The release of leukotriene B4-like material in biologically active amounts from the lesional skin of patients with psoriasis.

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.

Pharmacologic and clinical effects of lonapalene (RS 43179), a 5-lipoxygenase inhibitor, in psoriasis.

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.

Increased concentrations of arachidonic acid, prostaglandins E2, D2, and 6-oxo-F1 alpha, and histamine in human skin following UVA irradiation.

The buttock skin of clinically normal human subjects was subjected to approximately 2.5 minimal erythema doses of ultraviolet A irradiation. Deep red erythema developed during irradiation, faded slightly within the next few hours, increased to maximum intensity between 9-15 h, and decreased gradually thereafter although still persisting strongly at 48 h. Suction blister exudates were obtained at 0, 5, 9, 15, 24, and 48 h after irradiation as well as suction blister exudates from a contralateral control site and assayed for arachidonic acid, prostaglandins D2 and E2, and the prostacyclin breakdown product 6-oxo-prostaglandin F1 alpha by gas chromatography-mass spectrometry, and for histamine by radioenzyme assay. Increased concentrations of arachidonic acid and prostaglandins D2, E2, and 6-oxo-prostaglandin F1 alpha were found maximally between 5-9 h after irradiation, preceding the phase of maximal erythema. Elevations of histamine concentration occurred 9-15 h after irradiation, preceding and coinciding with the phase of maximal erythema. At 24 h, still at the height of the erythemal response, all values had returned to near control levels. Hence increased concentrations of arachidonic acid and its products from the cyclooxygenase pathway, and of histamine, accompany the early stages up to 24 h. A causal role in production of the erythema seems likely for these substances although other mediators are almost certainly involved.

Vitamin B-12 deficiency and malabsorption are highly prevalent in rural Mexican communities.

Vitamin B-12 status of rural Mexicans was evaluated in two studies, 6 y apart. In the first, a single blood sample was collected from children and adults, including pregnant and lactating women. Prevalence of deficient plasma vitamin B-12 values ranged from 19% to 41% among groups, but plasma folate status was normal in all individuals. Breast milk vitamin B-12 concentration was low in 62% of samples. The second study was conducted in 219 children aged 18-36 mo in five communities, whose prevalence of deficient and low plasma vitamin B-12 concentrations, respectively, was 8% and 33% on entry, 3% and 22% 6 mo later, and 7% and 29% 12 mo later. Prevalence of low holotranscobalamin II concentrations, indicating malabsorption of the vitamin, averaged 18-40% across the three same periods. Both vitamin B-12 status indicators differed significantly between communities. The widespread vitamin B-12 deficiency was probably caused by malabsorption, perhaps exacerbated by low dietary intake and, for young children, maternal depletion of the vitamin.

The release of prostaglandin D2 from human skin in vivo and in vitro during immediate allergic reactions.

1. The release of prostaglandin D2 (PGD2) during immediate allergic reactions in human skin was investigated in vivo and in vitro. 2. Skin exudates were collected from abraded sites on the thigh of atopic subjects sensitive to D. pteronyssinus antigen and from non-atopic control subjects. Challenge with antigen caused the release of PGD2 and histamine, but not PGE2, from the skin of the atopic subjects. The molar ratio of histamine to PGD2 was about 140:1. Control subjects were unresponsive. 3. PGD2 was released from passively sensitized human skin challenged with antigen in vitro. The time course was similar in vitro and in vivo. The ratio of histamine to PGD2 in vitro was 78:1. 4. The identities of the prostaglandins were confirmed by high performance liquid chromatography and radioimmunoassay to PGD2 and PGE2. 5. PGD2 is the major arachidonic acid cyclo-oxygenase product synthesized by human mast cells. It is pro-inflammatory in human skin but its functions as a mediator in immediate hypersensitivity reactions in human skin are not clear. The results of this study suggest that, relative to histamine, PGD2 contributes little to the oedema and erythema of immediate reactions in human skin.

Leukotriene B4-like material in scale of psoriatic skin lesions.

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.

The pathogenesis of urticaria.

The underlying pathophysiology of chronic urticaria is mast cell activation, with release of histamine and other mast cell mediators. A weal producing factor has been identified in the serum of 60% of patients with chronic idiopathic urticaria. In half of these patients there is evidence for functional autoantibodies against the high affinity IgE receptor or IgE, or both. These autoantibodies release histamine from basophils and mast cells. It is therefore likely that there is an autoimmune basis for up to 30% of patients with idiopathic urticaria. In the other half of patients whose serum causes weals, the factor releases histamine from mast cells only and is as yet unidentified. So far no clinical difference has been associated with presence/absence or type of weal producing factor. Exacerbating factors in chronic urticaria such as aspirin, food additives, febrile illness and psychological stress should be identified and avoided. Treatment is symptomatic with the low sedation antihistamines. In the most severe cases not responding to conventional therapy and which may have the weal producing factor, treatments with non specific immune therapy such as cyclosporin, and intravenous gammaglobulin and also plasmapheresis have been promising.

Nevus oligemicus. A variant of nevus anemicus.

A man had a long history of a persistent, fixed area of livid erythema on the trunk. The distribution of hair, sweat, and sensation were normal as were the histologic findings in the affected skin. The involved area had a decreased total skin blood flow and a lower surface temperature compared with surrounding uninvolved skin, but showed normal responses to vasoconstrictor and vasodilator stimuli. Incomplete sympathetic blockade partially abolished the erythema. We suggest that the appearance of the nevus is caused by increased vasoconstrictor tone in the thermoregulatory vessels of the involved skin, leading to relative stasis in the superficial "nutritional" vasculature. This would seem to be a new example of a "pharmacological nevus" showing similarities to and differences from nevus anemicus.

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.

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.

The effects of topical corticosteroids on delayed pressure urticaria.

Six patients with delayed pressure urticaria (DPU) applied clobetasol propionate (0.05%) ointment or its base to predetermined test sites on the right and left thigh as part of a randomized, double-blind study. A pressure challenge was administered to each test site at the initial visit and repeated after 3 days and 6 weeks of treatment and at between 4 and 8 weeks after treatment. The areas of pressure-induced weals were measured 6 h after each challenge. At the 6-week visit, a 4-mm punch biopsy was taken from pressure-challenged skin on each test site. Sections were stained for mast cells and immunohistochemical labelling was used to demonstrate neutrophils (neutrophil elastase), eosinophils (eosinophil cationic protein), monocytes/macrophages (EBM 11), cells expressing the beta-2 integrins (CD11/18) and the vascular adhesion molecules, E selectin and intercellular adhesion molecule-1 (ICAM-1). In the steroid-treated sites, there was a significant decrease (P < 0.05, Wilcoxon's matched-pairs test) in the size of the pressure weals compared with baseline at 3 days, 6 weeks and at follow-up. Demonstrable mast cells were significantly decreased (P = 0.059) in the pressure-challenged areas in the steroid-treated sites compared with the base-treated sites. The histological response to pressure was minimal in both sites perhaps demonstrating an active pharmacological effect of the ointment base. In conclusion, the application of potent topical steroids significantly reduced the clinical response to pressure in patients with DPU, possibly through a reduction in mast cells.

Urticarial vasculitis.

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The incidence of vasculitis in patients with apparent urticaria is between 2% and 20%. The diagnosis is suggested clinically by more persistent (lasting > 24 hours) and more symptomatic weals than in ordinary urticaria and by the presence of residual bruising. In addition to the skin the musculoskeletal, respiratory, renal and gastrointestinal systems may be involved in the disease, which is probably an immune complex mediated process. Urticarial vasculitis is most commonly an acquired idiopathic phenomenon but may occur in association with other disorders most often systemic lupus erythematosus, Sjögren's syndrome and serum sickness. In this article we review the background, histopathology, clinical features, extracutaneous manifestations, pathogenesis, aetiology, associated diseases, investigation, treatment, course and prognosis of urticarial vasculitis.

Unusual urticarias.

Typical urticarial lesions are transient cutaneous swellings of sudden onset, often itchy, persisting for less than 24 hours and resolving to leave normal appearing skin. Angioedema lesions are similar subcutaneous lesions. Atypical urticarias persist for longer than 24 hours, may be painful and bruised in appearance and accompanied with severe systemic symptoms. Conditions where prolonged weals are present include delayed pressure urticaria and urticarial vasculitis. These conditions do not respond well to antihistamine therapy. In delayed pressure urticaria, weals appear after a delay of hours at sites of sustained pressure on the skin and occur in association with ordinary chronic 'idiopathic' urticaria. Weals of urticarial vasculitis show histological features of venulitis, and can be accompanied by arthralgia and abdominal pain. Rarely, the condition is due to infective or autoimmune disease. Urticarial diseases, sometimes with features of urticarial vasculitis, and with associated systemic features include Schnitzler's Syndrome, Still's disease and Muckle-Wells syndrome. The latter syndrome is linked with chromosome 1q44, as is autosomal dominant cold urticaria, an unusual physical urticaria. Persistent cholinergic erythema, a variant of cholinergic urticaria, has been mistaken for a drug eruption or cutaneous mastocytosis. Rarely, food and exercise induced urticaria and anaphylaxis occur when exercise follows a specific food or any meal within a few hours. The early stages of inflammatory disease may be mistaken for urticaria and angioedema, but lesions usually persist for longer than 48 hours and are accompanied by epidermal changes.

Inflammatory reactions induced by ultraviolet irradiation.

Exposure of human skin to short wavelength ultraviolet (U.V.) leads to increased concentrations of arachidonic acid and prostaglandins E2 and F2, but their role is uncertain. Although the levels of prostaglandins rise as erythema develops the correlation between intensity of erythema and prostaglandin activity is incomplete. There is mounting evidence that prostaglandins may regulate epidermal cell growth and differentiation through a cyclic-AMP dependent mechanism. The possibility therefore arises that prostaglandins, released in response to U. V. exposure, reduce proliferative activity in the exposed epidermis. This can be expected, in turn, to result in protection of skin from the mutagenic action of U. V. irradiation.

The clinical presentations of urticaria.

Urticaria is a common skin condition. Although an episode may be mild and last only a few days, chronic urticaria can significantly affect the quality of life. The condition is frequently misunderstood by patients who believe the condition is always the result of an allergy and is dangerous.

Mechanical trauma and urticaria.

Urticarial responses in skin may be elicited in different ways, viz, stroking (dermographism), after sustained pressure (delayed pressure urticaria), and after vibration (vibratory angio-oedema). Pressure may localise lesions of chronic idiopathic urticaria. Trauma may exacerbate hereditary angio-oedema. The extent of the morbidity caused by trauma-induced urticaria among workers is unknown.

Cloning and characterization of a lignin peroxidase gene from the white-rot fungus Trametes versicolor.

Six putative lignin peroxidase (LIP) genes were isolated from a lambda EMBL3 phage library of the white-rot fungus, Trametes versicolor, using the Phanerochaete chrysosporium LIP cDNA CLG5 as the probe. Sequence analysis of one of the genes, VLG1, showed that its coding region is interrupted by six small introns (49-64 bp) and that it encodes a mature LIP protein (341 aa; Mr: 36,714) that is preceded by a 25 aa signal sequence. This protein has a relatively high degree of aa homology to the N-termini of the LIP proteins purified from T. versicolor and has an aa homology of 55-60% to the LIP proteins of P. chrysosporium, which is comparable to that found between P. chrysosporium and Phlebia radiata LIP proteins.

Angiotensin-converting enzyme (ACE) inhibitors and angio-oedema.

Angiotensin-converting enzyme inhibitors (ACEIs) are used increasingly for the treatment of hypertension and chronic heart failure, and they reduce mortality when given after myocardial infarction. Of the patients prescribed these drugs 0.1-0.7% develop angio-oedema, but the association is not widely recognized. In 60% of cases the onset occurs during the first week of treatment; however, it may be considerably delayed. Angio-oedema nearly always occurs on the head and neck, frequently involving the mouth, tongue, pharynx and larynx. The course is unpredictable, and attacks vary in severity from mild to fatal from laryngeal obstruction. Severe ACEI-induced angio-oedema may require emergency treatment with adrenalin and early intubation. The drug should be withdrawn in any patient who presents with ACEI-induced angio-oedema, and treatment continued with an appropriate drug of a different class. Therapy with ACEIs is contraindicated in patients with a prior history of idiopathic angio-oedema, or in patients with hereditary or acquired C1 esterase inhibitor deficiency.

The anti-inflammatory and pharmacological effects of topically applied flurbiprofen on human skin 24 hours after ultraviolet B irradiation.

Human abdominal skin was irradiated, with three minimal erythema doses of ultraviolet B (290-320 nm) radiation, producing maximal erythema at 24h, with an associated rise in PGE2 and PGF2 alpha, measured by gas chromatograph-mass spectrometry. Topical applications of 5% flurbiprofen, a prostaglandin synthetase inhibiting drug applied immediately after irradiation, partially suppressed the u.v.B. evoked erythema at 24h but totally prevented elevation of PGE2 and PGF2 alpha, without any associated significant rise in arachidonic acid. These findings support the view that erythema due to u.v.B. is only partly mediated by products of cyclo-oxygenase pathway, and should prompt a search for other mediators, including non-prostaglandin metabolites of arachidonic acid.