 5-1ipoxygenase and a membranebound 18-kDa protein termed 5-1ipoxygenase-activating factor (FLAP), detected in cells able to produce leukotrienes, are necessary for cellular leukotriene synthesis [60]. The major effects of LTB 4 are directed at phagocytes [reviewed in [41]). When studied in vitro, LTB4 promotes chemotaxis of neutrophils, monocytes, and fibroblasts [24, 57, 44]. LTB 4 stimulates other neutrophil responses such as chemokinesis, adhesion to endothelium, aggregation, and degranulation through binding to specific receptors [38]. It promotes calcium movement into cells as calcium ionophores do [24]. Human keratinocytes may also be a target for LTB4 proliferative action, and specific

binding sites have been identified on their membranes [53, 61]. Indeed, LTB4 as well as LTC 4 and LTD 4 exert potent and stereospecific mitogenic effects on cultured human keratinocytes [37]. The presence of these arachidonic acid metabolites in psoriatic skin lesions may be pertinent to both inflammation and aberrant epidermal growth in psoriasis, as discussed below. As suggested by their potent inflammatory effects, leukotrienes may play a major pathogenic role in inflammatory processes in the skin (reviewed in [16, 25, 36]). After intradermal injection in human skin, LTB 4 elicits a transient weal and flare response followed by a persistent induration with perivascular neutrophil infiltrates and fibrin deposition [13, 69]. A small synergism with prostaglandin E 2 (PGE2) has been observed in man. Using a skin chamber model, we have shown that LTB4 induces a dose- and time-dependent migration of neutrophils within the dermis and strongly stimulates neutrophil degtranulation in vivo [46]. However, LTB 4 alone slightly increases vascular permeability, whereas in association with prostaglandins it induces an intense vasopermeability. By topical application under occlusion to the skin of normal individuals, LTB 4 produces dose-related erythema and swelling lasting up to 7 days. Histological examination showed intraepidermal neutrophil microabscesses which were maximal at 24 h and were accompanied by neutrophil and mononuclear dermal infiltrates [15, 58]. Such features mimic histopathological changes seen in early lesions of psoriasis; in particular, the neutrophil microabscesses are characteristically found in early as opposed to well-established chronic lesions of psoriasis. Similar appearances result from the application of LTB 4 to uninvolved skin in psoriasis [21]. However, there is no evidence of intradermal lymphocytic infiltrates or spongiosis around the microabscesses and no hyperplasia of the epidermis, features which also characterize psoriasis. Moreover, multiple applications of LTB 4 do not elicit lesions of psoriasis but result in attenuated responses with tolerance both clinically and histologically [21, 74]. Microabscesses from the epidermis observed in well-established lesions of chronic plaque psoriasis even disappear after repeated applications of LTB 4. Such tolerance to LTB 4, also observed after application of 12-hydroxyeicosatetraenoic acid (12-HETE) may be important in controlling the magnitude of the inflammatory events in psoriasis, limiting the neutrophil inflammatory response in situations in which neutrophilotactic substances are continuously over produced. Since no alteration in the LTB 4 receptor density or affinity on neutrophils from patients with psoriasis has been observed, neutrophil accumulation in psoriatic skin may be the result of an excess of cutaneous chemoattractant rather than the increased readiness of neutrophils to migrate towards LTB 4 due to altered LTB 4 receptor density or affinity [19]. However, to postulate the potential involvement of leukotrienes in the genesis of a pathological change and development of inflammatory skin diseases such as psoriasis, several criteria should be satisfied [16, 63]. In addition to the reproduction, at least in parL of the

S14 pathological changes observed in the disease by introduction of the mediator into the tissue in vivo, as discussed above, other criteria must be fulfilled, such as: (a) the demonstration of the release of the mediator in appropriate concentrations in samples from the inflammed skin in vivo, (b) the attribution of the mediator release to resident tissue cells or to infiltrating inflammatory cells, and (c) the modification of the pathological process by administration of specific enzyme inhibitors or receptor antagonists in vivo. With regard to these criteria, LTB 4 emerges as one of the major mediators that can be incriminated in the pathogenesis of psoriasis. Indeed, besides its potent neutrophil chemoattractant activity and its ability to reproduce accumulation of neutrophils and vasodilation that characterize psoriatic skin lesions [15, 69], samples from psoriatic lesions have been shown to contain biologically active and immunoreactive amounts of LTB4-iike material [8, 9, 13, 63]. Nevertheless, as LTB~ has been also detected in other inflammatory dermatoses such as urticaria, atopic dermatitis, and allergic contact dermatitis [16, 63], the local release of LTB4 in the skin might not be a primary pathogenic phenomenon in psoriasis. Moreover, other arachidonic acid products such as LTC 4, mono-hydroxyeicosatetraenoic acids (HETEs) and prostaglandins have been also recovered in psoriatic skin lesions [8, 9, 14, 22, 23, 30, 76]. It has been also reported that, although LTB 4 and 12- and 15-HETE have been detected in most psoriatic lesions, there was a remarkable variation from lesion to lesion from one anatomical region to another within the same patient [23]. In fact, the actual cellular origin of LTB4 and other arachidonic acid products found in psoriatic lesions has not been definitively established yet. Whether epidermal cells or invading neutrophils are the primary sources of LTB 4 within psoriasis or inflammatory dermatoses remains debatable. At the present time, the metabolic pathways of arachidonic acid in freshly isolated human epidermal cells are still controversial [16, 33, 63, 64]. Although it has been reported that human epidermal cells can synthesize low quantities of LTB 4 in vitro [27, 28, 63], the main products of the lipoxygenase pathway in both keratinocytes and Langerhans' cells in the presence of arachidonic acid seem to be 5-, 12-, and 15-HETE, with only small amounts of LTB 4 [63, 64]. The major cyclo-oxygenase product of both cell types would be PGD z, with minor amounts of PGE 2. Another recent report has also shown that epidermal cells transform arachidonic acid mainly into 12-HETE and PGE2, with, to a lesser extent, formation of PGD2 and PGF2~, 12-hydroxyeptadecatrienoic acid, 15-, and l l-HETE [68]. However, no eicosanoid derived from the 5-1ipoxygenase pathway was detected in this in vitro study. Interestingly, this work demonstrates the existence of a LTA4 epoxide hydrolase activity in epidermal cells. By conversion of neutrophilproduced LTA 4 to LTB4, epidermal cells could cooperate to LTB 4 biosynthesis by transcellular metabolism of LTA 4 in lesions of psoriasis and possibly other dermatoses characterized by increased LTB 4 synthesis and prominent polymorphonuclear leukocyte infiltrates [68].

The main pathway by which LTB 4 can be catabolized appears to involve co-oxidation and yields 20-OH-LTB4, which is subsequently oxidized to 20-COOH-LTB 4 [66]. In human skin LTB~ has been shown to be catabolized by the cytochrome P-450-dependent enzyme sytem [52]; the addition of radioactive LTB 4 to primary human keratinocytes followed by incubation at 37 ~ resulted in time-dependent disappearance of LTB 4 and appearance of 20-OH-LTB 4 and 20-COOH-LTB 4 in the medium. Such metabolization of LTB4 by human epidermis may participate in modulating the effects of this proinflammatory lipid in this tissue. Indeed, such 20-C metabolites have been recovered from cell cultures and inflammatory cutaneous lesions [27, 63]. Most of the results obtained with LTB 4 can be transposed to paf, and according to the criteria developed above it appears that paf may also play an important role in the development and maintenance of cutaneous inflammation and in the pathogenesis of inflammatory dermatoses, such as psoriasis. Indeed, PAF is a potent in vivo agonist capable of inducing inflammatory events in human skin. Intradermal injection of paf in normal individuals elicits persistent clinical and histopathological responses characterized by a biphasic inflammatory response (i.e., early weal and flare response succeeded by a late-onset erythema), reminiscent of the dual response to allergen in sensitized patients [1]. It induces acutely increased plasma extravasation and a 24-h persistent accumulation of inflammatory cells with, in normal skin, predominantly neutrophils as well as in older lesions, appearance of monocytes and lymphocytes within the dermis [2, 46]. When applied locally to human dermis, it increases vascular permeability and neutrophil infiltration, with appearance of intravascular basophils after a 24-h challenge [46]. Although paf is a potent basophil agonist capable of inducing histamine relase as well as de novo synthesis of LTC 4 in vitro [10], no evidence of basophil degranulation was observed in vivo. While intradermal injection of paf in normal individuals elicits a wheal and flare response with a perivascular neutrophil infiltrate, intradermal injection of paf in allergic patients induces a typical hypersensivity cutaneous reaction associated with an intense eosinophil infiltration similar to that induced by antigen in atopic individuals [31, 32]. As pal can activate eosinophils to release granule constituents and generate noxious superoxide anions, and as eosinophils can produce large amounts of paf under appropriate stimuli [39], such results are of particular pathophysiological releavance and suggest that paf may play a central role in the development of late-phase allergic reactions in vivo. Accordingly, we recently showed that prolonged contact of allergen with the dermis of atopic volunteers induces the appearance of paf and intense eosinophil recruitment in vivo [47, 48]. We also observed that, in response to antigen, precursors (lyso-paf and 1-alkyl-2-acyl-glycerophosphocholine) were released in the skin chamber fluids placed on pollen-sensitive patients. In such patients, paf and its precursors appeared during the late phase of the reaction and persisted for at least 18 h after the allergen

Sl5 had been removed, paf has been also identified in inflammatory dermatoses; for instance, pal has been found in psoriatic scales [43] and has been shown to be associated with primary acquired cold urticaria [29]. However, as for LTB4, the cellular origin of paf in inflammatory dermatoses is not clearly defined. Inflammatory cells such as eosinophils or neutrophils migrating to the inflammatory site may produce paf [5)]. Furthermore, resident cutaneous cells may also synthesize paf. Indeed, we recently demonstrated that at least two populations of cutaneous cells, one the fibroblasts in the dermis [49] and the other the keratinocytes in the epidermis [50], produce paf in response to calcium ionophore. Addition of lyso-paf to fibroblast cultures enhanced paf synthesis twofold. By contrast, addition of lyso-paf to cultured keratinocytes did not modify pal production. However, acetyl-coenzyme A did enhance epidermal paf production fivefold. During inflammatory reactions, platelets or neutrophils may carry exogenous lyso-paf and/or acetate donors to fibroblasts or epidermal cells, thus increasing the production of paf by these cells. At the present time, the physiological signals that induce fibroblasts or epidermal cells to produce paf are unknown. One possibility is that paf production is induced by cytokines present in the skin such as interleukin 1 (IL-1). Epidermal cells secrete IL-1 in large amounts [40], and IL-1 induces paf synthesis in endothelial cells [11] and monocytes [70]. In fact, there is increasing evidence to suggest that the p r o d u c t i o n of eicosanoids, paf, and cytokines may be interrelated (reviewed in [62]). For instance, LTB4 can stimulate IL-1, IL-6, and T N F production in monocytes, and endogenous leukotriene production may play a role in IL-6 synthesis. Paf can augment IL-1, IL-6, and T N F production by human cells, whereas IL-1 and T N F can in turn induce the synthesis of paf in several cell types including endothelial cells and neutrophils. Added to the fact that paf can stimulate LTB~ production, these findings suggest that new drugs with a broad spectrum o f anti-inflammatory action are more likely to be effective in inflammatory dermatoses than compounds that inhibit the formation or effects of a single mediator. However, the latter can be quite effective in some dermatoses, and, for instance, topical lonapalene, a 5-1ipoxygenase inhibitor, has been shown to reduce LTB 4 levels in psoriatic lesions and to clinically improve lesional skin [35], Further pharmacological research may provide new anti-inflammatory tools, and it could be interesting to study molecules such as synthetic anti-flammins. These peptides include lipocortins and uteroglobin that are endogenous cellular phospholipase A 2 inhibitors induced by steroids [17]. They present potent anti-inflammatory properties; they can inhibit synthesis of phospholipid mediators such as paf and can suppress the inflammatory reaction induced by intradermal injection of potent agents such as complement component C5a in rabbit skin. Such molecules may be able to regulate inflammatory events in human skin by modulating the release of phospholipid mediators, in particulary LTB 4 and paf, as steroids do, with, hopefully, fewer side effects.

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Leukotriene B4 and platelet-activating factor in human skin.

Acute inflammatory reactions are characterized by leukocyte infiltration associated with increases in vascular permeability and in local blood flow. L...
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