prostaglandin-d2 and Erythema

To investigate the kinetics and pattern of allergenically induced mediator release in the human skin, we have studied 24 ragweed- and grass-allergic patients with a blister-chamber technique. Chambers sealed to the skin around a denuded area, formed by unroofing a blister, were challenged with 0.5 ml of either diluent or 10 or 100 times the concentration of allergen required for 4+ early intradermal reaction. Chamber fluids were removed hourly 1 to 8 hours after antigen challenge and examined for the presence of histamine, leukotriene C4 (LTC4), and prostaglandin D2 to compare inflammatory mediator levels with the clinical early response and late-phase response (LPR), as assessed by erythema around the chamber. An initial erythema developed rapidly and began to subside after 1 hour in all patients, but a late-phase local erythema and subcutaneous swelling around the chamber (i.e., greater than 2.5 cm, the outside diameter of the chamber) developed in 13/15 challenges only when the higher concentration of antigen was used. At both allergen concentrations, histamine levels peaked sharply at the first hour (20.6 +/- 2.3 ng/ml) and progressively declined during the next 4 hours by 75%, but remained above control levels for at least 7 hours. Despite high control values, LTC4 levels were significantly elevated (p less than 0.01) 4 to 6 hours after challenge. In visible reactions, maximal LPR around the chamber correlated with LTC4 levels obtained 6 and 7 hours after challenge (p less than 0.05). Prostaglandin D2 rose gradually in antigen-challenged chambers to a peak at 5 to 6 hours. Thus, early rises in histamine were temporally related to the immediate erythema, whereas the arachidonic acid metabolites from both cyclooxygenase and lipoxygenase pathways that appeared in the skin after allergen challenge followed kinetics that corresponded to the time course of cutaneous LPR.

Topics: Adolescent; Adult; Antigens; Erythema; Female; Histamine Release; Humans; Kinetics; Male; Middle Aged; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Skin; Skin Tests; Skin Window Technique; SRS-A; Time Factors

Oral administration of niacin (nicotinic acid) at pharmacologic doses that reduce serum cholesterol levels induces intense flushing in humans. We have recently shown that the vasodilation following ingestion of niacin is due to the release of prostaglandin (PG) D2. However, the site from which PGD2 is released is not known. It has previously been shown that topical application of methylnicotinate causes local cutaneous erythema. Thus, we investigated whether topical methylnicotinate causes a release of PGD2 locally from skin and the possibility that skin may be a major contributor to the release of PGD2 when niacin is administered by mouth. Topical administration of methylnicotinate (10(-1) M) to the forearms of human volunteers resulted in 58- to 122-times increases in levels of PGD2 and 25- to 33-times increases in levels of the metabolite of PGD2, 9 alpha,11 beta-PGF2, in blood drawn from the antecubital vein draining the treated sites. Increased levels of PGD2 and 9 alpha,11 beta-PGF2 were not found in blood drawn simultaneously from veins in the contralateral arm, indicating that the PGD2 was released from the site of methylnicotinate application. The release of PGD2 in response to topically applied methylnicotinate occurred in a dose-dependent manner over the concentration range of 10(-3) to 10(-1) M. The release of PGD2 was not accompanied by a release of histamine, suggesting that the release of PGD2 was not from the mast cell. Following oral ingestion of niacin, levels of PGD2 in superficial venous blood draining the skin were 14 to 1200 times higher than the level in arterial blood supplying the skin of the same arm. This finding indicates that the skin is a major site from which PGD2 is released following oral ingestion of niacin. These studies thus indicate that the cutaneous vasodilation that occurs following oral administration of niacin is primarily due to a release of PGD2 from a niacin responsive cell that resides in the skin.

Topics: Administration, Oral; Administration, Topical; Adult; Dinoprost; Erythema; Histamine Release; Humans; Mast Cells; Middle Aged; Niacin; Nicotinic Acids; Prostaglandin D2; Skin; Vasodilation

The interaction of prostaglandin D2 (PGD2) and histamine in human skin was studied by intradermal injection of the compounds alone or in combination in healthy volunteers. Responses were recorded by measurement of areas of wheal and erythema, and changes in cutaneous blood flow quantified using a laser Doppler flow meter. The effect of a near-threshold dose of PGD2 on histamine dose-response relationships and on the response to a single low dose of histamine were examined. Histamine caused dose-related increases in blood flow and in areas of wheal and erythema in human skin. Prostaglandin D2 caused dose-related increases in blood flow and erythema area, but not wheal area, in the dose range used. When the compounds were injected together, PGD2 did not potentiate the increase in blood flow and areas of wheal and erythema due to histamine. The modest augmentation of histamine response in the presence of PGD2 could be attributed to summation alone. The role of PGD2 in cutaneous disorders such as the physical urticarias, in which its release has been demonstrated, is therefore uncertain. In the amounts measured in the urticarias, it is unlikely alone to cause a significant cutaneous response; nor does it appear to act by potentiation of the response to histamine.

Topics: Adult; Aged; Differential Threshold; Dose-Response Relationship, Drug; Drug Interactions; Erythema; Female; Histamine; Humans; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Regional Blood Flow; Skin; Urticaria

The skin response to UVB irradiation in mice was evaluated by means of ear swelling. ICR albino mice were irradiated with 500 mJ/cm2 UVB and the effect of various drugs on ear swelling was examined 24 h after irradiation. Intravenous injections of betamethasone (0.8 microgram/g body wt.) or indomethacin (24 micrograms/g) remarkably inhibited ear swelling, whereas intraperitoneal injections of diphenhydramine (20 micrograms/g), cimetidine (10 micrograms/g), or a combination of both these antihistamines did not. In contrast, the number of sunburn cells counted 24 h after UVB irradiation (200 mJ/cm2) in mouse ears was not affected by these drugs. The amount of prostaglandin D2 (PGD2) in mice ears at various intervals after irradiation with 500 mJ/cm2 UVB was determined by radioimmunoassay. Compared with the values before irradiation, the PGD2 levels were significantly higher 3 and 6 h after irradiation and gradually decreased and returned to the basal level by 12 h, although ear swelling continued after 12 h. These results suggest that prostaglandins are responsible at least in part for the development of ear swelling, but not for sunburn cell formation induced by UVB, and that ear swelling represents a simple and useful response model for the rapid in vivo screening of nonsteroidal or steroidal anti-inflammatory agents.

Topics: Animals; Betamethasone; Cimetidine; Diphenhydramine; Ear, External; Edema; Erythema; Indomethacin; Male; Mice; Mice, Inbred ICR; Prostaglandin D2; Prostaglandins D; Skin; Ultraviolet Rays

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.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acids; Dinoprostone; Epoprostenol; Erythema; Female; Histamine; Humans; Male; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Skin; Skin Temperature; Ultraviolet Rays

Topics: Adult; Aspirin; Erythema; Humans; Hypotension; Male; Prostaglandin D2; Prostaglandins; Prostaglandins D; Shock; Syndrome; Urticaria Pigmentosa

The inside skin of the forearm of healthy volunteers was irradiated with an infrared (IR) lamp for 1 hr, resulting in the rapid appearance of an erythema and an elevation of skin surface temperature from 30 +/- 1 degree C to 38 +/- 2 degrees C within 5 min. The erythema and elevated skin surface temperature decayed within 10-30 min when the IR irradiation was stopped. Suction blisters were raised on nonirradiated skin and on irradiated skin both during irradiation and at various times after irradiation stopped. Elevated levels of free arachidonic acid, PGE2, PGD2, PGF2 alpha and 6-oxo-PGF1 alpha were found up to 24 h after irradiation. By 48 h the prostaglandin levels had returned to control values whereas the free arachidonic acid levels were still elevated at 72 h. The peak level of 6-oxo-PGF1 alpha appears between 0-6 h whereas for PGE2, D2, and F2 alpha it is between 6-16 h, suggesting a different cellular source for this prostaglandin.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arachidonic Acids; Dinoprost; Dinoprostone; Erythema; Female; Forearm; Humans; Male; Middle Aged; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Skin; Skin Temperature; Ultraviolet Rays