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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 235 records · Page 13Linked to original sources
PubMed1992

Differential regulation of tyrosine hydroxylase, neuropeptide Y and galanin gene expression in the pons and medulla oblongata following chronic oral administration of 2% saline: a combined in situ hybridisation and immunohistochemical study.

In situ hybridisation histochemistry and immunohistochemistry was used to study the response of the noradrenergic A6 and A2 cell groups in the rat following oral administration of 2% saline for 12 days. Messenger ribonucleic acid (mRNA) encoding tyrosine hydroxylase and neuropeptide Y increased by 85 and 65%, respectively (p less than 0.05) in A6, while levels in A2 were unaltered after saline ingestion. The observed changes in mRNA were accompanied by increased expression of neuropeptide Y and tyrosine hydroxylase immunoreactivities in A6 neurons, whereas A2 neurons were unaffected. In contrast, mRNA encoding galanin, which is also colocalised with noradrenaline in A6 cells, was unaltered by osmotic stimulation. Our results suggest that noradrenaline and neuropeptide Y transmitter systems in the A6 group are activated whereas the galanin transmitter system remains unaffected during saline ingestion.

Animals↗
PubMed1992

Dexamethasone and aldosterone modulate corticotropin-releasing factor-41 release from cultured rat fetal hypothalamic cells through type II and type I corticosteroid receptors respectively.

Dexamethasone and aldosterone inhibit hypothalamic corticotropin releasing factor-41 (CRF) release. The possible receptors through which these adrenal steroids affect CRF release were studied using rat fetal hypothalamic cell cultures. Neither the antimineralocorticoid RU 28318 nor the antiglucocorticoid RU 38486 alone had any effect on forskolin-stimulated CRF release. RU 38486 and RU 28318 however suppressed dexamethasone (1 microM)- and aldosterone (1 microM)-induced inhibition of forskolin (20 microM)-stimulated CRF release, respectively, suggesting that dexamethasone and aldosterone reduce CRF release through type II and type I corticosteroid receptors, respectively. RU 38486 had no effect on aldosterone-induced inhibition of forskolin-stimulated CRF release, nor did RU 28318 have any effect on dexamethasone-induced inhibition of forskolin-stimulated CRF release, indicating specificity of the binding of aldosterone with type I receptors, and dexamethasone with type II receptors in the hypothalamic cell cultures.

Aldosterone↗
PubMed1992

Mechanisms of norepinephrine mediated corticotropin-releasing factor-41 release from cultured fetal hypothalamic cells.

Catecholamines have been shown to activate hypothalamic corticotropin-releasing factor-41 (CRF) synthesis and release. In order to study the mechanisms involved, fetal hypothalamic cells were cultured and CRF release was measured by radioimmunoassay. Norepinephrine (NE) induced CRF release in a dose-dependent manner. Further studies were performed with a protein kinase C inhibitor, H-7(1-(5-isoquinolinesulfonyl)-2-methylpiperazine) and a protein kinase A inhibitor, IP-20. NE-stimulated CRF release was reduced by H-7 (5 and 50 microM) in a dose-dependent fashion, while 5 microM IP-20 resulted in a small but significant inhibition. Pretreatment of the cells for 15 h with 20 and 200 nM 12-O-tetradecanoylphorbol-13-acetate, which down-regulates protein kinase C activity, blocked the release of CRF in response to NE (1 microM), further supporting protein kinase C as a mediator for NE-activated CRF release. Pretreatment with 50 and 500 ng/ml pertussis toxin (15 h) resulted in a dose-dependent inhibition of NE-activated CRF release. Both dexamethasone and aldosterone at the concentrations of 1 microM reduced NE-induced CRF release. These results suggest that CRF can be released from hypothalamic neurons in response to NE through both protein kinase C- and protein kinase A-dependent mechanisms, and that pertussis toxin-sensitive G-proteins are also involved in this response. Furthermore, glucocorticoids and mineralocorticoids can reduce NE-activated CRF release from cultured hypothalamic cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Suckling is a persistent stimulus to the adrenocortical system of the rat.

The present experiments investigated the hypothesis that lactation constitutes a chronic stress to the adrenocortical system. To determine whether the normal circadian control of the adrenocortical system or the ability to mount an adequate ACTH response to stress are modified during lactation, we compared morning and evening basal and stress-induced ACTH, corticosterone (B), and PRL secretion as well as pituitary ACTH content and thymus weight in virgins and lactating females on day 10 of lactation. We also compared the capacity of B to suppress ACTH secretion in adrenalectomized virgin or lactating females, both given various B pellet replacement doses (40-130% B) for 5 days. In addition, we investigated the influence of decreased litter size and increased caloric intake on basal circadian activity in the adrenocortical system. Finally, we measured suckling-induced activation of ACTH and B release and restoration of basal morning ACTH and B levels after pup separation. In all 10-d lactating females, basal PRL levels were elevated compared to virgins and the circadian rhythm observed in virgins (P less than 0.05) was absent in all lactating females. By contrast, diurnal variations in ACTH and B secretion (P less than 0.05 or 0.01) were observed in all females regardless of lactation and changes in caloric intake or litter size. Plasma ACTH and B were elevated during the trough of the diurnal rhythm in mothers, compared to virgins. The amplitude of the increase in ACTH between trough and peak was greater in mothers than virgins; however, the amplitude of the increase in plasma B was greater for virgins than mothers, probably because of the higher levels of corticosteroid binding globulin in the former. Diurnal rhythms in stress responsiveness and sensitivity of ACTH to B feedback were normal in mothers; however, the magnitude of their ACTH, B, and PRL response to ether stress was less in mothers than virgins. Attempts to normalize basal ACTH and B concentrations by increasing calorie consumption were unsuccessful. However, we found that suckling caused marked stimulation of ACTH and B secretion; moreover, within 24 h after pups removal, trough ACTH and B concentrations were restored to normal values.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗
PubMed1992

Paradoxical responses of hypothalamic corticotropin-releasing factor (CRF) messenger ribonucleic acid (mRNA) and CRF-41 peptide and adenohypophysial proopiomelanocortin mRNA during chronic inflammatory stress.

We have determined the time course of the neuroendocrine response of Piebald-Viral-Glaxo (PVG) rats during the development of mycobacterially induced adjuvant arthritis. Anterior pituitary POMC mRNA increased at the time of onset of mycobacterially induced arthritis, but, paradoxically, coincident with the first signs of arthritis there was a consistent fall in CRF mRNA in the hypothalamic paraventricular nucleus. Coincident with this fall in CRF message, there was a corresponding decrease in CRF-41 peptide release into the hypophysial portal blood (HPB). In contrast, however, vasopressin release into the HPB was increased. There was an increase in adrenal weight associated with the development of arthritis, reflecting chronic activation of the HPA axis, which was reflected by increased circulating corticosterone concentrations. The synthetic adjuvant CP20961, which has different antigenic determinants, also caused an increase in POMC mRNA in the anterior pituitary, a decrease in CRF mRNA in the hypothalamic paraventricular nucleus, and a decrease in CRF-41 peptide release into the HPB in PVG rats 28 days after the induction of the arthritis. The arginine vasopressin level was not significantly different from the control value. In Sprague-Dawley rats, mycobacterial adjuvant resulted in a similar increase in POMC mRNA in the anterior pituitary 28 days after injection of the adjuvant. In this strain of rat there was no corresponding change in CRF mRNA. While there are some strain differences in the degree of change in CRF mRNA, both strains showed a common paradox of a marked increase in adenohypophyseal POMC mRNA not associated with increased CRF mRNA or peptide release. In the PVG strain of rat, CRF actually appears to be inhibited. The mechanisms involved in this disparity are unclear.

Adrenal Cortex Hormones↗
PubMed1992

Chronic activation of the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm during adjuvant-induced arthritis in the rat.

Adjuvant-induced arthritis (AA) in Sprague-Dawley rats resulted in a chronic increase in plasma levels of ACTH and corticosterone (B). Joint inflammation became clinically apparent between days 12-15 after injection of adjuvant and reached a peak on day 21, after which time it subsided. In AA animals, plasma ACTH and B levels in the morning (0800-0900 h) on days 7, 8, 9, and 21 were significantly higher than those in control animals (day 0). The corresponding evening ACTH and B levels in AA animals were not significantly different from evening levels in the control animals. Adrenal weight in AA animals was increased on day 21, while thymic weight diminished gradually from days 7-21 postinjection. Development of AA was associated with activation of the hypothalamo-pituitary-adrenal axis, with increased morning ACTH and B levels and abolition of normal diurnal ACTH and B rhythms. This model of chronic inflammatory stress clearly activates the ACTH drive despite increased corticosteroid feedback in the morning, resulting overall in chronically increased B secretion.

Adrenocorticotropic Hormone↗
PubMed1992

Growth hormone-releasing hormone transcripts in human pituitary adenomas.

We have investigated the possibility that local production of GHRH within the adenohypophysis could be an aetiological factor in the development of human pituitary somatotroph and other tumours. We examined 51 human pituitary adenomas for GHRH transcripts using in situ hybridization histochemistry. GHRH transcripts were identified in 13 of 17 somatotroph adenomas, 4 of 10 corticotrophs, 1 of 6 lactotrophs and 1 of 18 endocrinologically inactive adenomas. In 11 GHRH-expressing somatotroph adenomas, SRIH transcripts were also identified. In all cases except one (a corticotroph adenoma) the average number of GHRH transcripts exceeded that found in the arcuate nucleus of simultaneously hybridized rat brain sections. In some pituitary adenomas, GHRH transcripts were clearly localized to a discrete subpopulation of cells and in these, the amount of GHRH mRNA per cell was comparable to that found in the GHRH-expressing cells of the rat arcuate nucleus. Although we have not directly demonstrated an association between the two, the identification of localized, high level GHRH gene expression in somatotroph adenomas suggests that GHRH may have a role in pituitary adenoma formation.

Adenoma↗
PubMed1992

Glucocorticoid-mediated responses of plasma ACTH and anterior pituitary pro-opiomelanocortin, growth hormone and prolactin mRNAs during adjuvant-induced arthritis in the rat.

Adjuvant arthritis (AA) in the rat leads to chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the loss of its diurnal rhythmicity. We have investigated the effects of adrenalectomy (ADX) and different levels of corticosterone replacement upon plasma ACTH levels and anterior pituitary pro-opiomelanocortin (POMC), GH and prolactin mRNAs during the development of AA. In control ADX animals, we observed the negative feedback effects of exogenous corticosterone on plasma ACTH and anterior pituitary POMC mRNA. In the ADX animal with AA, however, the increased POMC mRNA which was observed was not reduced by exogenous corticosterone on day 7 of AA, although the negative feedback effect of corticosterone on plasma ACTH was intact. On day 14, however, even high dose corticosterone replacement failed to have a significant feedback effect on the raised levels of plasma ACTH. In control ADX animals, corticosterone replacement resulted in increased anterior pituitary GH mRNA and reduced prolactin mRNA. In contrast, in ADX animals with AA, GH mRNA was reduced and there was a further decrease in prolactin mRNA. In these animals, corticosterone replacement did not affect GH or prolactin mRNA expression. These data demonstrate a disruption of the normal mechanisms underlying feedback inhibition of the HPA axis by glucocorticoids during AA. Similarly, the glucocorticoid-dependent regulation of GH and prolactin mRNA expression is altered in AA.

Adrenalectomy↗
PubMed1992

Release of corticotrophin-releasing factor-41, arginine vasopressin and oxytocin from rat fetal hypothalamic cells in culture: response to activation of intracellular second messengers and to corticosteroids.

The effects of the activation of protein kinase A (PKA), protein kinase C (PKC) and corticosteroids were investigated on the release of corticotrophin-releasing factor-41 (CRF), arginine vasopressin (AVP) and oxytocin from rat fetal hypothalamic cells in culture. Both forskolin and PMA (phorbol 12-myristate 13-acetate) increased CRF, AVP and oxytocin release, while dexamethasone and aldosterone only reduced basal secretion of CRF. Both steroids also inhibited forskolin-induced CRF, AVP and oxytocin responses to PMA. These data provide direct evidence for a role for both PKC- and PKA-mediated mechanisms in the regulation of CRF, AVP and oxytocin release and for differential effects of both glucocorticoids and mineralocorticoids on PKA- and PKC-stimulated responses.

Adrenal Cortex Hormones↗
PubMed1992

Effect of food deprivation and altered thyroid status on the hypothalamic-pituitary-thyroid axis in the rat.

Propylthiouracil (PTU) was administered to rats for different lengths of time with or without food deprivation on the last 2 days. Within 4 days of PTU treatment peripheral 3,5,3'-tri-iodothyronine (T3) fell to low levels and beta-subunit of thyroid-stimulating hormone (beta-TSH) mRNA increased significantly in the anterior pituitary. Pro-thyrotrophin-releasing hormone (pro-TRH) mRNA in the hypothalamic paraventricular nucleus (PVN) increased significantly in the control group of animals by 8 days and in the food-deprived group by day 12; the increment of pro-TRH mRNA in the food-deprived group on day 12 was significantly less than that in the control group. In a second study, animals were treated with intraperitoneal injections of T3 with or without the food deprivation. After 4 days of T3 treatment, peripheral T3 levels were markedly increased and pro-TRH mRNA in the PVN and beta-TSH mRNA in the anterior pituitary were significantly reduced. Food deprivation had no additional suppressive effect. These studies confirm that the predominant effect of food deprivation on the thyroid axis is at the hypothalamic or suprahypothalamic level and that it can, at least in part, overcome the increase in TRH mRNA due to diminished T3 feedback.

Animals↗
PubMed1992

The effects of recombinant human interleukin (IL)-1 alpha, IL-1 beta or IL-6 on hypothalamo-pituitary-adrenal axis activation.

We have investigated the effects of recombinant human interleukin (IL)-1 alpha, IL-1 beta and IL-6 on the activation of the hypothalamo-pituitary-adrenal axis. We have determined the effects of a single i.p. injection of cytokine on circulating ACTH and corticosterone levels, corticotrophin-releasing factor (CRF) mRNA in the parvocellular cells of the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary at both 4 h and 24 h after injection. IL-1 alpha had no effect on any of the parameters measured at either time-point. In contrast, IL-1 beta increased CRF mRNA in the parvocellular paraventricular nucleus and POMC mRNA in the anterior pituitary 4 h after injection. Plasma ACTH and corticosterone were increased at 4 h and circulating ACTH was still increased at 24 h after treatment with IL-1 beta. IL-6 had no effect on message levels but did increase circulating ACTH and corticosterone levels both 4 h and 24 h after injection. The mechanism responsible for the increase in circulating ACTH after IL-6 injection is unclear but would appear to be different from that which is activated by IL-1 beta which also results in increased CRF and POMC gene expression.

Adrenocorticotropic Hormone↗
PubMed1992

Distribution of relaxin between human maternal and fetal circulations and amniotic fluid.

Relaxin was measured in maternal blood and amniotic fluid samples at 9-40 weeks and in fetal blood samples at 19-41 weeks of pregnancy. In amniotic fluid, concentrations of relaxin rose from 58 ng/l (geometric mean) at 10 weeks to 142 ng/l at 14 weeks and declined subsequently to 55 ng/l at 22 weeks. In maternal blood, mean relaxin concentrations were ten times greater than in amniotic fluid, and concentrations decreased with gestation. Since there was no significant association between the relaxin concentrations in the two compartments, relaxin in the amniotic fluid may be derived from the decidualized endometrium rather than the maternal circulation, alternatively its metabolism may be different in the two compartments. The absence of detectable concentrations of relaxin in any of the fetal blood samples demonstrates that there is no significant placental transfer or fetal synthesis of this peptide.

Amniotic Fluid↗
PubMed1992

Distribution of IL-2R and CD45Ro expression on CD4+ and CD8+ T-lymphocytes in the peripheral blood of patients with posterior uveitis.

Different lines of evidence support a major role for activated T-lymphocytes in the pathogenesis of posterior uveitis. The initial site of activation of these autoreactive T-cells, either locally in the eye or in the peripheral immune compartment, is still unknown. This study was undertaken to investigate whether with currently available techniques, it is possible to detect alterations in the levels and subsets of activated T-cells in the peripheral blood of patients with posterior uveitis. For this reason, 3-colour immunofluorescent staining was performed to assess the distribution of IL-2 receptors (IL-2R) and the CD45RO-antigen on CD4+ and CD8+ subsets of peripheral blood lymphocytes (PBLs) from patients with posterior uveitis (n = 29). Only the subgroup of patients with posterior uveitis as part of a systemic immune-mediated disease (sarcoidosis, Behçet's disease) (n = 9) showed a significant increase in IL-2R expression on peripheral blood lymphocytes (p less than 0.005) when compared to normals (n = 12). This increased expression was reflected much more significantly in the CD4+ (p less than 0.0005) rather than in the CD8+ subset (p less than 0.05) of lymphocytes. In contrast, no significant increase in CD45RO expression on either subset of T lymphocytes was found in any subgroup of posterior uveitis in comparison with normals.

Antibodies, Monoclonal↗
PubMed1992

CD4+ lymphocyte involvement in ocular Behçet's disease.

Despite extensive study, the pathogenic mechanisms of Behçet's disease remain uncertain. The ocular inflammation caused by this disease is severe, often causing significant visual loss and, although the nature of the cellular infiltrate has been examined in many of the involved organs, the infiltrating cells in inflamed eyes have not. To investigate the mechanisms involved in perpetuating the ocular inflammation, five enucleated eyes from patients with Behçet's disease were examined by immunohistochemical staining using a panel of monoclonal and polyclonal antibodies. Control eyes from patients with chronic intraocular inflammation from other causes were also examined. Cellular infiltrates were a consistent finding in choroid and periretinal scar tissue, formed almost entirely by mononuclear cells. T lymphocytes were found to predominate (largely the CD4+ subset). B lymphocytes and NK cells were infrequent findings but macrophages were present in significant numbers. No complement or immunoglobulin deposits were found. Infiltrating lymphocytes and macrophages were HLA DR positive. Retinal vascular and retinal pigment epithelium were only occasionally positive. Our findings suggest that cell mediated immunity, rather than immune complex deposition is responsible for the perpetuation of the ocular inflammation in Behçet's disease and that CD4+ T lymphocytes play a central role in this.

Adolescent↗
PubMed1992

Interferon-gamma (IFN-gamma) production in vivo in experimental autoimmune uveoretinitis.

Experimental autoimmune uveoretinitis (EAU) is a well-characterized model of immune-mediated intraocular inflammation. The intraocular infiltrate in EAU consists predominantly of T lymphocytes. The in vivo production of interferon-gamma (IFN-gamma) by these T cells was investigated immunohistochemically and by in situ hybridization using a cDNA probe to rat IFN-gamma mRNA. Positive localization of IFN-gamma mRNA began simultaneously with disease onset and increased as the inflammatory tissue destruction progressed. The positive signal was seen on cells in the retina, uveal tract and extraocular region where collections of inflammatory cells contained many T lymphocytes. Numerous cells in these locations also stained positively immunohistochemically for IFN-gamma. These results indicate that the in vivo production of IFN-gamma within the eye could play a role in the immune regulation of intraocular inflammatory disease.

Animals↗
PubMed1991

Corticotrophin-releasing factor and arginine vasopressin in the hypothalamo-hypophyseal portal blood of rats following high-dose glucocorticoid treatment and withdrawal.

Hypothalamo-hypophyseal portal blood was obtained from rats treated with chronic, high-dose prednisolone in the drinking water and after subsequent withdrawal of the steroid for up to 7 days. Corticotrophin-releasing factor (CRF) immunoreactivity in portal blood was reduced by treatment with prednisolone but not completely abolished. There was a rapid recovery of CRF to control values within 3 days of withdrawal of prednisolone. There was no significant change in arginine vasopressin (AVP) in portal blood over the time-course of the experiment.

Animals↗