leukotriene-b4 and Psoriasis

Leukotriene B

Topics: Animals; Asthma; Leukocytes; Leukotriene B4; Mice; Psoriasis; Receptors, Leukotriene B4

Remarkable effects of anti-IL-17A and anti-IL-23 antibodies on psoriasis indicate deep involvement of IL-23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen-presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, "detachment-mediated cell proliferation." This passing is continuously repeated and leads to elongation of rete ridges. The IL-23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL-17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL-23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL-23 and IL-1β. In this manner, the framework of the IL-23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL-17A production by neutrophils and ending in IL-17A production by nTh17 cells. Therapeutic mechanisms of anti-IL-17A and anti-IL-23 antibodies, targeting neutrophils, were also described.

Topics: Animals; Antibodies, Monoclonal; Cell Communication; Cell Movement; Cell Proliferation; Chemokine CCL20; Disease Models, Animal; Epidermis; HSP70 Heat-Shock Proteins; Humans; Interleukin-17; Interleukin-23; Keratinocytes; Leukotriene B4; Neutrophils; Psoriasis; Receptors, CCR6; Th17 Cells; Toll-Like Receptor 4

Topics: Culture Techniques; Denmark; Epidermis; Epoxide Hydrolases; Humans; Leukotriene B4; Psoriasis

The 5-lipoxygenase (5-LO) product of arachidonic acid, leukotriene (LT-)B4, is considered to play a significant role in the pathogenesis of psoriasis. In vitro LTB4 is a potent chemoattractant for leukocytes, and it increases DNA synthesis in human cultured keratinocytes. Intradermal injection of LTB4 into human skin in vivo results in a wheal and flare reaction, and topical application produces intraepidermal microabscesses and induces hyperproliferation. Furthermore, LTB4 has been determined in biologically active amounts in psoriatic skin lesions. Despite the importance of LTB4 in psoriasis, the capacity of the human epidermis to synthesize LTB4 has remained controversial. Recently, a very limited 5-LO activity was reported in human epidermis. Thus, it was shown that human epidermis can contribute significantly to LT formation by transcellular LT synthesis. By this mechanism, LTA4 released from activated leukocytes is further transformed into LTB4 in the keratinocytes by the LTA4 hydrolase. Transcellular metabolism may be of importance in psoriasis where neutrophils migrate into the epidermis, because in human neutrophils the LTA4 hydrolase has been shown as the rate-limiting step in LTB4 formation. The LTA4 hydrolase was localized in the epidermis by activity determination, by inhibition of enzyme activity with known LTA4 hydrolase inhibitors, by Western blotting and by immunohistochemical staining. Moreover the enzyme was purified and further characterized from human cultured keratinocytes and human epidermis. Because of these recent results it is concluded that LTB4 is of significance in the pathogenesis of psoriasis, and it is suggested that future work should focus on developing potent LTA4 hydrolase inhibitors for treatment of psoriasis.

Topics: Amino Acids; Epoxide Hydrolases; Humans; Leukotriene B4; Psoriasis; Skin

It has been suggested in the literature that 5-lipoxygenase activation may be an important pathological event in psoriasis and that 5-lipoxygenase inhibitors may thus have some beneficial therapeutic effect in this disease. This is because (1) neutrophil activation is a prominent feature of the disease, (2) leukotriene B4 is a potent chemotactic agent for neutrophils and is present in psoriatic lesions, (3) 5-lipoxygenase is present in human epidermis, (4) inhibition of 5-lipoxygenase may affect the disease. These concepts are questioned, and in particular it is suggested that (1) the leukotriene B4-like material found in psoriatic skin has never been shown to have the correct stereochemistry to indicate that it is 5-lipoxygenase derived, (2) there is no convincing evidence for the presence of the 5-lipoxygenase enzyme in human skin, (3) drugs purported to have some benefit in psoriasis through 5-lipoxygenase inhibitory mechanisms act through other mechanisms and (4) selective leukotriene biosynthesis inhibitors have no therapeutic utility in psoriasis. It is concluded that 5-lipoxygenase activation does not play a significant role in the pathology of psoriasis and therefore selective leukotriene biosynthesis inhibitors would have no significant role in the treatment of this disease.

Topics: Arachidonate 5-Lipoxygenase; Cell Movement; Epidermis; Humans; Leukotriene Antagonists; Leukotriene B4; Neutrophils; Psoriasis

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 B4 (LTB4) and paf-acether (formerly known as platelet-activating factor) that can be generated within inflammatory lesions. Vascular permeability and increase in blood flow are also affected by LTB4 and paf-acether, as well as by several other substances, including histamine and prostaglandins. Derived from arachidonic acid via the 5 lipo-oxygenase pathway, LTB4 is one of the most potent leukocyte chemotactic substances known. Intradermal injections of LTB4 induce dermal neutrophil infiltration in animal models and in humans. Topical application of LTB4 to human skin induces intraepidermal micro-abscesses containing numerous intact neutrophils. LTB4 has been found to be increased in psoriatic lesions, but its synthesis by epidermal cells remains undecided. Like other leukotrienes, LTB4 can stimulate DNA synthesis in cultured human epidermal keratinocytes. However, receptors for LTC4 but not for LTB4 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 paf-acether 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Dermatitis; Humans; Leukotriene B4; Platelet Activating Factor; Psoriasis; Skin Physiological Phenomena

The purpose of this review is to underline the interactions between eicosanoids, platelet activating factor and IL-1. While the evidence for arachidonate metabolites, especially 12-HETE and the leukotrienes, as major mediators of skin inflammation is persuasive, we wish to draw attention to the potential importance of leukotrienes and prostaglandins as modulators of PAF and IL-1 activity. Phospholipase A2 emerges as a key enzyme in relation to the three above-mentioned mediator classes of human skin. Activation of phospholipase A2 leads to synthesis of both eicosanoids and PAF. Leukotriene products in addition to being pro-inflammatory per se also enhance IL-1 formation whilst cyclo-oxygenase products inhibit IL-1. Prostaglandin E2 also potentiates the actions of PAF. In this scheme it appears improbable that selective inhibition of one component (e.g. a PAF antagonist) or one enzyme (e.g. a 5-lipoxygenase inhibitor) would do more than create an imbalance in this closely integrated network of mediators which might not necessarily be beneficial. On the other hand phospholipase A2 inhibitors including lipocortin would seem to have a greater chance of clinical usefulness because of the central role this enzyme appears to play in the formation or modulation of all these classes of mediator.

Topics: Annexins; Arachidonic Acid; Arachidonic Acids; Dermatitis; Glycoproteins; Humans; Interleukin-1; Leukotriene B4; Lipoxygenase; Phospholipases; Platelet Activating Factor; Prostaglandins; Psoriasis

Topics: Arachidonic Acids; Cyclic AMP; Cyclic GMP; Humans; Leukotriene B4; Polyamines; Psoriasis; Skin; SRS-A

Topics: Acne Vulgaris; Bacteria; Chemotactic Factors; Chemotaxis, Leukocyte; Child; Communicable Diseases; Complement C3; Complement C5; Disease Susceptibility; HLA Antigens; Humans; Hypersensitivity; Leukotriene B4; Neutrophils; Psoriasis; Skin Diseases; Wiskott-Aldrich Syndrome

The leukotrienes (LTs) are a novel group of biologically active mediators derived from arachidonic acid via lipoxygenase enzymes. LTB4 is a potent chemotactic agent for polymorphonuclear leukocytes and in vivo may mediate inflammatory reactions by inducing leukocyte recruitment by mediating indirectly vascular permeability charges and by modulating pain responses. LTC4 and LTD4 collectively account for the biological activity known as slow-reacting substance of anaphylaxis and are potent smooth muscle contracting agents. They may mediate inflammatory reactions by producing changes in blood flow and increases in vascular permeability. Evidence for LT involvement in a number of pathological conditions including diseases such as asthma, psoriasis, ulcerative colitis, and gout is now accumulating.

Topics: Animals; Arthritis, Rheumatoid; Asthma; Colitis, Ulcerative; Gout; Humans; In Vitro Techniques; Inflammation; Leukotriene B4; Neutrophils; Psoriasis; Rabbits; SRS-A

The leukotrienes, so named because of their initial identification in leukocyte preparations and the presence of three conjugated double bonds (a conjugated triene), are metabolites of the same polyunsaturated fatty acids (e.g., arachidonic acid) that give rise to the prostaglandins, thromboxanes, and several other families of biologically active lipids. Their potential clinical importance derives from their effects on vascular and other smooth muscle reactivity and on leukocyte function. Several leukotrienes may markedly influence the cellular and vascular responses that constitute an integral part of hypersensitivity and inflammatory reactions of the skin. Preliminary data from several laboratories have been presented that implicate a specific leukotriene in the evolution of the lesions of psoriasis.

Topics: Arachidonic Acid; Arachidonic Acids; Humans; Leukocytes; Leukotriene B4; Muscle, Smooth; Muscle, Smooth, Vascular; Psoriasis; Skin; SRS-A; Urticaria

Topics: Chemical Phenomena; Chemistry; Dermatitis; Fatty Acids, Essential; Humans; Leukotriene B4; Lipid Metabolism; Lipoxygenase; Phospholipases A; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Psoriasis

Clinical trials successfully using antibodies targeting IL-17 in psoriasis support the importance of IL-17 in the pathophysiology of this disease. However, there is a debate concerning the source and dynamics of IL-17 production in inflamed skin. Here we characterized IL-17-producing immune cells over time, using two established in vivo models of human skin inflammation that share many histological features with psoriasis, i.e., leukotriene B4 application and tape-stripping. Both treatments revealed a clear influx of neutrophils and T cells. Staining for IL-17 revealed that the majority of IL-17 was expressed by neutrophils and mast cells, in both models. Neutrophils, but not mast cells, coexpressed the IL-17-associated transcription factor RORγt and were able to form extracellular traps. While the presence of mast cells remained steady during the skin inflammatory process, the presence of neutrophils was clearly dynamic in time. Therefore, it is attractive to hypothesize that IL-17+/RORγt+ neutrophils contribute to human skin inflammation in vivo and possibly to the pathogenesis of skin diseases such as psoriasis. Surprisingly, T cells represented a minority of the IL-17-expressing cell population. These observations challenge the classical opinion that IL-17 is predominantly associated with T cells in skin inflammation.

Topics: Adaptive Immunity; Adolescent; Adult; Biopsy; Dermatitis; Female; Healthy Volunteers; Humans; Immunity, Innate; Interleukin-17; Leukotriene B4; Male; Mast Cells; Middle Aged; Neutrophils; Nuclear Receptor Subfamily 1, Group F, Member 3; Psoriasis; Skin; Surgical Tape; T-Lymphocytes, Regulatory; Young Adult

Research has revealed new insights into the pathogenesis of psoriasis, leading to new therapeutic options. So far the order of changes in the pathogenesis of psoriasis is unclear. The responses to cutaneous leukotriene B4 (LTB4) application have been studied in the past as an in vivo model for inflammation. The aim of the present study is to find out the order of changes of key steps in inflammation, which all have been shown to be involved in mature psoriatic lesions.. To study the dynamics of the consecutive stages of inflammation in challenged skin as a reflection of a psoriasis-like inflammatory response.. We examined the dynamics of epidermal growth control and the key representatives of the innate and acquired immune system during the first 72 h after challenging the skin by LTB4 application.. Interleukin 17-positive (IL-17+) cells dominate the acute phase of inflammation, whereas T-Bet+ cells seem to increase gradually during the entire observation period. This indicates a more important role for IL-17 in the unstable phase of inflammation and a more prominent role for T-Bet+ cells within the chronic phase.. The present model is highly reproducible and is useful in studying the dynamics of a psoriasis-like inflammation with respect to key components of immunity. It could provide a useful tool to study the immediate biological effects of new therapies like anti-IL-17 drugs on IL-17 production and effects on cutaneous inflammation and epidermal proliferation in vivo.

Topics: Adult; Female; Humans; Inflammation; Interleukin-17; Leukotriene B4; Male; Middle Aged; Models, Biological; Psoriasis; Reproducibility of Results; Skin; Th1 Cells; Th17 Cells; Young Adult

Leukotriene B4 (LTB4) receptor antagonists have been the subject of several studies in the treatment of inflammatory diseases, including psoriasis. A novel oral LTB4 antagonist, VML 295 (LY-293111) has recently been developed and has a pronounced effect on epidermal inflammatory parameters. However, oral treatment of psoriasis for 4 weeks did not result in a decrease in disease severity. The present study was performed in order to investigate whether prolonged treatment with VML 295 up to 8 weeks has a beneficial effect on the overall severity of psoriasis. Moreover, we studied to what extent VML 295 is able to prevent relapse in psoriasis. In the present study, 35 patients with stable chronic plaque psoriasis were included. A representative plaque of at least 16 cm2 was initially treated with clobetasol-17-propionate lotion under hydrocolloid occlusion in all patients. Clearance was achieved within 6 weeks in 31 patients. After clearance, the patients were randomized to treatment and received oral VML 295 capsules 200 mg twice daily or placebo for 8 weeks. Twenty-five patients completed the study. The psoriasis area and severity index (PASI) was assessed before treatment, at clearance, and on days 15, 29, 43 and 5 7 of the treatment period. Biopsies were taken from the treated lesion before treatment, after clearance and at relapse, and cells were analysed by flow cytometry with markers for differentiation (keratin 10), inflammation (vimentin), and proliferation (DNA content). After 8 weeks of treatment, 14 of 15 VML 295-treated patients had relapsed and 11 of 16 placebo-treated patients had relapsed. A total of six patients were withdrawn. The time to relapse and the number of relapsed patients was not significantly different comparing the treatment groups. There was no significant difference in PASI scores between VML 295-treated patients and placebo-treated patients after 8 weeks of treatment. Flow cytometric parameters for differentiation, inflammation and proliferation did not show significant differences between VML 295- and placebo-treated patients. We conclude that oral VML 295 (LY-293111) is not effective in preventing relapse in psoriasis, either clinically or at the cellular level, and that in our group of patients VML 295 had no beneficial effect on overall psoriasis severity. Moreover, we conclude that further development of LTB4 modulating drugs for the treatment of psoriasis is not indicated.

Topics: Administration, Topical; Anti-Inflammatory Agents; Benzoates; Clobetasol; Drug Therapy, Combination; Flow Cytometry; Glucocorticoids; Humans; Leukotriene Antagonists; Leukotriene B4; Psoriasis; Recurrence; Severity of Illness Index

Profound changes in the metabolism of eicosanoids with increased concentrations of free arachidonic acid (AA) and its proinflammatory metabolites have been observed in psoriatic lesions. Free eicosapentaenoic acid (EPA) may compete with liberated AA and result in an antiinflammatory effect.. Our purpose was to assess the efficacy and safety of intravenously administered fish-oil-derived lipid emulsion on chronic plaque-type psoriasis.. A double-blind, randomized, parallel group study was performed in eight European centers. Eighty-three patients hospitalized for chronic plaque-type psoriasis with a severity score of at least 15 according to the Psoriasis Area and Severity Index (PASI) participated in a 14-day trial. They were randomly allocated to receive daily infusions with either a omega-3 fatty acid-based lipid emulsion (Omegavenous; 200 ml/day with 4.2 gm of both EPA and docosahexaenoic acid (DHA); 43 patients) or a conventional omega-6-lipid emulsion (Lipovenous; EPA+DHA < 0.1 gm/100 ml; 40 patients). The groups were well matched with respect to demographic data and psoriasis-specific medical history. Efficacy of therapy was evaluated by changes in PASI, in an overall assessment of psoriasis by the investigator, and a self-assessment by the patient. In one center neutrophil 4- versus 5-series leukotriene (LT) generation and platelet 2- versus 3- thromboxane generation were investigated and plasma-free fatty acids were determined.. The total PASI score decreased by 11.2 +/- 9.8 in the omega-3 group and by 7.5 +/- 8.8 in the omega-6 group (p = 0.048). In addition, the omega-3 group was superior to the omega-6 group with respect to change in severity of psoriasis per body area, change in overall erythema, overall scaling and overall infiltration, as well as change in overall assessment by the investigator and self-assessment by the patient. Response (defined as decrease in total PASI of at least 50% between admission and last value) was seen in 16 of 43 patients (37%) receiving the omega-3 emulsion and 9 of 40 patients (23%) receiving omega-6 fatty acid-based lipid emulsion. No serious side effects were observed. Within the first few days of omega-3 lipid administration, but not in the omega-6 supplemented patients, a manifold increase in plasma-free EPA concentration, neutrophil leukotriene B5 and platelet thromboxane B3 generation occurred.. Intravenous omega-3-fatty acid administration is effective in the treatment of chronic plaque-type psoriasis. This effect may be related to changes in inflammatory eicosanoid generation.

Topics: Adult; Arachidonic Acids; Double-Blind Method; Eicosapentaenoic Acid; Fat Emulsions, Intravenous; Fatty Acids, Omega-3; Female; Follow-Up Studies; Humans; Leukotriene B4; Male; Middle Aged; Psoriasis; Thromboxane B2; Thromboxanes; Time Factors

Fish oil may be beneficial in the treatment of psoriasis and in RA. We examined the potential benefit of Efamol Marine, a combination of evening primrose oil and fish oil in the treatment of 38 patients with PsA. Patients with PsA were entered in a double-blind placebo controlled study and received either 12 Efamol Marine capsules or 12 placebo capsules daily for 9 months. All patients received placebo capsules for a further 3 months. At month 3 of the study patients were asked to reduce their intake of NSAIDs and maintain that decrease provided there was no worsening of their joint symptoms. Clinical assessments of skin and joint disease severity and activity were performed at 0, 1, 3, 6, 9 and 12 months. All measures of skin disease activity including severity, percentage body affected and itch were unchanged by Efamol Marine. The NSAID requirement remained the same between both treatment groups. In addition, there was no change demonstrated in the activity of arthritis as measured by duration of morning stiffness. Ritchie articular index, number of active joints, ESR and CRP. However, a rise in serum TXB2 was observed in the active group during the placebo phase; in addition a fall in leukotriene B4 production occurred during the active phase period followed by a marked rise during the placebo phase suggesting some laboratory documented anti-inflammatory effect. In conclusion, this study suggests that Efamol Marine may alter prostaglandin metabolism in patients with PsA, although it did not produce a clinical improvement and did not allow reduction in NSAID requirement. A larger dose of essential fatty acid may be needed to produce a clinical benefit.

Topics: Administration, Oral; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Psoriatic; Double-Blind Method; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Humans; Leukotriene B4; Linoleic Acids; Male; Middle Aged; Neutrophils; Oenothera biennis; Plant Oils; Prostaglandins; Psoriasis; Severity of Illness Index; Thromboxane B2

Antipsoriatic agents have been shown to decrease skin levels of arachidonic acid and its metabolites including 12-monohydroxy-eicosatetranoic acid (12-HETE), and leukotriene B4 (LTB4). In addition, specific systemic and topical lipoxygenase inhibitors have been reported to be effective in the treatment of psoriasis. The objective of this study was to investigate the effect of a potent oral leukotriene biosynthesis inhibitor (MK886) in patients with chronic plaque psoriasis. Clinical response together with the changes of LTB4 levels in lesional skin biopsy specimens, and urinary leukotriene E4 (LTE4) excretion were evaluated. In addition, markers of inflammation, proliferation and keratinization were studied immunohistochemically. No change in clinical scores or lesional LTB4 levels were observed with a 10 1/3-day course of MK886. A statistically significant reduction in urinary LTE4 excretion was observed: mean LTE4 (ng/h) were 5.14 before treatment and 1.51 on day 11 with MK886; and 7.55 before treatment and 6.57 on day 11 with placebo treatment. Epidermal accumulation of polymorphonuclear leukocytes (PMN) tended to diminish in the MK886 treatment group. These results indicate that although a reduction (greater than 70%) in urinary LTE4 excretion was found, and a slight decrease of epidermal PMN accumulation was observed, no correlative changes in clinical scores or LTB4 levels in skin lesion were found with a short course of MK886.

Topics: Administration, Oral; Adult; Aged; Biomarkers; Biopsy; Dermatitis; Double-Blind Method; Female; Humans; Immunohistochemistry; Indoles; Keratins; Leukotriene Antagonists; Leukotriene B4; Male; Middle Aged; Psoriasis; Skin

The pharmacologic and clinical effects of the 5-lipoxygenase inhibitor, lonapalene, have been determined in a double-blind, placebo-controlled, topical study in ten volunteers with psoriasis. A statistically significant clinical improvement was seen in lesions treated with 2% lonapalene ointment as compared with vehicle-treated sites. Although there was a statistically significant reduction in the levels of material similar or identical to the chemoattractant arachidonate 5-lipoxygenase product, leukotriene B4, in skin chamber fluid samples from lonapalene versus vehicle treated lesions, no significant reduction in arachidonic acid or 12-hydroxy-5,8,10,14-eicosatetraenoic acid was seen. The reduction in leukotriene B4 equivalents occurred before significant clinical improvement in lesions was seen. This and the selectivity of the pharmacologic response suggest that the therapeutic effect of topical lonapalene in psoriasis might be related to inhibition of leukotriene B4 synthesis. These results support the view that 5-lipoxygenase inhibitors may be useful in the treatment of psoriasis, and that leukotriene B4 is a relevant mediator of the pathology of this disease.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Male; Middle Aged; Naphthalenes; Psoriasis

Various chemoattractants have been implicated in the aetiology of the polymorphonuclear leucocyte (PMN) migration into the epidermis seen in early lesions of psoriasis. Using an under-agarose technique, the in vitro chemotactic responses of PMN to the arachidonic acid lipoxygenase product leukotriene B4 (LTB4) were assayed in five groups of subjects: normal healthy volunteers (n = 12), untreated psoriatics (n = 11) and psoriatics treated with topical tar (n = 12), PUVA (n = 11) and UVB phototherapy (n = 10). No significant difference was observed between the responses of control subjects and of untreated psoriatics, nor between the untreated psoriatic group and the PUVA- and UVB-treated groups, respectively. However, comparison of the tar-treated and untreated groups revealed a significantly increased chemotactic response to LTB4 in the tar-treated group (p less than 0.01).

Topics: Chemotaxis, Leukocyte; Coal Tar; Dose-Response Relationship, Drug; Humans; Leukotriene B4; Neutrophils; Psoriasis; PUVA Therapy; Ultraviolet Therapy

Single topical application of the neutrophil chemoattractant arachidonic acid metabolites leukotriene B4 (LTB4) and 12-R,S-hydroxy-5,8,10,14-eicosatetraenoic acid [corrected] (12-HETE) to normal skin elicits a histological response similar to early psoriasis. This effect diminishes following repeated application indicating the development of local tolerance. In order to assess whether induction of tolerance could be exploited as a treatment for psoriasis we studied the clinical effects of topical application of LTB4 (n = 6) and 12-HETE (n = 3) under occlusion to small psoriatic lesions for 12 consecutive days. The area of the control lesions decreased significantly over the study period while the areas of lesions to which LTB4 and 12-HETE were applied remained unchanged. No other difference between responses of the three groups was detected. We have shown that, in the doses used, multiple applications of these substances to established stable psoriatic lesions do not produce a therapeutically useful response.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Aged, 80 and over; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Middle Aged; Psoriasis

In a double-blind trial, 21 patients with severe plaque psoriasis were randomly assigned to receive oral cyclosporine, 14 mg/kg/d, or its vehicle. After four weeks of therapy the 11 cyclosporine recipients had the following response to treatment: two had total clearing and six improved markedly, two moderately, and one minimally; whereas ten vehicle-treated patients showed no change or minimal improvement. Vehicle-treated patients, after a switch to cyclosporine for four weeks, demonstrated impressive improvement similar to that seen in patients who initially received only cyclosporine. Moderate or marked improvement or total clearing was noted in 17 (81%) of 21 and 20 (95%) of 21 after one and four weeks of therapy, respectively. Mitotic figures and leukotriene B4 levels in lesions decreased 86% and 64%, respectively, after seven days of cyclosporine therapy. Mononuclear (including activated T cells) and polymorphonuclear leukocyte infiltrates were markedly reduced in lesions of all patients after seven days of cyclosporine therapy. These results suggest that psoriasis may have an immunologic basis mediated by activated T cells and/or other immune cells; if a long-term regimen with a favorable efficacy-side effect ratio can be determined, cyclosporine would be a significant advance in the treatment of psoriasis.

Topics: Adult; Cyclosporins; Double-Blind Method; Female; Humans; Leukocytes; Leukotriene B4; Male; Microscopy, Fluorescence; Middle Aged; Psoriasis; Random Allocation; Skin

Twenty-four patients with psoriasis completed a double-blind trial of benoxaprofen for their cutaneous lesions. Six out of thirteen on the active drug showed very marked improvement. It is believed that benoxaprofen acts by interfering with the migration of polymorphs into the skin through inhibition of leukotriene B4 synthesis.

Topics: Adult; Aged; Arachidonate Lipoxygenases; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Male; Middle Aged; Propionates; Psoriasis

Clinical studies have shown that diets enriched with omega-3 (also know as n-3) polyunsaturated fatty acids could relieve the symptoms of patients with psoriasis. However, the mechanisms involved remain poorly understood. The aim of this study was to investigate the effects of α-linolenic acid (ALA) on the proliferation and differentiation of psoriatic keratinocytes in a three-dimensional skin model. Skin models featuring healthy (healthy substitute) or psoriatic (psoriatic substitute) cells were engineered by the self-assembly method of tissue engineering using a culture medium supplemented with 10 μM ALA in comparison with the regular unsupplemented medium. ALA decreased keratinocyte proliferation and improved psoriatic substitute epidermal differentiation, as measured by decreased Ki67 staining and increased protein expression of FLG and loricrin. The added ALA was notably incorporated into the epidermal phospholipids and metabolized into long-chain n-3 polyunsaturated fatty acids, mainly eicosapentaenoic acid and n-3 docosapentaenoic acid. ALA supplementation led to increased levels of eicosapentaenoic acid derivatives (15-hydroxyeicosapentaenoic acid and 18-hydroxyeicosapentaenoic acid) as well as a decrease in levels of omega-6 (also know as n-6) polyunsaturated fatty acid lipid mediators (9-hydroxyoctadecadienoic acid, 12-hydroxyeicosatetraenoic acid, and leukotriene B

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; alpha-Linolenic Acid; Cell Differentiation; Cell Proliferation; Dietary Supplements; Extracellular Signal-Regulated MAP Kinases; Humans; Keratinocytes; Leukotriene B4; Psoriasis; Tissue Engineering

The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.

Topics: Animals; Cell Movement; Dendritic Cells; Dermatitis; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Humans; Inflammation; Interleukin-17; Leukotriene B4; Mice; Mice, Inbred C57BL; Psoriasis; RNA, Messenger; Skin; Th17 Cells

The synthesis and structure-activity relationships (SARs) of a series of novel 10-arylacetyl-1,8-dihydroxy-9(10H)-anthracenones are described. Acylation of anthralin with either the appropriate arylacetyl chlorides or arylacetic acids in the presence of pyridine or via the coupling agent dicyclohexylcarbodiimide (DCC), respectively, furnished this structural class of antipsoriatic agents. Potential antipsoriatic activity was evaluated in complementary assays specifically addressed to three important aspects of psoriasis. First, several compounds were identified which are equally potent as inhibitors of human keratinocyte growth as the antipsoriatic agent anthralin. Furthermore, improved ratio of antiproliferative activity to cytotoxicity is demonstrated by the reduced potential of the novel analogues to induce membrane damage, which is a benefit of their reduced ability to generate oxygen radicals as documented by deoxyribose degradation. Second, analogue 3o bearing a hydroxamate functional group was also a highly potent inhibitor of LTB(4) biosynthesis in addition to its excellent antiproliferative activity. SARs of these inhibitors of both keratinocyte growth and LTB(4) biosynthesis with respect to the nature of the para-substitution in the 10-phenylacetyl side chain are discussed. Third, the compounds were also evaluated for their ability to induce the formation of cornified envelope protein in keratinocytes. Cross-linking of cellular protein as a marker of terminal differentiation of keratinocytes was observed for many 10-arylacetyl analogues at concentrations required to arrest cell growth. This newly uncovered activity of the novel anthracenones suggests antipsoriatic potential with respect to disturbance of keratinocyte differentiation, in addition to hyperproliferative and inflammatory aspects of psoriasis.

Topics: Acetanilides; Anthracenes; Anti-Inflammatory Agents, Non-Steroidal; Cell Differentiation; Cell Division; Cell Line; Cell Membrane; Humans; Keratinocytes; Leukotriene B4; Oxidation-Reduction; Psoriasis; Structure-Activity Relationship

Leukotriene B(4) (LTB(4)) is a potent chemoattractant and activator of both granulocytes and macrophages. The actions of LTB(4) appear to be mediated by a specific G protein-coupled receptor (GPCR) BLT1, originally termed BLT (Yokomizo, T., T. Izumi, K. Chang, Y. Takuwa, and T. Shimizu. 1997. Nature. 387:620-624). Here, we report the molecular cloning of a novel GPCR for LTB(4), designated BLT2, which binds LTB(4) with a Kd value of 23 nM compared with 1.1 nM for BLT1, but still efficiently transduces intracellular signaling. BLT2 is highly homologous to BLT1, with an amino acid identity of 45.2%, and its open reading frame is located in the promoter region of the BLT1 gene. BLT2 is expressed ubiquitously, in contrast to BLT1, which is expressed predominantly in leukocytes. Chinese hamster ovary cells expressing BLT2 exhibit LTB(4)-induced chemotaxis, calcium mobilization, and pertussis toxin-insensitive inhibition of adenylyl cyclase. Several BLT1 antagonists, including U 75302, failed to inhibit LTB(4) binding to BLT2. Thus, BLT2 is a pharmacologically distinct receptor for LTB(4), and may mediate cellular functions in tissues other than leukocytes. BLT2 provides a novel target for antiinflammatory therapy and promises to expand our knowledge of LTB(4) function. The location of the gene suggests shared transcriptional regulation of these two receptors.

Topics: Amino Acid Sequence; Animals; Arthritis, Rheumatoid; Asthma; Base Sequence; Cell Line; CHO Cells; Cloning, Molecular; Cricetinae; DNA, Complementary; Humans; Inflammatory Bowel Diseases; Leukotriene B4; Mice; Molecular Sequence Data; Psoriasis; Receptors, Leukotriene B4; Renal Insufficiency; Sequence Homology, Amino Acid; Signal Transduction; Tissue Distribution

Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported.. The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B(4) in the formation of pustules of PPP.. Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB(4) were measured in these 7 patients before and 48 hours after metal patch tests.. Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB(4) in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests.. Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB(4) concentration in the pustules.

Topics: Administration, Topical; Female; Humans; Hypersensitivity; Leukotriene B4; Male; Metals; Middle Aged; Patch Tests; Psoriasis

The role of inflammatory mediators in the pathogenesis and pathophysiology of skin diseases is now widely accepted. We analysed the profiles of inflammatory mediators in normal, sensitive (past history of eczema, but currently patch test negative) and diseased (psoriasis and eczema) skin types to identify the patterns associated with various degrees of inflammatory dermatoses. Compared with normal skin, prostaglandin E2 was increased approximately 3.8-fold (p<0.0002) and 4.7-fold (p<0.0001) in suction blister fluids from sensitive and diseased skin types, respectively. Leukotriene B4 and interleukin-1alpha showed no differences between normal and sensitive skin types. However, in lesional skin from psoriasis and eczema patients, leukotriene B4 was increased approximately 6.6-fold (p<0.0001), whereas interleukin-1alpha was decreased approximately 3.1-fold (p<0.001). Interleukin 6 and tumour necrosis factor-alpha could not discriminate between skin types. We conclude that only prostaglandin E2 showed a significant stepwise increase on progression from normal through sensitive and inflammatory skin diseases. Levels of leukotriene B4 and interleukin-1alpha were also indicative of disease state and may be important in the pathophysiology of these conditions.

Topics: Adult; Dermatitis, Atopic; Dinoprostone; Disease Progression; Eczema; Humans; Immunoenzyme Techniques; Inflammation Mediators; Interleukin-1; Interleukin-6; Leukotriene B4; Middle Aged; Psoriasis; Skin; Tumor Necrosis Factor-alpha

Application of leukotriene B4 (LTB4) to normal human skin induces changes similar to those found in psoriatic skin, and it has proved to be a useful model for studying the pathogenesis and treatment of psoriasis. We studied the expression patterns of molecules that have recently been shown to be altered in lesional psoriatic skin, including the extracellular matrix protein tenascin (TN) and the basement membrane and cell surface-associated heparan sulfate proteoglycans (HSPGs). During 72-h the expression of these markers was studied immunohistochemically and the expression of TN was correlated with epidermal proliferation and influx of inflammatory cells. Following the peak influx of polymorphonuclear leukocytes, a marked increase in TN expression was noted in the papillary dermis 72 h after LTB4 application. The expression patterns of basal membrane-associated epitopes of HSPG remained unaltered, whereas the expression of cell surface-associated HSPG disappeared 72 h after LTB4 application. A significant correlation was found between dermal TN expression and epidermal hyperproliferation, and between TN expression and the presence of dermal T cells. These findings indicate that the model of LTB4-induced acute cutaneous inflammation displays many characteristics of early psoriatic lesions and could serve as a model to study some of the cell biological changes in this disease.

Topics: Administration, Cutaneous; Adult; Cell Division; Dermatitis, Irritant; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunohistochemistry; Inflammation; Leukotriene B4; Male; Models, Biological; Proteoglycans; Psoriasis; Skin; Tenascin

Leukotriene A4 (LTA4) hydrolase which transforms LTA4 into the proinflammatory compound LTB4 has been identified in human epidermis. The purpose of this study was to investigate the potential role of this enzyme in psoriasis, in which LTB4 is present in biologically active concentrations. The concentration and activity of LTA4 hydrolase was determined in normal skin and in matched samples of involved and uninvolved psoriatic skin. The enzyme content was determined using an affinity-purified antibody. This antibody was also used for immunohistochemical staining of skin biopsies. Immunohistochemically LTA4 hydrolase was localized predominantly in the basal and spinous layers in normal skin and in involved and uninvolved psoriatic skin. The LTA4 hydrolase content varied between 2.8 and 3.1 micrograms enzyme/mg protein and was found to be similar in normal and psoriatic skin, involved as well as uninvolved. In contrast, the activity of the enzyme was decreased significantly in involved psoriatic skin (9.9 +/- 2.1 micrograms LTB4/mg enzyme per min) compared with matched uninvolved psoriatic skin (16.4 +/- 3.5 micrograms LTB4/mg enzyme per min), but was decreased only insignificantly compared with normal skin (12.4 +/- 1.8 micrograms LTB4/mg enzyme per min). It was found that the conversion of LTA4 to LTB4 results in inactivation of LTA4 hydrolase activity. This finding is compatible with the idea that the decreased LTA4 hydrolase activity in involved psoriatic skin reflects transcellular LTB4 formation in vivo. In peripheral lymphocytes the enzyme content was 1.3 +/- 0.3 microgram enzyme/mg protein in normal lymphocytes and 1.4 +/- 0.3 microgram enzyme/mg protein in psoriatic lymphocytes, which was significantly lower than in the skin. In contrast, the specific LTA4 hydrolase activities in normal and psoriatic lymphocytes (23.4 +/- 1.3 and 21.3 +/- 1.7 micrograms LTB4/mg enzyme per min) were significantly higher than in normal skin. These findings may indicate the existence of LTA4 hydrolase isoforms in human lymphocytes and human skin.

Topics: Animals; Epoxide Hydrolases; Humans; Immunohistochemistry; Leukotriene A4; Leukotriene B4; Lymphocytes; Osmolar Concentration; Psoriasis; Rabbits; Skin; Staining and Labeling

Leukotriene A4 hydrolase is a key enzyme in the biosynthesis of leukotriene B4, a potent pro-inflammatory compound. The purpose of this study was to determine the capacity of antiinflammatory and anti-proliferative compounds to regulate the levels and activity of leukotriene A4 hydrolase in cultured human keratinocytes. The content of leukotriene A4 hydrolase was determined by Western blot analysis, and the activity of leukotriene A4 hydrolase was expressed as the leukotriene B4 formation after incubation of keratinocyte cultures with leukotriene A4. Leukotriene B4 was measured by revered-phase high performance liquid chromatography. Preincubation for 10 min of the cultured keratinocytes with the leukotriene A4 hydrolase inhibitor RP 64699 (0.1-10 microM) caused a significant dose-dependent inhibition of leukotriene B4 formation (IC50 = 0.7 microM). Cyclosporin A (0.1 micrograms/ml and 1.0 micrograms/ml) had no direct effect on leukotriene A4 hydrolase activity, but after incubation for 72 h there was a decrease in the mean leukotriene B4 formation per culture dish (35% and 48%, respectively). The decreased leukotriene B4 formation was caused mainly by a decrease in the mean leukotriene A4 hydrolase content per mg protein (30.1% at 0.1 micrograms/ml cyclosporin A and 40.0% at 1.0 micrograms/ml cyclosporin A), although keratinocyte proliferation was also slightly decreased. Incubations with 1.25-dihydroxyvitamin D3 (10(-7)-10(-10) M), all-trans retinoic acid (10(-6)-10(-10) M), eicosartienoic acid (10(-6)-10(-8) M), dexamethasone (10(-5)-10(-7) M), interferon-gamma (10 and 100 units/ml) or methotrexate (0.1-10 micrograms/ml) had no effect on either the leukotriene B4 formation or the amount of leukotriene A4 hydrolase in keratinocyte cultures. These results show that cyclosporin A, in contrast to other anti-inflammatory and anti-proliferative compounds, inhibits the level of leukotriene A4 hydrolase in keratinocyte cultures. Since similar cyclosporin A concentrations are obtained during treatment of psoriasis with cyclosporin A, the effect on leukotriene A4 hydrolase may play a role in the anti-inflammatory action of cyclosporin A.

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Antineoplastic Agents; Calcitriol; Cells, Cultured; Cyclosporine; Dexamethasone; Down-Regulation; Epoxide Hydrolases; Humans; Interferon-gamma; Keratinocytes; Leukotriene B4; Methotrexate; Psoriasis; Thiophenes; Tretinoin

Arthritis is a frequent complication of pustular psoriasis. However, the mechanism of onset of this arthritis still remains unclear.. The present study was conducted to determine whether leukotriene (LT) B4 or LTC4 is one of the proinflammatory mediators that possibly enhance exacerbation of the arthritis lesions.. We investigated the condition of the arthritis and autopsy findings of two cases of generalized pustular psoriasis with the severe complication of aseptic purulent arthritis. We also measured the synovial fluid levels of LTB4 and LTC4 by radioimmunoassay.. The collected synovial fluid was purulent, but nonbacterial, and the synovium of the knee joint showed histopathologic evidence of polymorphonuclear leukocyte (PMN) invasion, edema and dilatation of small vessels showing similarity to a histologic reaction in the skin lesions. The immunoreactive (i-) LTB4 and i-LTC4 in the samples significantly exceeded the amount measured in osteoarthritis patients used as the controls.. Thus, i-LTB4 and i-LTC4 appear to be generated in the arthritis lesions of pustular psoriasis, the former attracting PMNs to the joints and the latter causing exudation of synovial fluid.

Topics: Aged; Arthritis; Female; Humans; Leukotriene B4; Leukotriene C4; Leukotrienes; Male; Middle Aged; Myocardial Infarction; Neutrophils; Psoriasis; Radioimmunoassay; Synovial Fluid; Synovitis

The fern Polypodium decumanum, commonly called Calaguala, has a clinically documented use in South America and Spain in the treatment of psoriasis. One of the inflammatory mediators isolated in abnormally high quantities in the psoriatic skin is leukotriene B4 (LTB4). Calaguala was tested in an in vitro model using human leukocytes for its ability to inhibit the LTB4 formation. The inhibition was found to be caused by the polyunsaturated fatty acids (PUFAs) linoleic, linolenic and arachidonic acid. IC50 values were determined for the isolated acids and compared to a group of closely related acids also commonly found in nature. The IC50 values for most acids tested were of the same magnitude (20-60 microM) except for arachidonic acid which showed stimulatory activity and 8(R) hydroxylinoleic acid which gave 30% inhibition with the highest dose tested (120 microM). The amounts of PUFAs in different Calaguala extracts were quantitatively analysed and it is concluded that the fatty acid constituents of Calaguala may contribute to the clinical effects of the extract.

Topics: Chromatography, High Pressure Liquid; Fatty Acids; Fatty Acids, Unsaturated; Humans; In Vitro Techniques; Leukotriene B4; Plant Extracts; Plants, Medicinal; Psoriasis

A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthracenones were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the growth of human keratinocytes. Structure-activity relationships are discussed with respect to the following redox properties of the compounds: reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydroxyl radicals as measured by deoxyribose degradation, and inhibition of lipid peroxidation in model membranes. Inhibition of cell proliferation seemed to be related to these properties, whereas 5-LO inhibition was not. Within a class of structural analogs the activity against 5-LO, which was markedly improved as compared to that of the antipsoriatic drug anthralin, correlated well with the overall lipophilicity. Even though a number of compounds in this series enhanced oxidative damage to nonlipid molecules such as deoxyribose, their antioxidant properties predominate in membrane lipids. Among the prooxidant compounds were also the most potent antiproliferative agents (IC50 values in the 10(-7) M range).

Topics: Administration, Topical; Animals; Anthracenes; Anti-Inflammatory Agents; Antioxidants; Cattle; Cell Division; Cells, Cultured; Humans; Hydroxyeicosatetraenoic Acids; Keratinocytes; Leukotriene B4; Lipid Peroxidation; Liposomes; Lipoxygenase Inhibitors; Malondialdehyde; Molecular Structure; Neutrophils; Oxidation-Reduction; Psoriasis; Structure-Activity Relationship

The purpose of the present study was to develop an ex vivo skin model to determine the capacity of lesional skin of psoriasis to form leukotriene B4 and other eicosanoids. Keratomed skin samples were incubated in the presence of the calcium ionophore A23187 and arachidonic acid for 45 min at 37 degrees C. After extraction of lipids, eicosanoids were determined by quantitative reversed-phase high-performance liquid chromatography in combination with specific radioimmunoassays. We found that stimulation of skin samples with A23187 and arachidonic acid increased the amount of leukotriene B4 4.0-fold. The 12-lipoxygenase product, 12-hydroxy-eicosatetraenoic acid, and the 15-lipoxygenase product, 15-hydroxy-eicosatetraenoic acid, were both increased 2.7-fold. The cyclooxygenase product, prostaglandin E2, was increased 8.0-fold. Similar incubations using psoriatic scales did not result in formation of eicosanoids. Incubations with the 5-lipoxygenase inhibitor RS43179 inhibited the formation of leukotriene B4 and prostaglandin E2 without significantly affecting the formation of 12-hydroxy-eicosatetraenoic acid and 15-hydroxy-eicosatetraenoic acid. These results reveal that lesional psoriatic skin ex vivo has the enzymatic capacity to increase the levels of eicosanoids. This provides an ex vivo skin model to determine whether putative lipoxygenase inhibitors are able to modulate the formation of eicosanoids in psoriatic skin.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Calcimycin; Chromatography, High Pressure Liquid; Dinoprostone; Eicosanoids; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Naphthalenes; Psoriasis; Radioimmunoassay; Skin

Topics: Humans; Interleukin-8; Leukotriene B4; Psoriasis; Skin

Gas chromatographic-(tandem) mass spectrometric (GC-MS(-MS)) methods for the analysis of cysteinyl leukotrienes (LTs) and leukotriene B4 (LTB4) in biological fluids were developed. The enzymatic synthesis of the stable-isotope labelled analogues [1,1-18O2] LTE4 and [14,15,17,17,18,18-2H6] LTB4 in high isotopic purity is described. Utilizing [1,1-18O2] LTE4 as an internal standard and GC-MS-MS enhanced cysteinyl LTs synthesis was found in patients with multiple trauma and psoriasis compared to healthy volunteers, respectively. The metabolism of LTB4 by human monocytes was investigated and two novel LTB4 metabolites were structurally identified by GC-MS as 10,11-dihydro-LTB4 and 10,11-dihydro-12-oxo-LTB4.

Topics: Gas Chromatography-Mass Spectrometry; Humans; Leukotriene B4; Leukotriene E4; Monocytes; Multiple Trauma; Psoriasis; SRS-A

Topics: Calcimycin; Dinoprostone; HEPES; Humans; Inflammation; Leukotriene B4; Luminescent Measurements; Neutrophils; Psoriasis; Reference Values; Skin Diseases; Taurine

Two new elastase inhibitors (SKALP, skin-derived antileucoproteases) were recently described in the lesional skin in psoriasis. The present study investigated the distribution of SKALP activity in the marginal zone of spreading psoriatic plaques. In a 4-mm zone immediately adjacent to the erythemato-squamous plaques, SKALP activity was slightly increased compared to distant uninvolved skin. Within the lesion the anti-elastase activity was pronounced, but was significantly higher in the central zone of the plaque compared to the periphery. The appearance of SKALP in the psoriatic lesion appears to be a late event compared to endothelial involvement, intraepidermal accumulation of PMNs, epidermal proliferation and abnormal keratinization. This observation lends further support for the hypothesis that the induction of anti-elastase activity is associated with the off-switch of cutaneous inflammation.

Topics: Adult; Aged; Biopsy; Female; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Proteinase Inhibitory Proteins, Secretory; Proteins; Psoriasis; Serine Proteinase Inhibitors; Skin

In the present study the ultrastructural aspects of the migration of polymorphonuclear leukocytes (PMN) in apparently normal skin following the epicutaneous application of leukotriene B4 (LTB4) were studied and it was investigated whether this model is representative of the migration of PMN in psoriatic skin. At the ultrastructural level the following features were observed: degranulation of PMN, formation of fenestrations and gaps of the endothelium, a multilayered basal lamina and hyperactive endothelial cells with protrusions and focal necrosis of these cells. Epicutaneous application of LTB4 is a practical approach to study the dynamics of the interaction between PMN and the endothelium in vivo.

Topics: Administration, Cutaneous; Adult; Blood Vessels; Capillary Permeability; Cell Migration Inhibition; Female; Humans; Leukotriene B4; Male; Neutrophils; Psoriasis; Skin

The transepidermal migration of polymorphonuclear leukocytes is a well established target for antipsoriatic therapies. Tetracycline, although inhibiting the movement of PMN, is not an effective treatment for psoriasis. In contrast to the inhibition of PMN chemotactic response to serum and bacterial products, the leukotriene B4-induced and trauma-induced intraepidermal accumulation of PMN was unaffected by tetracycline.

Topics: Adult; Biopsy; Cell Aggregation; Cell Movement; Chemotaxis; Epidermis; Female; Humans; Leukotriene B4; Male; Neutrophils; Psoriasis; Tetracyclines

The random migration and chemotaxis of polymorphonuclear leukocytes (PMN) in agarose were studied in 21 patients with psoriasis and 10 healthy controls. Different concentrations of LTB4 were used as chemoattractants. The random migration and chemotaxis towards lower concentrations of LTB4 were enhanced and that towards higher concentrations of LTB4 reduced in psoriasis. The differences of body involvement, sex, and family history of psoriasis had no influence on PMN migration.

Topics: Adult; Chemotaxis, Leukocyte; Female; Humans; Leukotriene B4; Male; Neutrophils; Psoriasis

The concentrations of arachidonic acid and its lipoxygenase metabolites were measured in exudates from lesional psoriatic skin during treatment with 0.25% dithranol (anthralin) applied topically for 10 days. Dithranol caused a reduction in the concentration of arachidonic acid at 10 days (167 +/- 42 and 358 +/- 55 ng ml-1 treated and control sites respectively, p less than 0.05) concurrent with clinical improvement of the lesions. Neither 12-hydroxyeicosatetraenoic acid nor leukotriene B4 concentrations were significantly affected. These results do not support the view that lipoxygenase products are of major importance in the pathogenesis of psoriasis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Administration, Cutaneous; Adult; Anthralin; Arachidonic Acid; Arachidonic Acids; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Psoriasis

In view of the presence of the polymorphonuclear leukocyte (PMN) chemoattractant Leukotriene B4 (LTB4) in the surface scale of the psoriatic lesion and the known therapeutic effect of phototherapy in psoriasis, the photostability of LTB4 was investigated. LTB4 was irradiated with dosages of UVB (290-320 nm) ranging from 100-1500 mJ cm-2 and with dosages of UVA (320-400 nm) ranging from 5-40 J cm-2. Topical application of UVB irradiated LTB4 to the forearm skin of normal volunteers showed a marked reduction in cutaneous erythema, paralleled histologically by reduced transepidermal PMN migration when compared with sites of application of unirradiated and UVA irradiated LTB4. High performance liquid chromatography (HPLC) demonstrated a dose-dependent photodegradation of LTB4 by UVB irradiation. UVA irradiation produced no such effect. The wavelengths responsible lie within the absorption spectrum of LTB4. In vitro chemotaxis studies, using an under agarose technique, showed a statistically significant reduction in the migration of PMN from both psoriatic and non-psoriatic subjects to the UVB irradiated LTB4 compared with the unirradiated LTB4, whilst UVA irradiated LTB4 produced a normal PMN chemotactic response.

Topics: Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Humans; Leukotriene B4; Neutrophils; Photochemistry; Psoriasis; Ultraviolet Rays

The biochemical changes underlying the clinical manifestations of psoriasis are unknown. Certain chemotactic eicosanoids derived from arachidonic acid metabolism have been suggested to play important roles in psoriasis, because of their presence in lesional psoriatic skin and their ability to elicit skin inflammation and to stimulate epidermal proliferation. The purpose of the present study was to elucidate which eicosanoids might be involved in the early phases of the inflammatory processes of psoriasis. Eicosanoids were analyzed in scale and in lesional skin without scale both in acute guttate and chronic plaque psoriatic lesions. Methods for identification of eicosanoids included reversed-phase high-performance liquid chromatography combined with radioimmunoassay. Leukotriene B4 was present in both acute guttate and chronic plaque skin lesions in biologically active amounts (acute guttate lesions: 18.7 +/- 7.1 ng/g wet tissue in scale and 3.2 +/- 1.5 ng/g wet tissue in lesional skin without scale; chronic plaque lesions: 33.1 +/- 9.7 ng/g wet tissue in scale and 5.3 +/- 2.0 ng/g wet tissue in lesional skin without scale). 12- and 15-hydroxy-eicosatetraenoic acid (HETE) reached biologically active concentrations only in scale of chronic plaque lesions (1,512 +/- 282 and 1,441 +/- 411 ng/g wet tissue, respectively). The level of prostaglandin E2 in chronic plaque lesions was similar to the level in normal skin, while the level in acute guttate lesions was increased twofold (71.0 +/- 14.8 ng/g wet tissue). These results demonstrate that leukotriene B4, but not 12-HETE, is present in acute guttate psoriatic skin lesions in concentrations able to exert biologic effects. Leukotriene B4 may therefore participate in inflammatory changes of acute psoriasis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Chromatography, High Pressure Liquid; Chronic Disease; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Psoriasis; Radioimmunoassay; Skin

Topics: Adult; Aged; Chronic Disease; Eicosapentaenoic Acid; Female; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Psoriasis

Topics: Adult; Aged; Arachidonate 5-Lipoxygenase; Calcimycin; Eicosapentaenoic Acid; Erythema; Female; Glucuronidase; Humans; In Vitro Techniques; Kinetics; Leukotriene B4; Male; Middle Aged; Neutrophils; Psoriasis; Skin

Clinical studies have indicated that dietary fish oil may have therapeutic value in the treatment of psoriasis, a hyperproliferative, inflammatory skin disorder characterized by elevated LTB4. To evolve a possible mechanism for these beneficial effects, we determined the metabolic fate of fish oil derived n-3 fatty acids in the skin. Specifically, we incubated guinea pig epidermal enzyme preparations with [3H]eicosapentaenoic acid (20:5 n-3) and [14C]docosahexaenoic acid (22:6 n-3). Analyses of the radiometabolites revealed the transformation of these n-3 fatty acids into n-6 lipoxygenase (arachidonate 15-lipoxygenase) products: 15-hydroxyeicosapentaenoic acid (15-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHE), respectively. Since 15-lipoxygenase products have been suggested as possible endogenous inhibitors of 5-lipoxygenase (an enzyme which catalyzes the formation of LTB4) we tested the ability of 15-HEPE and 17-HDHE in vitro to inhibit the activity of the 5-lipoxygenase. Incubations of these metabolites with enzyme preparations from rat basophilic leukemia (RBL-1) cells demonstrated that 15-HEPE (IC50 = 28 microM) and 17-HDHE (IC50 = 25 microM) are respectively potent inhibitors of RBL-I-5-lipoxygenase. The inhibitory potential of these fish oil metabolites provides a possible mechanism by which fish oil might act to decrease local cutaneous levels of LTB4, and thereby alleviate psoriatic symptoms.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Docosahexaenoic Acids; Eicosapentaenoic Acid; Epidermis; Fatty Acids, Unsaturated; Fish Oils; Guinea Pigs; Leukotriene B4; Lipoxygenase Inhibitors; Male; Psoriasis; Tumor Cells, Cultured

Polymorphonuclear leukocyte (PMNL) infiltration is an important characteristic in psoriatic lesions. Elevated concentrations of the chemoattractant eicosanoid leukotriene B4 (LTB4) are present in psoriatic skin. Its chemotactic activity is mediated via high affinity receptors on PMNL. The goal of our work was to ascertain whether PMNL infiltration in psoriasis can be accounted for by functional abnormalities of the circulating PMNL due to alterations in the LTB4 receptor density or affinity (or both). No significant difference was found between patients with psoriasis, healthy controls and patients with another inflammatory dermatosis (atopic eczema) with regard to the binding parameters of LTB4 receptors on PMNL. Our findings suggest that PMNL accumulation in psoriatic skin may be the result of an excess of cutaneous chemoattractant rather than the increased readiness of psoriatic PMNL to migrate towards LTB4 due to altered LTB4 receptor density or affinity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Dermatitis, Atopic; Female; Humans; Kinetics; Leukotriene B4; Male; Middle Aged; Neutrophils; Protein Binding; Psoriasis; Receptors, Immunologic; Receptors, Leukotriene B4

Several studies have indicated that certain lipoxygenation products of arachidonic acid, particularly leukotriene B4 (LTB4), may be involved in psoriatic pathophysiology. One way of inhibiting the formation of LTB4 is to replace arachidonic acid in phospholipids with eicosapentaenoic acid. Eicosapentaenoic acid is converted into LTB5, which has a lower biologic activity than LTB4. In the present study psoriatic patients were put on a low-fat diet supplemented with dietary fish oil (Max-EPA 30 ml daily), a source of eicosapentaenoic acid, for 4 months. Twenty-six out of 30 patients with psoriasis vulgaris completed the study. Moderate or excellent improvement was observed in 58% of the patients, while mild improvement or no change was observed in 19% and 23%, respectively. The capacity of peripheral blood neutrophils to synthesize LTB4 and LTB5 in vitro was determined after stimulation with A23187. Before the study, negligible amounts of LTB5 were formed. After 1 month the average of LTB5/LTB4 ratio was 0.42. No further increase of the LTB5/LTB4 ratio was found. There existed no relationship between the clinical response and the LTB5/LTB4 ratio. The results of the present study suggest that dietary fish oil supplementation may be used in the therapy in psoriasis. However, studies defining the dose and the quality of fish oils are imperative.

Topics: Adolescent; Adult; Aged; Child; Dietary Fats; Docosahexaenoic Acids; Drug Combinations; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Female; Fish Oils; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Psoriasis

1 3-hydroxy-5-trifluoromethyl-N-[2-(2-thienyl)-2-phenyl-ethenyl]-benzo(B) thiophene-2-carboxamide (L-652,343) is a 5-lipoxygenase and cyclo-oxygenase inhibitor in vitro. 2 In psoriasis increased concentrations of arachidonic acid transformation products are found in the lesional skin which may be important in the pathogenesis of the disease. We have measured the effect of orally administered L-652,343 on the concentration of LTB4 and prostaglandins in the lesional skin. 3 Eight patients with stable chronic plaque psoriasis received 500 and 250 mg of L-652,343, 12 h apart. A chamber technique was used to collect skin exudate samples from abraded plaques before and at 4, 24 and 48 h after the first dose. Exudates were analysed for LTB4 by a neutrophil chemokinesis assay and for PGE2 and PGD2 by RIA. 4 PGE2 and PGD2 levels were significantly reduced at 4 and 24 h after the first dose of L-652,343 but LTB4 levels were not affected indicating inhibition of the cyclo-oxygenase pathway but not of the 5-lipoxygenase pathway. This shows the importance of confirming that the action of 5-lipoxygenase inhibiting drugs in vitro occurs in vivo.

Topics: Adult; Arachidonate Lipoxygenases; Cyclooxygenase Inhibitors; Dinoprostone; Humans; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Psoriasis; Skin; Thiophenes

An open study testing the effects of fish oil supplementation on psoriasis in 26 patients is described. None of the patients with plaque-type psoriasis vulgaris showed clinically significant improvement; however, a patient with generalized pustular psoriasis showed marked improvement with the fish oil supplementation. In this patient, scale leukotriene B4 levels were determined and shown to be significantly decreased after completion of the study, but the leukotriene B4 levels did not correlate with her clinical course. The results of our study are contrasted with those of a recent study that did show beneficial effects of fish oil supplementation on plaque-type psoriasis.

Topics: Adult; Diet; Female; Fish Oils; Humans; Leukotriene B4; Male; Middle Aged; Psoriasis; Skin

A case of annular pustular psoriasis is described. The annular zone of the lesion provides a model for studying the dynamics of intraepidermal accumulation of polymorphonuclear leukocytes in psoriasis. It could be shown that the unstimulated accumulation of polymorphonuclear leukocytes was limited to the clinically involved skin. The appearance of polymorphonuclear leukocytes proved to be associated with acanthosis. The micropustule formation following topical application of leukotriene B4 was markedly decreased in lesional, prelesional and postlesional skin, compared to the response in the clinically uninvolved skin of patients with chronic plaque psoriasis. Although leukotriene B4 might have an initiating role in the intraepidermal accumulation of polymorphonuclear leukocytes other factors are a conditio sine qua non for the peripheral spreading of the lesion in annular pustular psoriasis.

Topics: Aged; Cell Aggregation; Epidermis; Female; Humans; Leukotriene B4; Neutrophils; Psoriasis

Topics: Chemotactic Factors; Chemotaxis, Leukocyte; Humans; Interleukin-8; Leukotriene B4; Molecular Weight; Psoriasis

The aim of the reported series of experiments was to examine the possible role played by arachidonic acid (Aa) derivatives in monocyte aggregation in psoriasis. Twenty patients with active plaque-type psoriasis covering not less than 20% of body surface area and 20 age-matched controls were investigated. Peripheral blood monocytes were harvested according to the technique recently set up by Colotta et al. These preparations usually contained more than 95% monocytes, as assessed by morphology and esterase staining. Aggregation tracings were plotted using a common platelet aggregation recorder system and expressed in arbitrary units. Aa sodium salt, acetylsalicylic acid (ASA), indomethacin, nordihydroguaiaretic acid (NDGA), and leukotriene B4 (LTB4) were used during testing. Aa induced an enhanced aggregation of mononuclear leukocytes (MNL) in psoriatic patients versus normal controls in a concentration-dependent way. Furthermore, neither ASA nor indomethacin inhibited Aa aggregation, while both markedly increased the aggregation response in psoriasis. LTB4 induced an enhancement aggregation in psoriasis, whereas NDGA strongly inhibited it. Although the pathophysiological significance of MNL aggregation described here remains obscure, assembly of the cells at the site of psoriatic skin might be a crucial event.

Topics: Adult; Aged; Arachidonic Acid; Arachidonic Acids; Aspirin; Cell Aggregation; Female; Humans; In Vitro Techniques; Indomethacin; Leukotriene B4; Male; Masoprocol; Middle Aged; Monocytes; Psoriasis

The formation of leukotriene B4 and its omega-oxidised metabolites has been compared in calcium ionophore-stimulated polymorphonuclear leukocytes, in the absence of exogenous substrate, from fourteen psoriatic subjects and thirteen healthy controls. Although there was no significant difference in the levels of leukotriene B4, the psoriatic cells synthesised significantly greater amounts of omega-oxidation products than control cells. This difference was confirmed in an experiment comparing the time course of formation of the omega-oxidation products of leukotriene B4, under similar conditions, in polymorphonuclear leukocytes from four psoriatic subjects and three healthy controls. The kinetic constants for the metabolism of exogenous leukotriene B4 by 20-hydroxylase were determined by a radiochromatographic enzyme assay in polymorphonuclear leukocytes from three patients with psoriasis and three healthy controls. No significant differences were found in the apparent Km and Vmax values. It is concluded that the increased formation of omega-oxidation products in psoriatic cells may be secondary to increased synthesis of leukotriene B4 by these cells, with consequent increased metabolism, rather than to an inherent abnormality of the 20-hydroxylase system. Further work is needed to determine the kinetics of the enzymes involved in leukotriene B4 synthesis in the psoriatic polymorphonuclear leukocyte, and also to assess the contribution of the leukotriene B4 and omega-oxidation products from polymorphonuclear leukocytes infiltrating the skin to the pathogenesis of the psoriatic lesion.

Topics: Adult; Calcimycin; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Female; Humans; Kinetics; Leukotriene B4; Male; Mixed Function Oxygenases; Neutrophils; Oxidation-Reduction; Psoriasis

Topics: Administration, Topical; Humans; Leukotriene B4; Neutrophils; Pancreatic Elastase; Psoriasis; Skin

Topics: Adult; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Eicosapentaenoic Acid; Female; Humans; Leukotriene B4; Male; Neutrophils; Psoriasis

The effect of etretinate on the intra-epidermal accumulation of polymorphonuclear leukocytes following epicutaneous application of leukotriene B4 was studied in five psoriatic patients. Polymorphonuclear leukocytes were quantified using the marker enzyme elastase. An inverse relationship was found between the dosage of etretinate and the number of infiltrating polymorphonuclear leukocytes.

Topics: Administration, Cutaneous; Adult; Dose-Response Relationship, Drug; Etretinate; Female; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Psoriasis; Skin

The intraepidermal accumulation of polymorphonuclear leukocytes following the epicutaneous application of leukotriene B4 (LTB4) was studied in lesional and clinically uninvolved skin of five patients with chronic stable plaque psoriasis. The lesions were found to be wholly unresponsive to LTB4, doses of 100 ng failing to produce either micropustules or exocytosis. This phenomenon was sharply localized; the response immediately adjacent to the lesion being identical to that in more distant uninvolved skin. We speculate that both the reduced response to LTB4 in the psoriatic patient and also the tolerance to LTB4 seen after repeated applications, result from the induction of a P450-linked hydroxylase.

Topics: Administration, Cutaneous; Adult; Female; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Psoriasis; Skin

Topics: Arachidonic Acids; Calmodulin; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Psoriasis

The arachidonate lipoxygenase products 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 5(S),12(R)-dihydroxy-6,8,10,14-eicosatetraenoic acid (leukotriene B4, LTB4) are potent leucocyte chemoattractants in vitro and in vivo. Both 12-HETE and LTB4-like material are found in increased amounts in lesional skin in psoriasis. Epicutaneous administration of 12(R,S)-HETE and LTB4 in normal skin evokes neutrophil and mononuclear dermal infiltrates accompanied by collections of neutrophils in the epidermis. Similar appearances result from the application of LTB4 to uninvolved skin in psoriasis. We have now investigated the effects of single and multiple epicutaneous applications of 12(R,S)-HETE and LTB4, both alone and in combination, in normal human skin and in clinically uninvolved skin of patients with psoriasis. As in the case of LTB4, erythematous responses to 12(R,S)-HETE were similar in normal skin and in psoriasis. Similar neutrophil polymorphonuclear responses were evoked by topical application of 50 ng LTB4 and 20 micrograms 12(R,S)-HETE. Application of the combination of 12(R,S)-HETE and LTB4 evoked only a partially additive erythematous response, and no evidence of an additive neutrophilotactic response was detected histologically. Multiple applications resulted in tolerance both clinically and histologically. Cross tolerance to 12(R,S)-HETE and LTB4 occurred in the majority of subjects. These results suggest that both 12(R,S)-HETE and LTB4 may be important in the production and control of the magnitude of the inflammatory events in psoriasis.

Topics: Dose-Response Relationship, Drug; Erythema; Humans; Hydroxyeicosatetraenoic Acids; Immune Tolerance; Leukotriene B4; Neutrophils; Psoriasis; Skin

Several biologically active lipoxygenase products or arachidonic acid (AA) have been demonstrated in psoriatic skin lesions. The purpose of the present study was to determine the amounts of the different lipoxygenase products simultaneously in psoriatic skin. Slices of psoriatic skin were obtained at different levels with a keratome. Extracted lipids were identified by high performance liquid chromatography, UV-absorption spectrum, radioimmunoassay, and chemokinesis. Leukotriene B4 (LTB4), and 12- and 15-hydroxy-eicosatetraenoic acid (HETE) were detected in most psoriatic lesions. However, there was a remarkable variation from lesion to lesion. The biopsy specimens contained: 276.2 +/- 126.0 pg/g wet tissue of LTB4, 3,130.0 +/- 2,898.0 ng/g wet tissue of 12-HETE, and 3,633.0 +/- 1,692.0 ng/g wet tissue of 15-HETE. No correlation was found between the levels of the different lipoxygenase products. The content of each of the identified lipoxygenase products was higher in the superficial part of the biopsy specimen consisting of approximately two-thirds of the epidermis plus papillary dermis than in the lower part consisting of approximately one-third of the epidermis plus some reticular dermis. Also, there was a great variation from one anatomical region to another within the same patient. Because these lipoxygenase products possess different biological activities, the variation in their occurrence may be important for understanding their potential role in psoriasis. To determine which lipoxygenase products may be of pathogenic importance, analysis of early psoriatic lesions is warranted.

Topics: Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Psoriasis; Skin

The formation of LTB4 and its omega-oxidation products 20-hydroxy- and 20-carboxy-LTB4 from exogenous [14C]arachidonic acid (AA) by neutrophils from 12 psoriatic patients and 10 healthy controls was investigated. Only a slight difference was detected in the mean amount of [14C]LTB4 produced. In contrast, the amounts of [14C]omega-oxidation products obtained from psoriatic PMN were 2.4-fold higher than the amounts from PMN of healthy controls. We conclude that in vitro, psoriatic PMN synthesize more LTB4 from exogenous AA than do PMN of healthy individuals and due to an efficient omega-oxidation system, the net release of LTB4 in both groups appears to be similar.

Topics: Adult; Arachidonic Acids; Chromatography, Thin Layer; Female; Humans; Leukotriene B4; Male; Neutrophils; Psoriasis

The in situ infiltration of polymorphonuclear leukocytes following the topical application of leukotriene B4 to the clinically uninvolved skin of psoriatic patients and the skin of normal controls has been quantified using elastase as a marker enzyme. The magnitude of this response in the psoriatic patients proved to be significantly diminished compared with the response in the controls. The time course of the response was similar in both groups, maximum elastase activity being seen about 18 h after application of the LTB4.

Topics: Administration, Topical; Adult; Humans; Leukotriene B4; Neutrophils; Psoriasis

The leukotriene B4 (LTB4)-induced intraepidermal accumulation of polymorphonuclear leukocytes (PMN) was quantified, using an elastase assay, in psoriatic patients receiving methotrexate and in untreated psoriatic patients. Methotrexate in therapeutic dosages inhibited PMN infiltration in six patients who had improved considerably on treatment with the drug, a gradual increase being seen during the days on which no methotrexate was taken. Two patients were in relapse, despite methotrexate treatment, and both failed to show any change in LTB4-induced accumulation of PMN.

Topics: Adult; Humans; Leukotriene B4; Methotrexate; Middle Aged; Neutrophils; Psoriasis; Skin

We carried out quantification of the levels of leukotriene B4 (LTB4), a highly potent cell membrane-derived leukocyte chemotactic factor, in scale extracts of psoriasis and related inflammatory dermatoses characterized by sterile subcorneal pustule formation by using radioimmunoassay. A small amount of LTB4 was demonstrable even in extracts from non-inflammatory stratum corneum, but larger amounts were detected in the scale extract from pustular psoriasis and in those from psoriasis vulgaris. There was a significant correlation between the LTB4 and C5a levels in scale extracts, suggesting that complement activation and generation of LTB4 are a closely related event in psoriatic lesions. However, in contrast to highly significant correlation noted between the amount of C5a and chemotactic activity for polymorphonuclear leukocytes (PMN) detectable in scale extracts, LTB4 levels correlated only marginally with the chemotactic activity.

Topics: Chemotaxis, Leukocyte; Complement C5; Complement C5a; Dermatitis, Exfoliative; Humans; Ichthyosis; Leukotriene B4; Pityriasis Rubra Pilaris; Psoriasis; Radioimmunoassay; Skin Diseases, Vesiculobullous

Purified serum samples from asthmatic and psoriatic patients and healthy controls were analysed by high-pressure liquid chromatography (HPLC) and the amounts of leukotrienes were measured from the corresponding HPLC fractions by specific radioimmunoassays. In the serum of healthy controls the amounts of leukotrienes B4, C4 and D4 were very small or negligible. Rather great amount of leukotriene B4 was, however, detected in the serum of many asthmatic and psoriatic patients. The amount of leukotriene B4 was in the serum of asthmatic patients 120 +/- 20 pmol/ml (n = 11, mean +/- SEM) and in that of psoriatic patients 100 +/- 10 pmol/ml (n = 10). The amounts of leukotrienes C4 and D4 were rather small in the serum of most patients. The amount of leukotriene C4 was, however, very high (250 pmol/ml) in the serum of a psoriatic patient. Significant amount of leukotriene D4 was also detected in the serum of this patient. The present study indicated that leukotrienes are formed during blood clotting in the leukocytes of asthmatic and psoriatic patients and that the rate of formation is so high that leukotrienes may have a role in these diseases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Asthma; Chromatography, High Pressure Liquid; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Psoriasis; SRS-A

The metabolism of endogenous arachidonic acid by human polymorphonuclear leukocytes (PMNL) isolated from peripheral blood has been studied in 19 patients with chronic plaque psoriasis and 19 healthy controls. Using calcium ionophore A23187 as a stimulus, the PMNL synthesized leukotriene B4 (LTB4), 6-trans-leukotriene B4, 12-epi-6-trans-LTB4, and 5-hydroxy-6,8,11,14-eicosatetraenoic acid. There was no significant difference in the amounts of the products formed between the psoriatic and control groups. The elevated levels of LTB4 that have been described in psoriatic skin may therefore be due to the PMNL infiltrate or to enhanced synthesis by another cell type. The reported increase in activity of the circulating PMNL in psoriasis does not appear to be due to increased 5-lipoxygenase activity in these cells.

Topics: Adult; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Calcimycin; Chromatography, High Pressure Liquid; Chronic Disease; Female; Humans; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Neutrophils; Psoriasis

The percentage of non-diploid epidermal cells was determined by flow cytometry following application of leukotriene B4 (LTB4) to human skin. Doses in the range 35-500 ng were shown to cause a marked increase in proliferation, the non-diploid cells reaching a maximum between 72 and 96 h after LTB4 application. No difference was observed between the response of healthy controls and the uninvolved skin of psoriatic patients. We suggest, therefore, that the hyperproliferation is a consequence of the physical disruption of the stratum corneum accompanying the rupture of microabscesses.

Topics: Abscess; Cell Division; Epidermis; Humans; Leukotriene B4; Psoriasis; Skin Diseases

Peripheral blood neutrophils and eosinophils from 70 patients and controls were studied for their in vitro chemotactic and chemokinetic responses towards synthetic leukotriene B4 (LTB4), 20-OH-LTB4 and 20-COOH-LTB4. All three factors induced chemotaxis and chemokinesis of cells. 20-OH-LTB4 was always less and 20-COOH-LTB4 even less active than the parent compound. Cells from patients with atopic eczema and T cell lymphoma moved less than cells from normal controls or from patients with psoriasis. In the presence of LTB4, 20-OH-LTB4 and buffer alone, more eosinophils than neutrophils moved to the lower side of the filter, while this did not occur with platelet activating factor as chemoattractant. Studies of neutrophil and eosinophil chemotaxis in the presence of LTB4 should therefore always take into account a high variability of the quantitative response which is donor and disease dependent.

Topics: Chemotaxis, Leukocyte; Dermatitis, Atopic; Eosinophilia; Eosinophils; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lymphoma; Neutrophils; Psoriasis

Sera obtained from 12 patients with moderate to severe psoriasis were investigated for the presence of arachidonate lipoxygenase metabolites using reverse-phase high-performance liquid chromatography after extraction on silicic acid columns. Peaks which co-chromatographed with standards of synthetic leukotriene B4 (LTB4) were collected, and the material was tested for chemotactic activity. In the sera of 5 of the patients, chemotactic activity was demonstrable in these 'LTB4' peaks. Although minor peaks co-chromatographing with LTB4 were found in control sera, none of them contained chemotactic material. Isolated monocytes from the psoriasis patients showed enhanced chemotactic activity as compared to monocytes obtained from healthy controls. The results of our study support the view that abnormal 5-lipoxygenase activity is present in psoriasis. Further investigation is required to determine whether LTB4 is released from circulatory leukocytes or the skin.

Topics: Adult; Aged; Arachidonate Lipoxygenases; Chemotactic Factors; Chemotaxis, Leukocyte; Female; Humans; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Monocytes; Psoriasis

Polymorphonuclear leukocytes (PMN) from ten patients with chronic stable plaque psoriasis, five of whom had more than 40% skin involvement and five with less than 20% involvement, responded in a dose-related fashion to stimulation with the arachidonic acid lipoxygenase products 5- and 12-hydroxyeicosatetraenoic acid (5- and 12-HETE) and leukotriene B4 (LTB4) in an in vitro chemokinesis assay. There was no significant difference in either the random migration or the chemokinetic response of psoriatic PMN to LTB4 when compared to the responses of PMN from a group of age- and sex-matched healthy controls. Psoriatic PMN migrated further in response to low doses of 5- and 12-HETE although the distance moved after maximal stimulation was no different to that observed in controls. No significant difference was observed in the responses of PMN obtained from patients with less than 20% skin involvement when compared to those with more extensive psoriasis. The small differences measured between the chemokinetic responses of psoriatic and control PMN to the lipoxygenase products tested are unlikely to be of pathogenetic significance.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Arachidonate Lipoxygenases; Chemotaxis, Leukocyte; Female; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Neutrophils; Psoriasis; Skin

Since the biochemical events leading to cutaneous inflammation in atopic dermatitis and psoriasis are unknown, we studied the levels of arachidonic acid-derived mediators of inflammation as well as histamine in the suction blister fluid obtained from lesional and nonlesional skin of patients with these dermatoses. Mediator levels were determined radioimmunologically. Skin from healthy controls and uninvolved skin from patients contained very low or unmeasurable levels of the 5-lipoxygenase metabolite of arachidonic acid, leukotriene (LT) B4. In contrast, higher levels of LTB4-like immunoreactivity were detected in suction blister fluid from lesional atopic dermatitis skin, and even higher concentrations occurred in psoriasis lesions. LTB4-like immunoreactivity from atopic dermatitis suction blister fluid cochromatographed on reverse-phase high-pressure liquid chromatography with authentic LTB4, thus excluding cross-reaction of the LTB4-antibody with arachidonic acid or monohydroxyeicosatetraenoic acids. In contrast, suction blister concentrations of the cyclooxygenase metabolite of arachidonic acid prostaglandin (PG) E2 showed no significant differences between lesional and nonlesional patient skin and healthy control skin. PGD2 determined as a stable metabolite could not be detected in these samples. Histamine concentrations in lesional skin were within normal range. The elevated levels of the potent proinflammatory and immunomodulating mediator LTB4 could be involved in the pathogenesis of cutaneous inflammation in atopic dermatitis and psoriasis. In addition, they might explain the therapeutic efficiency of glucocorticosteroids, which among other actions inhibit the release of arachidonic acid from phospholipid stores by blocking the enzyme phospholipase A2. However, the specificity of disease expression in atopic dermatitis and psoriasis must be due to factors other than cutaneous LTB4 elevation.

Topics: Adolescent; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Dermatitis, Atopic; Dinoprostone; Female; Histamine; Humans; Leukotriene B4; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Psoriasis; Skin

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Naphthalenes; Psoriasis; Skin

Chemotactic activity of purified monocytes and polymorphonuclear leukocytes was studied in fifty patients with psoriasis vulgaris and in forty-five healthy individuals by an objective in vitro assay with the use of a 51Cr-labeling technic. Both monocytes and polymorphonuclear leukocytes showed a statistically significant increase in chemotactic response, which was positively correlated with disease activity but not with the extent of the cutaneous lesions. The chemotactic activity of monocytes correlated with that of polymorphonuclear leukocytes in the same patients. Exacerbation of psoriasis was preceded by a rapid increase of polymorphonuclear leukocyte chemotaxis, and a decline of chemotaxis occurred during clinical improvement. The psoriatic leukocytes were 22% more sensitive than normal leukocytes to leukotriene B4 than to N-formyl-methionyl-leucyl-phenylalanine. Psoriatic plasma showed chemotaxis-enhancing properties, but only in patients with widespread cutaneous lesions. Additionally, monocyte and polymorphonuclear leukocyte chemotaxis was studied in twenty patients with pustular psoriasis and in fifteen patients with psoriatic arthritis. The chemotactic profiles in pustular psoriasis were different from those in psoriasis vulgaris. Patients with pustular psoriasis had significantly higher polymorphonuclear leukocyte chemotaxis than patients with psoriasis vulgaris, but the chemotactic activity of monocytes was normal. The presence of seronegative arthritis had no influence on chemotactic activity of psoriatic leukocytes.

Topics: Adolescent; Adult; Aged; Arthritis; Chemotaxis, Leukocyte; Female; Humans; Leukotriene B4; Male; Middle Aged; Monocytes; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Prognosis; Psoriasis

Topical clobetasol propionate or vehicle ointment was applied daily for 3 days to psoriatic plaques on eight patients. Skin chamber exudates from untreated, steroid and vehicle treated lesions were assayed for arachidonic acid (AA), leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) before, and at 24 h and 72 h after treatment. Significant reductions in AA and LTB4 were observed at 72 h in steroid treated lesions. The reduction in 12-HETE levels observed after steroid treatment was not statistically significant. PGE2 levels in lesional psoriatic skin were unaltered. The reduction of AA, and LTB4 was associated with clinical improvement of psoriasis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonic Acid; Arachidonic Acids; Betamethasone; Clobetasol; Dinoprostone; Exudates and Transudates; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Prostaglandins E; Psoriasis; Skin

Topics: Acne Vulgaris; Arachidonic Acid; Arachidonic Acids; Capillary Permeability; Dermatitis, Atopic; Dermatitis, Contact; Humans; Leukotriene B4; Lipoxygenase; Lymphocytes; Phagocytes; Psoriasis; Skin; Skin Diseases; SRS-A; Urticaria

Topical application of single doses of leukotriene B4, (5-500 ng) under occlusion to the skin of normal volunteers and to the clinically normal skin of patients with untreated stable plaque psoriasis caused an inflammatory reaction lasting several days. Histologically, intraepidermal neutrophil microabscesses were seen in both groups following 50 ng applications of leukotriene B4, but there were significantly fewer intraepidermal neutrophils in the psoriatic than in the normal subjects. Nine repeated daily applications of leukotriene B4 (50 ng) to the same site were associated with a reduction of the visible inflammatory response in both volunteer groups, although application of a single 50 ng dose of leukotriene B4 to an adjacent, previously untreated site at the end of the multiple dose experiments elicited acute erythema and edema. Histologically, there were significantly fewer intraepidermal neutrophils in biopsies from sites to which 9 applications of leukotriene B4 were made than in sites to which 1 dose had been applied at the end of the multiple-dose experiments in both psoriatic and normal volunteers. Therefore, repeated application of leukotriene B4 is associated with decreased responsiveness which is due to a local mechanism in the repeatedly treated skin. No subject developed psoriasis following single or multiple applications of leukotriene B4, suggesting that the production of leukotriene B4 in the epidermis is unlikely to be a primary pathogenic event in this disease.

Topics: Administration, Topical; Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Leukotriene B4; Middle Aged; Psoriasis; Skin

Chemoattractant arachidonate lipoxygenase products have been recovered from the skin lesions of psoriasis, and may play a role in eliciting the intra-epidermal neutrophil infiltrate that characterises this disease. In view of evidence for lipoxygenase activity in psoriasis, the characteristic vasodilation in psoriatic lesions, and the vasodilator properties of leukotriene (LT) C4 and D4 in human skin, the presence of these LTs in psoriatic lesions has been investigated. Skin chamber fluid from abraded psoriatic lesions contained significantly greater amounts of immunoreactive material than that from clinically normal skin, as determined by a double antibody radioimmunoassay (RIA) that uses antiserum cross-reacting with both LTC4 and LTD4. Purification of lesional chamber fluid and scale extracts by high performance liquid chromatography (HPLC) and RIA of fractions showed immunoreactivity which co-eluted with standard LTC4 and LTD4. These findings suggest that LTC4 and LTD4 may play a role in mediating the vasodilation and increased blood flow that characterise psoriatic skin lesions.

Topics: Adolescent; Adult; Aged; Humans; Leukotriene B4; Lipoxygenase; Middle Aged; Psoriasis; Radioimmunoassay; Skin; SRS-A

The pros and cons concerning the involvement of arachidonic acid metabolism in the pathogenesis of psoriasis are presented. The isolation of arachidonic acid metabolites from psoriatic lesions, their extraordinary biological activity, and the therapeutic efficiency in psoriasis of inhibitors of arachidonic acid metabolism all argue in favor of leukotrienes and monohydroxy fatty acids playing an important role in the development of psoriasis plaques. On the other hand, the lack of specificity of the biochemical findings, the failure to reproduce psoriatic lesions by arachidonic acid metabolites, and the therapeutic activity of drugs that have no effect on arachidonic acid metabolism show that the role of arachidonic acid metabolism in the pathogenesis of psoriasis is still controversial. The availability of selective inhibitors of arachidonic acid-metabolizing enzymes for clinical testing is a prerequisite before pathophysiological conclusions can be made, as the present status of knowledge makes any conclusions premature.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Anthralin; Anti-Inflammatory Agents; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Glucocorticoids; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Propionates; Psoriasis; Retinoids; Skin

Leukotrienes in psoriatic skin lesions are potent mediators of inflammation. We have studied the capacity of leukotrienes to stimulate the DNA synthesis of cultured human epidermal keratinocytes. At concentrations ranging from 10(-12) to 10(-8) M, LTB4 produced a 100% increase of DNA synthesis determined both as the incorporation of [3H] thymidine and as the labelling index. In comparison, LTB4 had no effect on the DNA synthesis of dermal fibroblast cultures. 5S,12S-LTB4 and 5S,12S-all-trans-LTB4 did not change the DNA synthesis of keratinocytes, but the effect of LTB4 was abolished in the presence of 5S,12S-all-trans HLTB4. Being less potent than LTB4 the peptidoleukotrienes (LTC4, LTD4) also stimulated keratinocyte DNA synthesis. The effect of the peptidoleukotrienes, but not of LTB4, was antagonized by FPL 55712. These results show that leukotrienes B4, C4 and D4 exert potent and stereospecific mitogenic effects on cultured human keratinocytes. The presence of these arachidonic acid metabolites in psoriatic skin lesions may be pertinent to both inflammation and aberrant epidermal growth in psoriasis.

Topics: Adult; Cells, Cultured; Chemotaxis, Leukocyte; DNA; Dose-Response Relationship, Drug; Epidermal Cells; Fibroblasts; Humans; Leukotriene B4; Neutrophils; Psoriasis; Skin; SRS-A

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Chemotactic Factors; Chronic Disease; Epidermis; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Psoriasis; Skin

5-lipoxygenase-derived products of arachidonic acid are implicated in the pathophysiology of psoriasis, a common hyperproliferative and inflammatory skin disease. We therefore examined whether there is an activation of this enzymatic pathway in extracutaneous tissues. For this purpose, we measured the conversion of 14C-arachidonic acid by polymorphonuclear leukocytes from psoriatic patients and controls. No significant difference in the generation of leukotriene B4 and 5-hydroxyeicosatetraenoic acid by polymorphonuclear leukocytes was noted between the two groups. We conclude that in psoriasis there is no enhanced activity of the 5-lipoxygenase pathway in circulating polymorphonuclear leukocytes.

Topics: Adult; Aged; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Neutrophils; Psoriasis

Monohydroxy acids (HETEs) and leukotriene B4 (LTB4) metabolites of arachidonic acid were measured in skin of healthy volunteers after ultraviolet B irradiation, and in the uninvolved skin of psoriatics after topical dithranol application. Exudate was collected from suction bullae on control and inflamed abdominal skin, and analysed for 12-HETE and PGE2 by GC-MS and LTB4 by bioassay. 12-HETE and PGE2 were raised at 24 h but not at 72 h after u.v.B irradiation: control and 24 h values were 13.7 and 41.5 ng ml-1 (P less than 0.05, n = 6) for 12-HETE respectively, and 4.5 and 30.2 ng ml-1 (P less than 0.01, n = 6) for PGE2. Dithranol application raised PGE2 levels from 23.1 ng ml-1 in control exudate to 62 ng ml-1 (P less than 0.01, n = 6) at 24 h before declining to base levels at 72 h. However, 12-HETE was raised at 72 h (200 ng ml-1, P less than 0.01, n = 5) but not at 24 h (104 ng ml-1) compared to control levels (50 ng ml-1, n = 5). The levels of the LTB4 were low (less than 100 pg ml-1), and no significant increases were observed. Arachidonic acid in inflamed skin can be metabolised by the cyclo-oxygenase and lipoxygenase pathway. It is probable that the lipoxygenase product 12-HETE is involved in these inflammatory reactions.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Anthralin; Arachidonic Acid; Arachidonic Acids; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukotriene B4; Lipoxygenase; Male; Prostaglandins E; Psoriasis; Radiation Injuries; Skin; Time Factors; Ultraviolet Rays

The penetration of polymorphonuclear leukocytes (PMNs) into the epidermis following topical application of leukotriene B4 was assessed in the clinically uninvolved skin of psoriatic patients treated with methotrexate and of psoriatic patients without treatment, and in normal controls. Inhibition of PMN infiltration was observed in those patients treated with methotrexate while there was no significant difference between untreated psoriatic patients and normal controls.

Topics: Adult; Chemotaxis, Leukocyte; Epidermis; Female; Humans; Leukocytes; Leukotriene B4; Male; Methotrexate; Middle Aged; Neutrophils; Psoriasis

AA and its derivatives are a family of potent mediators and regulators of inflammation. There are several pieces of evidence to suggest a pathophysiologic role of certain AA derivatives in psoriasis. The complexity of the pathways in the generation of LTs and other LO products suggests that carefully designed systems will be needed to establish the exact role of these compounds in the pathogenesis of diseases such as psoriasis, and to test the effects of pharmacological inhibitors.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Arachidonic Acids; Fish Oils; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Leukotrienes; Lipoxygenase; Lipoxygenase Inhibitors; Psoriasis; Skin; SRS-A

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Arachidonic Acids; Dermatitis; Drug Tolerance; Forearm; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Psoriasis; Skin; Skin Tests; SRS-A; Time Factors

Leukotrienes (LTs) have potent biologic properties, suggesting a role in human disease. LTB4 release has been detected in inflammatory exudates in the rat. LTC4 release has been detected after antigen challenge of lung tissue in vitro and in tear fluid in man in vivo. There is some evidence to suggest that LTB4 is a mediator of ulcerative colitis in man and considerable evidence to suggest that LTB4, LTC4, and LTD4 may be involved in the pathogenesis of psoriasis.

Topics: Allergens; Colitis, Ulcerative; Humans; Inflammation; Leukotriene B4; Neutrophils; Psoriasis; Skin; SRS-A

Eight psoriatic patients were treated with etretinate (50 mg daily) for 6 weeks. Skin chamber exudates from involved and uninvolved skin were assayed for arachidonic acid, 12-HETE, PGE2 and for neutrophil chemokinetic activity co-chromatographing with leukotriene B4, before and at weekly intervals during therapy. Pre-treatment concentrations of arachidonic acid, 12-HETE and leukotriene B4-like chemokinetic activity but not of PGE2 were elevated in involved skin when compared to uninvolved skin. The concentrations of arachidonic acid and 12-HETE declined during therapy but changes in PGE2 were minimal. LTB4-like activity was detectable in involved skin both before and after etretinate treatment. Clinically, scaling and infiltration improved but erythema was still evident.

Topics: Adult; Arachidonic Acid; Arachidonic Acids; Etretinate; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Prostaglandin-Endoperoxide Synthases; Psoriasis; Skin

Acidic lipid extracts of scale from the lesions of the skin disease, psoriasis, were purified by straight phase high performance liquid chromatography (h.p.l.c.). Assay of fractions by an agarose microdroplet chemokinesis method showed the presence of biologically active material that coeluted with standard leukotriene B4 (LTB4). LTB4-like chemokinetic activity was also detected in fractions collected on reversed phase h.p.l.c. of psoriatic scale extracts that were initially purified by straight phase h.p.l.c. No LTB4-like activity was detected after similar purification of scale obtained by abrasion of large areas of normal skin. The LTB4-like material found in extracts of psoriatic scale may play a role in the pathogenesis of the neutrophil infiltrate which characterizes psoriasis.

Topics: Cell Movement; Chromatography, High Pressure Liquid; Humans; Leukotriene B4; Neutrophils; Psoriasis; Skin

Incubations of [14C]arachidonic acid [( 14C]AA) with cell-free preparations from normal, clinically involved and uninvolved epidermis from psoriatic subjects resulted in the formation of several radiolabeled metabolites of the lipoxygenase pathway. The identities of the monohydroxy-ETEs and dihydroxy-ETEs (products of the 12-lipoxygenase and 5-lipoxygenase pathways) were determined by comparison with authentic standards of 12L-hydroxy-5,8,10,14-eicotetraenoic acid (12-HETE) and authentic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (LTB4) by thin-layer chromatography in two solvent systems; by silicic acid column chromatography and by normal phase and straight phase high-pressure liquid chromatography. Activity of the enzymes which catalyze this transformation are localized in the soluble (105,000 g supernatant) fraction of the epidermal preparations. The activity of enzymes of both pathways were inhibited by 5,8,11,13-eicosatetraynoic acid (ETYA) and nor-dihydroguaretic acid (NDGA), known inhibitors of the lipoxygenase and cyclooxygenase pathways. Transformation of [14C]AA into [14C]LTB4-like metabolite by the soluble preparations from clinically involved psoriatic epidermis was significantly higher (p less than 0.001) than from paired uninvolved soluble preparations or from soluble preparations from normal subjects. Furthermore, biosynthesis of LTB4-like metabolite by the uninvolved soluble preparation was significantly higher (p less than 0.05) than preparations from normal epidermis. These results imply that the [14C]LTB4-like metabolite biosynthesized by the clinically involved soluble preparation was due at least in part to the increased activity of the lesional enzymes and not entirely due to possible intraepidermal infiltrating neutrophils. Human epidermal preparations, therefore, contain enzymes which catalzye the transformation of labeled AA into labeled LTB4-like metabolite as well as into other yet unidentified dihydroxy-ETEs. Localization of a soluble 5-lipoxygenase-like activity in the epidermis implies a possible role of the lipoxygenase products in the proliferative and inflammatory processes in this tissue.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 5,8,11,14-Eicosatetraynoic Acid; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Catechols; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Masoprocol; Psoriasis; Reference Standards; Skin

Skin biopsies and scale extracts from 22 patients with psoriasis were examined for the presence of chemotactic lipoxygenase products of arachidonate metabolism. Heat-stable leukocyte chemotactic activity in aqueous extracts of 2-mm punch biopsies from involved and uninvolved patient skin was significantly elevated, compared to healed psoriatic skin and to skin of normal controls. Ether extracts (pH 3.0) from 13 mg of psoriatic scales contained a mean chemotactic activity corresponding to that of leukotriene B4, 5 X 10(-8) M. On reverse phase high-pressure liquid chromatography, the main chemotactic lipids in scale extracts were leukotriene B4 and 5-HETE. Since lipoxygenase products are potent mediators of inflammation, they may play an important role in the evolution and maintenance of psoriatic lesions.

Topics: Arachidonic Acid; Arachidonic Acids; Biopsy, Needle; Chemotactic Factors; Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Psoriasis; Skin

Topics: Autoimmune Diseases; Chemotaxis, Leukocyte; Humans; Leukotriene B4; Neutrophils; Peritoneal Dialysis; Plasmapheresis; Psoriasis; Skin

Topics: Albuterol; Aminophylline; Cold Temperature; Histamine Release; Humans; Leukotriene B4; Models, Biological; Psoriasis; Skin; Urticaria

The recent definition of the pathways of generation and structures of diverse products of the lipoxygenation of arachidonic acid has established the identity of a new family of mediators of hypersensitivity and inflammation. Studies of the effects of these mediators have shown that leukotrienes C, D, and E, the constitutents of the slow-reacting substance of anaphylaxis (SRS-A), are extremely potent smooth muscle contractile and vasoactive factors. Leukotriene B is a highly active stimulus of neutrophil and eosinophil functions and suppresses the immunological capabilities of T lymphocytes. The development of specific and sensitive radioimmunoassays has permitted the detection of elevated concentrations of leukotrienes in tissues or exudates in several diseases, including asthma, diverse allergic states, adult respiratory distress syndrome, psoriasis, spondyloarthritis, and gout. The application of selective inhibitors and antagonists of leukotrienes will clarify their pathogenetic contributions in human diseases and may yield new therapeutic approaches.

Topics: Arachidonate Lipoxygenases; Arachidonic Acids; Arthritis; Asthma; Cystic Fibrosis; Humans; Hypersensitivity; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lipoxygenase; Psoriasis; SRS-A; Tears

The 5,12-dihydroxy metabolite of arachidonic acid, leukotriene B4, is a highly potent neutrophil chemoattractant. In view of the characteristic epidermal neutrophil infiltrate in psoriasis, the presence of leukotriene B4 in samples from untreated lesional and uninvolved skin has been sought. Chambers were fixed to abraded skin and filled with phosphate-buffered saline (PBS). After 35 min, the fluid was removed, and acidic lipids were extracted and subjected to high-performance liquid chromatography (HPLC). Extracts were purified by both straight- and reversed-phase HPLC, and assay of evaporated fractions by an agarose microdroplet chemokinesis technique indicated the presence of leukotriene B4-like material. No significant leukotriene B4-like activity was found in samples from uninvolved skin. Subsequent experiments using a modification of the initial skin chamber method indicated that leukotriene B4 was being released from deeper layers of lesional skin and not only from superficial scale. Monohydroxy-eicosatetraenoic acid-like activity was also seen in lesional samples as determined by straight-phase HPLC and chemokinesis assay. These findings and the proinflammatory properties of these compounds in human skin suggest that they may play a role in the pathogenesis of the psoriatic neutrophil infiltrate.

Topics: Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Humans; Leukotriene B4; Methods; Neutrophils; Psoriasis; Skin

Topics: Chemotactic Factors, Eosinophil; Humans; Leukotriene B4; Psoriasis; Skin

The relevance of arachidonic acid metabolites in inflammatory skin diseases has been expanded by recent developments in analytical chemistry. The metabolites include prostaglandins, leukotrienes and monohydroxy fatty acids. In ultraviolet light-induced inflammation the concentrations of arachidonic acid, prostaglandin E2, prostaglandin F2 alpha and 6-oxo-prostaglandin F1 alpha are elevated. Indomethacin totally suppresses the evoked prostaglandin increase, but erythema is only partially suppressed. This indicates that prostaglandins are partially involved in erythema production. In psoriasis the first histological change is an infiltration into the epidermis by neutrophilic leucocytes. It has been suggested that chemotactic factors, such as complement derived factors or leukotriene B4 play a role in the pathogenesis of psoriasis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acids; Cyclic AMP; Humans; Leukotriene B4; Leukotrienes; Mast Cells; Prostaglandins; Psoriasis; Skin; Skin Diseases; SRS-A; Ultraviolet Rays

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Arachidonic Acids; Humans; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Phospholipases A; Propionates; Prostaglandins; Psoriasis; Skin; Skin Diseases; Thromboxanes

Topics: Chemotaxis, Leukocyte; Epidermis; Humans; Leukotriene B4; Neutrophils; Psoriasis; Skin

In vitro monocyte chemotaxis towards leukotriene B4(LTB4) and platelet activating factor (PAF) was studied with cells from 51 patients with various inflammatory dermatoses and 12 normal volunteers. Monocytes from normal subjects responded poorly to LTB4 (10(-8)-10(-12) M) and PAF (10(-6)-10(-10) M), and cells from patients with urticaria pigmentosa and vericella were even less responsive, while monocytes from patients with severe psoriasis and atopic eczema exhibited markedly enhanced chemotaxis. These changes persisted during high dose therapy with oral steroids, but returned to normal with healing of the skin lesions. Pre-incubation of monocytes with histamine, LTB4, PAF, lymphokines or sera from patients and normal controls did not result in enhanced chemotaxis of the cells. The chemotactic activity of monocytes did not correlate with that of neutrophils in the same patients (r = 0.08). Altered monocyte chemotaxis in patients with inflammatory dermatoses is therefore a reversible process that is related to the severity of the cutaneous inflammation but is not limited to a specific disease.

Topics: Adolescent; Adult; Cells, Cultured; Chemotaxis, Leukocyte; Child; Dermatitis; Dermatitis, Atopic; Dose-Response Relationship, Immunologic; Female; Humans; Leukotriene B4; Male; Monocytes; Platelet Activating Factor; Psoriasis; Urticaria

Topics: Arachidonic Acids; Chemotactic Factors; Humans; Leukotriene B4; Psoriasis; Skin

Topics: Arachidonic Acids; Chemotaxis, Leukocyte; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Psoriasis

Topics: Animals; Arachidonic Acids; Humans; Inflammation; Leukotriene B4; Prostaglandins; Psoriasis; Skin; SRS-A