Jørgen Søndergaard

Recovery of Prostaglandins in Human Cutaneous Inflammation

An in-vivo skin perfusion technique has been used to study the pharmacological activity in inflamed skin of patients with allergic contact eczema. Perfusates from 35 out of 45 patients contained a smooth-muscle-contracting agent with prostaglandin-like properties. Solvent partition followed by thinlayer chromatography revealed this activity to be due to a mixture of prostaglandins E and F. This direct evidence supports the view that prostaglandins mediate inflammation in man.

Age‐related diurnal changes of dermal oedema: evaluation by high‐frequency ultrasound

Using high‐frequency ultrasound, we measured the influence of gravitational stress on skin echogenicity in 22 young (age range 17–27; median 19) and 22 elderly (age range 75–100; median 87) healthy adults. B‐mode ultrasound images were obtained from the medial malleolus, lateral calf, anterior thigh, volar forearm and the medial aspect of the arm three times daily; in the morning, immediately before rising, and 2 and 12 h later. The echogenicity was measured by counting the number of low echogenic pixels in the image. Pronounced changes of low echogenic pixel numbers were seen in the areas exposed to high gravitational stress, i.e, the ankle and calf. In the young age‐group echogenicity of the skin increased steadily during the day, whereas in the elderly population echogenicity decreased 2 h after getting up in the morning, and subsequently returned to the baseline level. In a control group of 10 people (aged 17–83; median 18), who remained in the supine position throughout the day, the echogenicity of the skin remained unchanged. As the echogenicity of the dermis is inversely related to the amount of fluid it contains, our results indicate that young skin responds to gravitational stress by fluid depletion. In the skin of the elderly, the mechanism of fluid removal appears to be defective. The impaired protection against the development of intradermal oedema in the elderly may predispose to the development of lipodermatosclerosis and leg ulceration.

Heat-separation of normal human skin for epidermal and dermal prostaglandin analysis.

SummaryHeat-separation was introduced as a simple, reliable method of obtaining pure epidermis and dermis for prostaglandin (PG) analysis. Heating of normal human skin at 60°C for 1 min resulted in a distinct separation of the epidermis from the dermis. After heat-separation the mean concentration ±SEM of PGE1 activity in normal epidermal tissue was 2906±281 pg/mg dry weight. The PGE1 level in the corresponding dermal samples was 30±4 pg/mg dry weight and the mean leakage of PGE1 from the tissue into the buffer used during heating was 426±54 pg/ml.

Treatment of Rheumatoid Arthritis with Prostaglandin E1, Precursors CIS-Linoleic Acid and γ-Linolenic Acid

20 patients with active rheumatoid arthritis were treated for 12 weeks with the prostaglandin E, precursors cis-linoleic acid and γ-linolenic acid in the form of primrose evening oil (Efamol®) and the co-factors zinc, ascorbic acid, niacin, and pyridoxin (Efavit®). There was a slight fall in skin reactivity to UV light during the treatment, but no effect on plasma or urine concentrations of PGE1, cAMP or cGMP. There was no effect of the treatment on ESR, P-fibrinogen, number of tender joints, number of swollen joints, the duration of morning stiffness, or on the patients estimation of pain.

Chemotactic Activity of LTB4 in Man

An improved skin window chamber technique has been developed and used for a quantitative study of the chemotactic effect of leukotriene B4 (LTB4). LTB4 (0.5 μM) was exposed to a skin window on the forearm of eight healthy volunteers, while phosphate buffered saline served as control in a skin window on the other forearm. Skin window exudates and samples of blood draining the skin window areas were collected after 1, 2, 4, 8, and 24 h. The samples were quantitated for the different types of leukocytes as well as the intra‐ and extracellular concentration of the eosinophilic cationic protein and lactoferrin as markers of eosinophil and neutrophil granulocytes. A significantly increased migration of neutrophil granulocytes into the skin window chamber containing LTB4 was found from the 2nd to the 8th hour after the initial LTB4 exposure. The eosinophils reached a significant peak at the 4th hour. The rise in the actual number of eosinophil cells did not reach significance, whereas measurements of the eosinophilic cationic protein in the cellular fraction of the exudate exhibited a significant increase as a reflection of the number of eosinophils. This highlights the potential clinical value of eosinophilic cationic protein measurements to reveal eosinophilic instead of the traditional eosinophil counts. Extracellular eosinophilic cationic protein and lactoferrin did not change significantly in the LTB4‐exposed skin window, implying that LTB4 does not activate the eosinophils and neutrophils to exocytosis of their enzymes. The present in vivo results support the concept of LTR4 being a potent chemoattractant to neutrophil and less so to eosinophil granulocytes in humans, a chemoattractant that recruits the leukocytes but does not seem to activate them.

PHARMACOLOGICAL STUDIES IN CUTANEOUS INFLAMMATION IN MAN USING AN IN VIVO PERFUSION METHOD

THE problem of pharmacological mediators of inflammation still remains unsolved despite the isolation and characterization of an increasingly wide range of naturally occurring vasoactive substances. This subject has recently been reviewed by Spector and Willoughby (1968).

Prostaglandins in Normal and Pathological Skin

T h e skin has served as a focus for miiltidiseiplinary research on prostaglandins for the past 5 years and several review articles (Fulghum 1970, Kumar & Solomon 1972, S0ndergaard 1973, Ziboh 1973b) have already coveted some dermatologieal aspects of the prostaglandins. The almost geometrieally increasing studies on prostaglandins have thrown so much new light on normal skill function and pathological skin conditions that it seems pertinent to review the subject. The aim of the present review is to survey the recent research developments in the prostaglandins related to dermatology. For more comprehensive reviews on prostaghinditis providing a key to non-dermatological areas the reader is referred to monographs by von Euler & Eliasson (1967), Ramwcll & Shaw (1970) and Ramwell (1973). It is eonvenient to divide this review into two main sections, dealing with experiments on normal and pathological skin. It is desirable to recall briefly some important teatures of structure, biosynthesis, metabolism, adenyl eyclase relationships and antagonists of the prostaglandins.

Blockade by polyphloretin phosphate of the prostaglandin E1‐induced human cutaneous reaction

The effect of polyphloretin phosphate (PPP) on the human cutaneous reaction induced by prostaglandin E1 (PGE1) has been studied in thirty subjects. Pre‐treatment of the skin with three intradermal injections of 1oo μg PPP reduced by 37% the magnitude of the erythema induced by intradermal injection of 1 μg PGE1. The PGE1induced weal, which is probably mainly due to PGE1‐induced endogenous histamine release, was not reduced. The specific nature of the PG‐blocking activity of PPP was supported, since PPP did not block the erythema and weal induced by intradermal injection of histamine and bradykinin. Intravenous injection of 100 mg PPP did not reduce the erythema due to intradermal injection of PGE1 probably because of too low tissue concentration of PPP.

The effect of leukotrienes C4 and D4 on microcirculatory flow in humans

By quantifying the flare response, leukotrienes LTC4 and LTD4 were shown to increase the microcirculatory flow in a sigmoidal dose‐response relation over the dose‐range of 6‐25‐800 pmol. LTD4 was found to be more potent than LTC4 after 5 min, but not after 15 min, as estimated by this method. Laser‐Doppler flowmeter studies confirmed that LTD4 is a more potent vasodilator than LTC4.

Electron microscopic cytochemical demonstration of adenyl cyclase activity in psoriatic epidermiso

SummaryIsoproterenol and sodium fluoride stimulated adenyl cyclase activity was detected in epidermal tissue from 2 patients with untreated psoriasis by an electron microscopic cytochemical technique. Adenyl cyclase activity was present on the outer surface of the cell membranes, predominantly in the basal cells and in the 4–5 lower Malpighian cell layers, while the superficial layers, stratum granulosum and stratum corneum showed no activity. The precipitates (lead-PPi complexes) after isoproterenol stimulation were larger and fewer in number than those seen after sodium fluoride stimulation. Isoproterenol stimulation was abolished by propranolol. Neither the uninvolved epidermis from the 2 patients with psoriasis nor the normal skin from 2 volunteer individuals showed any difference from the psoriatic epidermis.ZusammenfassungDurch Isoproterenol und Natriumfluorid stimulierte Adenylcyklaseaktivität wurde in der Epidermis von 2 Patienten mit unbehandelter Psoriasis mittels einer cytochemischen elektronenmikroskopischen Technik nachgewiesen. Adenylcyklaseaktivität war in den Außenflächen der Zellmembranen vornehmlich bei Basalzellen und in den vier unteren Schichten des Stratum malphigi festzustellen. Demgegenüber war in den oberen Zellagen einschließlich Stratum granulosum und Stratum corneum keine Aktivität festzustellen. Die Präzipitate Blei-PPI Komplexe nach Isoproterenolstimulierung waren größer, aber geringer in der Zahl als solche, die nach Natriumfluoridstimulation sich bildeten. Die Isoproterenolstimulierung wurde durch Propanol zum Verschwinden gebracht. Weder die nicht befallene Epidermis bei Patienten mit Psoriasis noch die normale Haut von 2 Freiwilligen zeigten irgendwelche Unterschiede zur psoriatisch veränderten Epidermis.