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Biomedical subjects

P M Dowd

Publications and source records attributed to P M Dowd.

At least 19 recordsLinked to original sources
PubMed1992

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

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-1 (0.3-10 microM) and carbachol (1-30 microM) 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.

Adult↗
PubMed1992

Characterization of histamine receptor sub-types regulating prostacyclin release from human endothelial cells.

1. The histamine receptor sub-types that are involved in the initiation and maintenance of prostacyclin (PGI2) release from human endothelial cells have been investigated. 2. Endothelial cells cultured from umbilical vein (HUVEC) were incubated with either histamine, the selective H1-receptor agonists, 2-methyl histamine (2-MeHA) or thiazolylethylamine (ThEA), the H1-agonist/H3-antagonist, beta-histidine (beta-His), the selective H2-agonist, dimaprit, the H2-agonist/H3-antagonist, impromidine, the selective H3-agonist, (R)alpha-methylhistamine ((R)alpha-MeHA) and the H3-antagonist, thioperamide. 3. The H1-agonists and the H3-agonist (R)alpha-MeHA induced a concentration (100 nM-1 mM) and time-dependent release of PGI2 as determined by radioimmunoassay for 6-keto-PGF1 alpha, but were less potent than histamine itself. The rank order of potency was the same following 30 min and 24 h incubation, i.e. histamine > ThEA > 2-MeHA >> beta-His > (R)alpha-MeHA. 4. Histamine and 2-MeHA (1 microM-1 mM), ThHEA (10 microM-1 mM) and (R)alpha-MeHA (1 mM), but not beta-His, induced a significantly greater increase in PGI2 release after 24 h incubation than after 30 min incubation (P < 0.05). 5. Neither the selective H2-agonist, dimaprit, nor the H2-agonist/H3-antagonist, impromidine alone induced release of PGI2. 6. The H1-antagonist, mepyramine (10 microM), abolished release of PGI2 induced by histamine, the H1-agonists and (R)alpha-MeHA but the H2-antagonist cimetidine (10 microM) and the H2/H3-antagonist, burimamide (10 microM) did not significantly modulate PGI2 release. 7. Although the H3-agonist (R)alphax-MeHA induced release of PGI2, it failed to modulate PGI2 release in the presence of histamine.8. Low concentrations of the H3-antagonist, thioperamide (100 nM) did not modulate histamine release of PGI2 at all but after 24 h incubation, thioperamide (10-4 M) partially reduced PGI2 release in the presence of histamine.9. These results indicate that PGI2 from HUVEC is initiated and maintained via histamine HI-receptor occupancy. There appears to be no involvement of either H2- or H3-receptors in this particular endothelial cell histaminergic response.

Cells, Cultured↗
PubMed1992

The effect of Mycobacterium tuberculosis on the susceptibility of human cells to the stimulatory and toxic effects of tumour necrosis factor.

It has previously been shown that the inherently tumour necrosis factor-alpha (TNF-alpha)-sensitive L929 murine fibroblast cell line becomes much more sensitive to the cytotoxic effect of this cytokine after exposure to Mycobacterium tuberculosis in culture. In this study it is now shown that normal human cells of types likely to be involved in tuberculous lesions are affected in a similar way. Growth of normal human fibroblasts is usually stimulated by TNF-alpha in vitro, but after exposure to M. tuberculosis or to extracts of this organism, these cells are killed rather than stimulated by subsequent exposure to TNF-alpha. Similarly, human endothelial cells become susceptible to doses to TNF-alpha which do not normally affect viability. Moreover this enhancement of sensitivity to TNF-alpha is not confined to its toxicity. Endothelial cells and HeLa cells exposed to M. tuberculosis express increased levels of ICAM-1 after subsequent exposure to TNF-alpha, implying synergy between the two stimuli. It is suggested that these effects contribute to the ability of M. tuberculosis to distort the normal protective role of TNF-alpha so that the cytokine becomes detrimental to the host.

Cell Adhesion Molecules↗
PubMed1991

Image analysis quantification of peptide-immunoreactive nerves in the skin of patients with Raynaud's phenomenon and systemic sclerosis.

Image analysis quantification was used to assess the results of immunocytochemistry for a neuronal marker and neuropeptides in digital skin biopsies from Raynaud's phenomenon (RP) and systemic sclerosis (SS) patients, to verify the possibility of a selective quantitative abnormality of immunoreactive nerves. The field area of specific immunostaining and nerve counts were evaluated on coded specimens, and the data compared by statistical analysis. Nerves immunoreactive for protein gene product 9.5 (PGP), a marker for neuronal elements, were decreased significantly in epidermal and subepidermal layers of digital skin in RP patients (P less than 0.0001). This change was paralleled by a decrease of calcitonin gene-related peptide (CGRP) immunoreactive nerves in the epidermis and around capillaries in the dermal papillae (P = 0.005). In the skin of RP patients, these changes were readily demonstrated by image analysis, although they were not always apparent on visual screening. In digital skin of SS patients, there was a generalized and very significant decrease of PGP, CGRP, and VIP immunoreactivities in all areas (P less than 0.0001). These results demonstrate that neuropeptide-containing nerves are involved in the digital pathology of RP and SS, and that image analysis quantification is an accurate and sensitive method for assessing morphological changes in pathological samples.

Adult↗
PubMed1991

The effect of capsaicin application on mast cells in normal human skin.

Peptides released from sensory nerves during an axon reflex are thought to cause mast cell degranulation, histamine (Hi) release and Hi-induced vasodilatation leading to the flare of the triple response. Capsaicin stimulates peptide release from sensory neurones and causes flare in vivo but does not cause Hi release from mast cells in vitro. The effects of capsaicin on mast cell degranulation in human skin in vivo has been studied by histological examination of skin biopsies after topical capsicin (1%) treatment of stratum corneum-denuded forearm in four volunteers. The results show a significant reduction in the visible numbers of mast cells and the appearance of degranulated mast cells ghosts in the skin six hours after capsaicin application. Since capsaicin itself does not release Hi from mast cells, these data suggest that capsaicin-induced release of peptides from neurones could cause mast cell degranulation.

Adult↗
PubMed1991

Vascular responses to histamine at low temperatures in normal digital skin and Raynaud's phenomenon.

A defective histaminergic dilating system in the digital vasculature has been proposed for the pathophysiology of Raynaud's phenomenon but this is not supported by studies of digital intradermal responses to histamine or agents which cause histamine release. The vascular responses (measured by planimetry and laser Doppler flowmetry) of digital skin over the middle phalanx to intradermal histamine, compound 48/80 and Substance P have now been studied at low temperatures (because it is in the cold that Raynaud's phenomenon occurs) in normal controls and patients with primary Raynaud's phenomenon. A cold-related attenuation of mast cell histamine release by compound 48/80 was observed in both normal and Raynaud's subjects. These results do not support a major histaminergic defect in the pathogenesis of Raynaud's phenomenon.

Adult↗
PubMed1991

Digital cutaneous vascular responses to histamine and neuropeptides in Raynaud's phenomenon.

The pathophysiology of Raynaud's phenomenon is not well defined, but active cutaneous microvascular vasoconstriction and emptying must occur to account for the pallor and are reasons for studying the microvasculature. It has been proposed that there may be a defect in a local histamine vasodilator mechanism. The role of the peptidergic nervous system in Raynaud's phenomenon has not been previously investigated. To study the histaminergic and peptidergic axes in Raynaud's phenomenon, we measured the cutaneous microvascular responses of patients with Raynaud's phenomenon to digital intradermal injections of saline, histamine, the histamine-releasing agent, compound 48/80, substance P, and calcitonin gene-related peptide. We compared these results with those obtained in normal subjects. Intradermal cutaneous microvascular blood flow responses were quantified by planimetry and laser Doppler flowmetry. The results show: a) that in primary Raynaud's phenomenon there is no evidence of local deficiency in histamine release or insensitivity to histamine in the cutaneous microvasculature; and b) that patients with Raynaud's phenomenon react normally to the neuropeptides calcitonin gene-related peptide and substance P, providing a rationale for treating Raynaud's phenomenon with vasoactive peptides.

Adolescent↗
PubMed1991

Blood mononuclear cells from patients with psoriasis exhibit an enhanced adherence to cultured vascular endothelium.

Blood mononuclear cells (MNC) from patients with psoriasis were more adherent to monolayers of endothelial cells prepared from human umbilical cord vein than otherwise similar cells from control subjects. This increase in adherence occurred in the presence (mean 37% increase; p less than 0.01) and absence (mean 47% increase; p less than 0.05) of 10% autologous serum and was not related to the disease severity of the patients. The augmented adhesiveness of the patients' cells was also apparent when using monolayers of endothelial cells isolated from human skin. The levels of immune complexes, complement, alpha 2-macroglobulin, acute phase proteins (alpha 1-acid glycoprotein, C-reactive protein and alpha 1-antitrypsin), and tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), and interleukin-1 beta (IL-1 beta) in the patients' sera were within normal limits. When MNC were added to endothelial monolayers that had been incubated with either TNF alpha or the highest concentration of rIL-1 beta used in the study, both the patients' and control's cells exhibited a similar increase in attachment (p less than 0.01). Pretreatment of endothelium with interferon-gamma did not enhance the attachment of MNC from either group of subjects. The augmented adherence of the patient's MNC appears to be due to an abnormal adhesiveness of the lymphocytes rather than the monocytes and is not related to an enhanced expression of the cell-surface adhesion molecules CD11a/CD18. It is likely that the circulating MNC of psoriatic patients may be predisposed for extravasation into skin.

Cell Adhesion↗
PubMed1991

Endothelin-1 in human skin: immunolocalization, receptor binding, mRNA expression, and effects on cutaneous microvascular endothelial cells.

Endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been implicated in the maintenance of systemic and peripheral vascular tone. We have therefore sought direct evidence of a role for ET-1 in the regulation of blood flow and vascular tone in the human cutaneous microvasculature. Immunostaining for ET-1 was observed in all cutaneous blood vessels of normal human skin including the capillaries of the dermal papillae. Autoradiography showed specific binding of 125I-ET-1 over capillaries and larger blood vessels as well as hair follicles and sweat glands. In situ hybridization with a 32P-labeled RNA probe for ET-1 demonstrated mRNA for ET-1 in cultured human dermal microvascular endothelial cells (HDMEC). In HDMEC, basal release of PGE2 was significantly attenuated by ET-1 (100 pM-100 nM) (p less than 0.05, n = 7) with maximum inhibition in cells incubated with 10 nM ET-1. ET-1 also increased intracellular cAMP in a dose-dependent manner with a significant increase in HDMEC incubated with 100 nM ET-1 (p less than 0.05, n = 4). In HDMEC incubated with 100 nM ET-1, inhibition of PGE2 release was unaffected by the dihydropyridine Ca++ channel antagonist nifedipine or the extracellular Ca++ chelator EGTA, whereas the intracellular Ca++ chelator TMB-8 partially blocked the action of ET-1. In contrast, cAMP accumulation was significantly attenuated by EGTA (p less than 0.05, n = 4), nifedipine (p less than 0.05, n = 4), and TMB-8 (p less than 0.05, n = 4), indicating that the endothelial cell responses to ET-1 are complex and appear to involve both Ca(++)-sensitive and -insensitive pathways. These results provide evidence of an autocrine/paracrine role for ET-1 in the human cutaneous microvasculature.

Calcium↗
PubMed1991

Responses of human dermal microvascular endothelial cells to histamine and their modulation by interleukin 1 and substance P.

The action of histamine on human dermal microvascular endothelial cells and modulation of its effects by the cytokine interleukin-1 and the vasoactive neuropeptide substance P have been investigated. Histamine (10(-6)-10(-3) M) induces release of prostaglandin E2 in a concentration- and time-dependent manner. Prostaglandin E2 release is facilitated principally by histamine H1 receptors as the H1 receptor antagonist pyrilamine attenuates prostaglandin E2 release whereas the H2 receptor antagonist cimetidine only slightly reduces release. In contrast to other cells, the histamine/receptor interaction is not associated with increased intracellular accumulation of the cyclic nucleotides, cyclic AMP, or cyclic GMP. Interleukin-1 induces a concentration-dependent release of prostaglandin E2 following 24 h incubation. However, substance P does not increase release of prostaglandin E2 above baseline. In cells incubated with 1 U/ml human recombinant interleukin 1 alpha for 24 h prior to stimulation with histamine (10(-5)-10(-3) M) for 30 min, there is a significant potentiation of histamine-induced release of prostaglandin E2 (p less than 0.05). Using a solubilized cell sonicate prepared from human dermal microvascular endothelial cells incubated with 1 U/ml human recombinant interleukin 1 alpha for 24 h, conversion of exogenous arachidonic acid into prostaglandin E2 increased by 60.19 +/- 18.28%. Cycloheximide partially reduces the increased conversion but completely blocks interleukin-1-induced release of prostaglandin E2 from intact cells. Substance P does not potentiate histamine-induced release of prostaglandin E2 or increase arachidonic acid conversion. These results demonstrate that human dermal microvascular endothelial cells are responsive to histamine and that interleukin-1, but not substance P, can potentiate histamine-induced release of prostaglandin E2. Interleukin-1 appears to act, at least in part, by regulating the availability of free arachidonic acid. Interactions between histamine and interleukin-1 may be important in the modulation of inflammatory reactions in skin.

Dinoprostone↗
PubMed1991

Isotretinoin and lung function in systemic sclerosis.

During an open prospective study of the synthetic retinoid isotretinoin in ten patients with systemic sclerosis, one patient developed an eosinophilic pleural effusion and two patients were noticed to have asymptomatic deterioration in pulmonary function tests. The pulmonary function of all treated patients was then compared retrospectively with a similar control group of patients not treated with isotretinoin. There was a significantly greater decrease in the 1-s forced expiratory volume and transfer coefficient in the patients with systemic sclerosis being treated with isotretinoin in comparison to the untreated control patients. Studies of lung function in patients treated with isotretinoin for other indications are required.

Adult↗
PubMed1991

The hormonal profile of women with acne and polycystic ovaries.

Most women with acne are found to have polycystic ovaries on high resolution pelvic ultrasonography, but most of these women do not manifest the other classical clinical characteristics of the polycystic ovary syndrome. We have compared the endocrinological profile of women with acne who were found to have polycystic ovaries with that of women with polycystic ovaries who presented to an endocrine clinic with hirsutes or non-dermatological manifestations of the polycystic-ovary syndrome. The group of women with acne had normal serum hormonal concentrations. Unlike other women with polycystic ovaries, they did not have significantly elevated serum concentrations of luteinizing hormone or testosterone. By clinical and endocrinological criteria, patients with acne who have polycystic ovaries appear to be a distinct sub-population of women with polycystic ovaries.

Acne Vulgaris↗
PubMed1991

Transforming growth factor alpha: in vivo release by normal human skin following UV irradiation and abrasion.

Transforming growth factor alpha (TGF alpha) is a keratinocyte-growth-stimulating factor which may have a role in epidermal hyperproliferation, psoriasis, and wound healing. Since increased epidermal proliferation occurs in response to UV radiation, we have measured the amount of TGF alpha in exudates from normal and UVB-irradiated human skin. Cutaneous exudates were obtained using the skin chamber abrasion technique from one side of the back of volunteers (n = 10) with normal skin (collected following skin contact times of 2 and 30 min). Exudates were similarly obtained from the contralateral side of the back at sites irradiated 2 h previously with 3 x the minimum erythemal dose UVB. Levels of TGF alpha were measured by radioimmunoassay. Normal human skin released TGF alpha immediately after abrasion: unirradiated, 63 +/- 18 ng/ml; irradiated, 89 +/- 15 ng/ml. Levels of TGF alpha increased within 30 min to 110 +/- 14 ng/ml in unirradiated skin and to 190 +/- 17 ng/ml in irradiated skin. Irradiated sites at 30-min time points were significantly higher (p less than 0.05) than all other samples. The presence of releasable TGF alpha in normal skin suggests a role for TGF alpha in wound repair mechanisms.

Adolescent↗
PubMed1991

Endothelin-1 in human skin: immunohistochemical, receptor binding, and functional studies.

The morphological distribution of endothelin-1 (ET-1) was investigated in human digital skin biopsies by immunohistochemistry using endothelin antisera, and by in vitro autoradiographic binding studies with 125I-labeled ET-1. In vitro studies on the responsiveness of cutaneous microvascular endothelium were carried out using human dermal microvascular endothelial cells (HDMEC) cultured from neonatal foreskin. Endothelin immunoreactivity was present in the endothelial cells of cutaneous blood vessels, in large and small arteries, veins in the dermis and capillaries, including those of the dermal papillae. Autoradiographic studies showed the presence of 125I-labeled ET-1 binding sites on the blood vessels and sweat glands. In confluent monolayers of HDMEC, ET-1 (100 pM-100 nM) significantly inhibited basal release of prostaglandin E2 (PGE2) (p less than 0.05), while causing a dose-dependent increase of intracellular cyclic adenosine monophosphate (cAMP) levels. cAMP accumulation, induced by 100 nM ET-1, was blocked by extracellular Ca2+ chelator EGTA, the intracellular Ca2+ chelator TMB-8, and dihydropyridine Ca(2+)-channel antagonist nifedipine (p less than 0.05), whereas ET-1 inhibition of PGE2 release was unaffected. These findings indicate that ET-1 may be important in the control of blood flow and vascular tone in the cutaneous microvasculature.

Adult↗