PaulineM. Dowd

Deficiency of calcitonin gene-related peptide in Raynaud's phenomenon

Skin biopsy samples from the fingers of nine patients with primary Raynauds phenomenon, nine with the disorder associated with systemic sclerosis, and eleven healthy controls were examined by immunocytochemistry. There were no differences between the groups in the distribution of PGP 9.5 (a pan-neuronal marker) immunoreactivity, but there was a significant reduction in the number of calcitonin gene-related peptide (CGRP) immunoreactive neurons in the skin of patients with primary Raynauds phenomenon and those with systemic sclerosis. These findings implicate dysfunction of the CGRP neurovascular axis in the pathophysiology of Raynauds phenomenon.

Leukotrienes C4 and D4 psoriatic skin lesions

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.

Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon

It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynauds phenomenon (RP). Both endothelin‐1 (ET‐1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature. and calcitonin gene‐related peptide (CGRP). a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET‐1 levels are raised, and there is a diminution of CORP‐containing perivascular nerves in linger skin in RP

The role of chemo-attractant lipoxygenase products in the pathogenesis of psoriasis.

The histopathology of chronic, stable plaque psoriasis is characterized by acanthosis with mitotic figures in the lower epidermis, abnormalities of differentiation, vascular dilatation and tortuosity, and leukocyte infiltrates. These infiltrates are composed of neutrophils and mononuclear cells, the former apparently migrating from the dermal papilla, through the Malpighian layer and into the parakeratotic stratum corneum. Mononuclear cells are evident in the superficial dermis and in the lower half of the epidermis (Ragaz & Ackerman, 1979; Soltani & Van Scott, 1972; Helwig, 1958; Pinkus & Mehregan, 1966). The nature of the earliest histopathological change in developing psoriatic lesions is the subject of controversy with, for example, one group (Chowaniec et al, 1981) reporting infiltration of polymorphonuclear leukocytes into the epidermis to be the earliest change, another (Ragaz & Ackerman, 1979) finding a superficial perivascular lymphocyte infiltrate, and yet another (Brody, 1984a, b) reporting mast cell degranulation as the primary event in acute guttate psoriasis. In addition, Braun-Falco and Schmoeckel (1977) found macrophages to be the predominant infiammatory cells in initial psoriatic lesions. In postulating a role for an endogenously released chemical mediator in the genesis of a pathological change, it is important (i) to recover elevated levels of the mediator from the involved tissue in vivo at an appropriate time, (2) to reproduce at least in part the pathological change by introduction ofthe mediator into the tissue in vivo, in appropriate concentrations, (3) to demonstrate mechanisms for the release and removal of the mediator in the involved tissue, (4) to modify the pathological process by administration of specific enzyme inhibitors or receptor antagonists in vivo, (5) to determine the relative amounts of other chemical mediators with similar modes of action in the involved tissue in vivo and (6) to determine whether production ofthe mediator occurs in other lesions, i.e. whether it is specific to the pathological process under study. It is noteworthy that most ofthe above, which are an extension ofthe criteria of Dale (1934), can only be investigated by in vivo studies. We have chosen to examine the role of acidic lipid neutrophil chemo-attractants in the pathogenesis ofthe infiammatory changes in chronic plaque psoriasis. The evidence obtained to date is presented here in six sections, according to the above criteria.

Further studies on the actions of endothelin-1 on blood flow in human skin.

Summary When injected into human skin, endothelin‐1 produces intense vasoconstriction localized to the site of the injection, but this area of vasoconstriction is surrounded by vasodilatation which spreads several centimetres from the injection site. The vasodilatation induced by intradermal injection of endothelin‐1 (63 pmol) into human skin is prevented by local anaesthetic. Pretreatment of human skin with capsaicin also inhibits this response. Pretreatment of subjects with the selective histamine H1‐receptor antagonist cetirizine, 10 mg orally 4 h before intradermal injections, inhibited vasodilatation caused by the intradermal injection of histamine (750 pmol), endothelin‐1 (63 pmol), and carbachol (750 pmol). Endothelin‐l (0.3–10 μm) and carbachol (1–30 μm) failed to induce histamine release from rat peritoneal mast cells. We conclude that the vasodilatation caused by intradermal injection of endothelin‐1 into human skin is neurogenic and is probably mediated by neuropeptide‐containing primary afferent neurones. Because neither carbachol nor endothelin‐1 cause histamine release from mast cells, our data suggest that histamine release from mast cells at the effector end of the axon reflex is responsible for the carbachol‐ and endothelin‐induced vasodilatation in human skin.

Raynaud's phenomenon, calcitonin gene-related peptide, endothelin, and cutaneous vasculature

I tested this hypothesis in 63 women consecutively having ELA for treatment of menorrhagia. A Weck-Baggish hysteroscope was used (Weck, ER Squibb, New Jersey). This hysteroscope had separate inflow, outflow, and laser fibre channels allowing a satisfactory fluid infusion system to be established. A standard laser regimen with a ’Surgical Laser Technology CL100 Nd-YAG’ laser (Malvern, USA)8 was used. In 30 women (group A) fluid was infused continuously by means of a simple roller pump. In the other 33 women (group B) fluid was pumped into the cavity with a ’Hamou Hysteromat’ (Karl Stortz, Tuttinglheim, Germany), consisting of a roller pump connected to a pressure transducer that allows control of intrauterine pressure. If the preset level is reached the roller pump is progressively slowed until the predetermined limit is regained. The closed pressure-controlled infusion system (group B) was associated with a reduction of 21% in treatment time, 39% in the volume of fluid infused, 86% in the volume absorbed, and 82% in the rate of fluid absorption: Mean Mean Mean Rate treatment volume volume fluid No with time infused absorbed absorbed fluid Group (min) (ml) (ml) (ml/min) balance A 28 5326 1537 57 z%) ) B 22 3245 219* 10* 18 (SS % )*

The Inflammatory Properties of Eicosanoids in Human Skin

Arachidonic acid metabolites have been implicated as mediators of both the vascular and cellular components of inflammatory processes. The importance of prostaglandins as pro-inflammatory agents was highlighted by the discovery that non-steroid anti-inflammatory drugs are cyclo-oxygenase inhibitors (1–3). Research into the role of eicosanoids as mediators of inflammation has been extended in recent years following the characterisation of biologically active products of arachidonate lipoxygenase systems. The formation of these lipoxygenase products is not significantly inhibited by conventional non-steroid anti-inflammatory drugs in doses which inhibit the cyclo-oxygenase system.