Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033860 (psoriasis)
 20,684 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Cutaneous responses to 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 5,12-dihydroxyeicosatetraenoic acid (leukotriene B4) in psoriasis and normal human skin. 282 51

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.
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PMID:Heterogeneous distribution of lipoxygenase products in psoriatic skin lesions. 282 53

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.
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PMID:Leukotrienes: their formation and role as inflammatory mediators. 298 30

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.
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PMID:Leukotrienes C4 and D4 in psoriatic skin lesions. 298 23

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.
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PMID:Chemotactic lipoxygenase products in sera from patients with psoriasis. 301 47

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.
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PMID:The chemokinetic response of psoriatic and normal polymorphonuclear leukocytes to arachidonic acid lipoxygenase products. 301 41

Despite the postulated role of arachidonic acid-derived metabolites in the pathophysiology of chronic inflammatory dermatoses such as psoriasis and atopic or contact dermatitis, the cutaneous effects of their chronic application have not yet been investigated. We therefore studied systematically the effects of chronic intracutaneous administration of arachidonic acid, prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and 12-hydroxyeicosatetraenoic acid (12-HETE) in guinea pigs, and describe previously unrecognized findings partly different from those reported in the past for short-term or topical application of these inflammatory mediators. Leukotriene B4 and 12-HETE led to massive histologic changes characteristic of leukocytoclastic vasculitis. These changes could be prevented by concomitant PGE2 administration. In epidermis, LTB4 and 12-HETE caused some spongiosis as well as hyperplasia and increased tritiated thymidine autoradiographic labeling index. Arachidonic acid and PGE2 alone had little effect. These data suggest that in addition to other inflammatory or hyperproliferative dermatoses, arachidonic acid metabolites formed via lipoxygenase pathways could play a major role in leukocytoclastic vasculitis, whereas PGs could exert a tissue-protective effect.
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PMID:Effects of chronic intracutaneous administration of arachidonic acid and its metabolites. Induction of leukocytoclastic vasculitis by leukotriene B4 and 12-hydroxyeicosatetraenoic acid and its prevention by prostaglandin E2. 302 88

Intensive studies of the molecular pathways involved in common inflammatory skin disorders, coupled with detailed pharmacologic evaluation of the responses of skin to the end products of these pathways, have resulted in a much clearer understanding of the mode of action of nonsteroidal anti-inflammatory drugs. In particular the development of lipoxygenase inhibitors is prompting intense interest in their possible role as anti-inflammatory agents in psoriasis and other dermatoses. Because of the potency of these and other classes of new anti-inflammatory drugs, careful monitoring of their pharmacokinetics in individual patients, especially those at risk for adverse reactions, will prove necessary, especially in the early stages of treatment. Meanwhile, currently available nonsteroidal anti-inflammatory drugs have a limited but significant place in the treatment of certain dermatoses. Current experience of the high incidence of adverse reactions to existing nonsteroidal anti-inflammatory drugs suggests that this will be no less a problem with new agents under development. The skin is frequently involved in adverse reactions to this class of drug, and past experience suggests that cutaneous reactions are among the earliest unwanted side effects reported in a new drug of this type. The dermatologist, therefore, has an important responsibility to observe, document, and report such "early warning signs" to the appropriate licensing authority and the manufacturer.
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PMID:Pharmacology and significance of nonsteroidal anti-inflammatory drugs in the treatment of skin diseases. 303 31

The metabolism of arachidonic acid by mixed suspensions of leukocytes and platelets prepared from peripheral blood has been studied in 20 patients with psoriasis and 21 healthy controls. A lipoxygenase-derived product, identified as 12,20-dihydroxy-5,8,10,14-eicosatetraenoic acid was formed in increased amounts by the cell suspension from the psoriatic patients. This product results from the metabolism of platelet-derived 12-hydroxy-5,8,10,14-eicosatetraenoic acid by the polymorphonuclear leukocyte 20-hydroxylase enzyme. By contrast, synthesis of the cyclo-oxygenase products 12-hydroxy-5,8,10-heptadecatrienoic acid and thromboxane B2 was diminished. Benoxaprofen, which is known to be beneficial in psoriasis, diminished the levels of 12,20-dihydroxy-5,8,10,14-eicosatetraenoic acid formed in vitro.
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PMID:Arachidonic acid metabolism by peripheral blood cells in psoriasis. 308 3

Epidermis of psoriatic skin lesions is characterized by elevated 5-lipoxygenase and 12-lipoxygenase products. 15-hydroxyeicosatetraenoic acid (15-HETE), the predominant lipoxygenase product in normal dermis, has the potential to inhibit 5-lipoxygenase and 12-lipoxygenase. The purpose of the present study was to determine the capacity of homogenized dermis from uninvolved psoriatic skin to form 15-HETE in vitro. Extracted lipids were separated by reversed-phase high-performance liquid chromatography. Each chromatographic peak was identified by its coelution with authentic standards, by ultraviolet spectrometry, and by radioimmunoassay. Dermis from uninvolved psoriatic skin generated on average 48% less 15-HETE than normal dermis (P less than .01). In contrast, the formation of 12-hydroxyeicosatetraenoic acid was increased by 56% in psoriatic dermis (P less than .01). Prostaglandin E2 formation was similar in normal and psoriatic dermis. Since 15-HETE can inhibit the synthesis of 5-lipoxygenase and 12-lipoxygenase products that possess inflammatory and proliferative capacities, a defective 15-HETE generation in dermis may be of importance for the development of psoriasis.
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PMID:Selective decrease of 15-hydroxyeicosatetraenoic acid (15-HETE) formation in uninvolved psoriatic dermis. 309 Sep 43


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