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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 127 records · Page 7Linked to original sources
PubMed1996

Differential regulation of the growth hormone receptor gene: effects of dexamethasone and estradiol.

GH receptor (GHR) expression differs during development between central and peripheral tissues. Peripheral GHR expression is known to be sensitive to gonadal and adrenal steroids, but little is known about their effects on GHR in the central nervous system. We have now studied the effects of estradiol (E2) or dexamethasone on GHR expression in rat arcuate nucleus (ARC) and hippocampus, using quantitative in situ hybridization. Dexamethasone, which strongly down-regulates hepatic GHR expression, had no effect on central GHR transcript abundance, whereas E2 treatment, which stimulates hepatic GHR expression, significantly reduced ARC GHR messenger RNA (mRNA) levels. E2 also increased somatostatin (SS) expression significantly in both ARC and periventricular nuclei but did not reduce ARC GH-releasing hormone (GHRH) mRNA levels. Ovariectomy stimulated GHR and GHRH mRNA levels in the ARC, whereas it lowered ARC SS expression. E2 replacement in ovariectomized animals restored GHRH and SS mRNA levels to control values. Hippocampal GHR mRNA transcripts showed the same response to these endocrine manipulations as seen in the ARC. The induction of hepatic GHR expression by E2 is known to involve the transcription of an alternate 5' untranslated first exon, GHR1. This was readily detectable in the liver using a specific GHR1 probe but could not be detected in any CNS area. Our results show that GHR expression in the CNS is sensitive to regulation by peripheral steroids but that CNS and hepatic expression of GHR is differentially regulated by the same treatments.

Animals↗
PubMed1995

Evidence for a role of pituitary ATP receptors in the regulation of pituitary function.

Despite a rapidly increasing acceptance for a role of ATP as an extracellular mediator in several biological systems, the present report shows that ATP may mediate physiological responses in pituitary cells. We have now been able to demonstrate a specific action of ATP receptors to mediate the release of luteinizing hormone from gonadotropes and have coupled them with further studies that clearly show that ATP can be exocytotically released from cultured rat pituitary cells. Both ATP and UTP (100 microM) caused a > 14-fold increase in the rate of luteinizing hormone release from superfused cells. Adenosine 5'-[alpha, beta-methylene]triphosphate and 5'-[beta,gamma-methylene triphosphate were ineffective, and 2-methylthio-ATP had only a modest stimulatory effect. Homologous and heterologous desensitization occurred with UTP and ATP, and these did not have additive effects. Thus, nucleotides can be effective stimulators of luteinizing hormone release through a single class of ATP receptor (P2U subtype). The calcium ionophore A23187 provoked release of a substantial amount of ATP from pituitary cells in a concentration- and Ca(2+)-dependent manner, which was desensitized by pretreatment with A23187. This implies a possible paracrine and/or autocrine mechanism by which nucleotides may exert their effects on pituitary cells. In conclusion, we have provided strong evidence for a novel role of extracellular nucleotides as mediators in pituitary--in particular, in gonadotrope--function.

Adenosine Triphosphate↗
PubMed1995

Treatment of major depression with metyrapone and hydrocortisone.

Eight inpatients with Major Depression were treated with metyrapone and hydrocortisone in a balanced order placebo-controlled single-blind cross-over study. The hydrocortisone dose (30 mg daily) was a physiological replacement dose and the metyrapone dose was titrated against plasma cortisol in order to keep cortisol within physiological limits. The treatment resulted in a significant reduction in depressive symptoms. This placebo-controlled study replicates the results of several uncontrolled studies but leaves open for further study the mechanism by which the combined administration of metyrapone and hydrocortisone might exert its antidepressant effect.

Adult↗
PubMed1995

Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress.

We have investigated the effects of a chronic inflammatory stress on substance P (SP) levels in the hypothalami of rats given adjuvant-induced arthritis (AA). Fourteen days after injection of Mycobacterium butyricum, substance P concentrations in the paraventricular nucleus (PVN) and median eminence/arcuate nucleus were significantly increased. In AA rats injected intraperitoneally with the specific neurokinin-1 receptor antagonist RP67580, plasma ACTH and corticosterone concentrations were significantly elevated, and corticotropin-releasing hormone (CRH) mRNA in the PVN was increased compared to the AA group which received saline alone. The increases in hypothalamic SP in AA, together with the data demonstrating that HPA axis activity is enhanced in AA following injection of a SP antagonist, are consistent with the hypothesis that SP is acting as an inhibitor of CRH expression in this model of chronic inflammatory stress.

Adrenocorticotropic Hormone↗
PubMed1995

Vasopressin is located within lymphocytes in the rat spleen.

Using dual antigen immunocytochemical staining with a specific antiserum for arginine vasopressin (AVP), we have detected AVP immunoreactivity in clusters of large immunoglobulin (Ig) G-containing cells, probably plasma cells, within the rat spleen, and in smaller cells which are IgG-negative. Vasopressin-positive cells were detected principally throughout the white pulp areas in the subcortical region of the spleen. IgG staining could only be detected within the cells and not on the cell surface, demonstrating that the antiserum is recognising genuine intracellular IgG and not cell surface antigens. Reversed-phase HPLC of spleen tissue extract revealed a single peak of AVP immunoreactivity which co-eluted with the standard. This is the first evidence that AVP is found within lymphocytes of the immune system and provides further information about the important interaction between the endocrine and immune systems.

Animals↗
PubMed1995

Changes in ACTH and beta-endorphin immunoreactivity in immune tissues during a chronic inflammatory stress are not correlated with changes in corticotropin-releasing hormone and arginine vasopressin.

We have previously demonstrated that the chronic inflammatory stress of adjuvant-induced arthritis in rats can alter levels of the neuropeptides adrenocorticotropin (ACTH), beta-endorphin, arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH) in tissues of the immune system. We now present data showing that the patterns of these changes in the spleens and thymuses of Piebald-Viral-Glaxo rats are quite dissimilar throughout the course of the disease. Immunoreactive (ir)-CRH, AVP, ACTH and beta-endorphin were measured by radioimmunoassays in spleen and thymic extracts taken at days 3, 7, 11 and 14 following injection of adjuvant. AVP was increased in the spleen at day 14 compared to the controls (79.4 +/- 4.4 and 60.0 +/- 9.0 fmol/g tissue respectively), but no change occurred in the thymus. CRH contents were increased in the spleen at day 14 (33.4 +/- 3.5) compared to controls (22.1 +/- 2.4 fmol/g tissue), and in the thymus at day 11 (24.0 +/- 2.3) compared to controls (14.1 +/- 2.5 fmol/g tissue). Increases in ACTH content were observed in spleens from arthritic rats at days 3 (365 +/- 23), 11 (359 +/- 32) and 14 (355 +/- 45 fmol/g tissue) compared to controls (198 +/- 37 fmol/g tissue). In the thymus, however, ACTH was elevated only at day 14. Beta-Endorphin levels in the spleen were elevated only at day 14 (289 +/- 41) compared to controls (97 /+- 22 fmol/g tissue).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1995

Antigen presentation by rat brain and retinal endothelial cells.

Brain and retinal endothelial cells (EC) form the blood-brain and vascular blood-retinal barriers, respectively, and are believed to play a role in mediating T cell responses in the central nervous system. In this study, Lewis rat retinal and brain EC grown in vitro were capable of expressing MHC class II I-A but not I-E molecules following treatment with interferon-gamma. In the presence of their antigen, CD4+ antigen-specific T cells were able to mediate lysis of retinal EC monolayers to a similar extent as brain EC. T cell proliferation was poorly supported by confluent retinal or brain EC monolayers, but subconfluent EC monolayers supported proliferation in a MHC class II (I-A)-restricted manner (P < 0.001). Exposure of T cells to confluent retinal EC monolayers resulted in them becoming less responsive to subsequent antigen presentation by thymocytes. Conversely, pre-exposure with subconfluent EC had no such effect. These results suggest that a non-proliferating EC monolayer is able to downregulate T cell responsiveness which may have important implications during lymphocyte traffic across the blood-tissue barriers of the central nervous system.

Animals↗
PubMed1995

Water deprivation in the rat induces nitric oxide synthase (NOS) gene expression in the hypothalamic paraventricular and supraoptic nuclei.

We examined the effects of water deprivation on nitric oxide synthase (NOS) gene expression in the rat hypothalamic paraventricular (PVN) and supraoptic nuclei (SON), using in situ hybridization histochemistry. Dehydration caused a significant increase in NOS gene transcripts in the PVN and SON but not in the subfornical organ (SFO). The results suggest that dehydration has a major effect on the NOS gene expression in the PVN and SON.

Animals↗
PubMed1995

Visual acuity following extracapsular cataract extraction in diabetes: a meta-analysis.

Although pre-operative retinopathy severity appears to be a major factor in determining the visual outcome of diabetic extracapsular cataract extraction, its precise relationship to post-operative visual acuity is ill defined. A meta-analysis was therefore carried out, and studies were included if pre-operative maculopathy and retinopathy status was sufficiently defined to permit discrimination of visual outcome between subgroups. Weighted mean proportions of eyes achieving a post-operative visual acuity > or = 6/12 were as follows: no retinopathy, 87%; non-proliferative retinopathy with no maculopathy, 80%; quiescent proliferative retinopathy with no maculopathy, 57%; non-proliferative retinopathy with maculopathy, 41%; quiescent proliferative retinopathy with maculopathy, 11%; active proliferative retinopathy, 0. Differences in visual outcome between groups were significant (chi 2 = 119.9, p < 0.0005), attributable mostly to the trend across groups (chi 2 for trend = 115.4, p < 0.0005). Logistic regression indicated that maculopathy was a more potent predictor of post-operative visual acuity < or = 6/12 (odds ratio 6.4, 95% CI 4.13-9.94, p < 0.0005) than quiescent proliferative retinopathy (odds ratio 3.33, 95% CI 2.04-5.42, p < 0.0005). The severity of retinopathy and maculopathy prior to cataract surgery in diabetics are the major determinants of post-operative visual acuity. Further study of the relationship between pre-operative retinopathy severity and the incidence of post-operative complications, progression of retinopathy and maculopathy is required to optimise the management of cataract in diabetes.

Cataract Extraction↗
PubMed1995

A protective role for testosterone in adjuvant-induced arthritis.

We have investigated the role of the gonadal steroids testosterone (T) and progesterone in modulating: (1) the onset and severity of adjuvant-induced arthritis (AA), (2) the response of the hypothalamo-pituitary-adrenal (HPA) axis, and (3) the levels of plasma prolactin and anterior pituitary prolactin messenger ribonucleic acid (mRNA) in the rat. Male rats were castrated (CSX) and received either no T, low T or high T delivered using silastic implants. In a second study experimental groups comprised CSX/AA, CSX/AA + progesterone or CSX/AA + progesterone + T. The time of onset was sooner and the severity of AA was greater in CSX rats. Inflammation was prevented by T replacement. Endogenous plasma T levels were decreased in AA rats. In control animals with AA there was an increase in pro-opiomelanocortin (POMC) mRNA in the anterior pituitary and of plasma corticosterone, and a decrease in corticotrophin-releasing factor (CRF) mRNA. These changes in the HPA axis of AA and CSX/AA rats were reversed by T replacement. These data suggest that T has an important protective effect on the progress and severity of AA. This was reflected by a reversal of the neuroendocrine changes of the HPA axis. Progesterone treatment alone had no effect on the severity of the disease. Prolactin mRNA in the anterior pituitary was decreased in the CSX and in the CSX/AA group but was not altered by AA. Plasma prolactin was raised in AA but T replacement did not reduce these elevated levels despite the absence of disease. Thus, prolactin provides a poor indicator of inflammation, suggesting that it may not be a potent pro-inflammatory compound in AA.

Analysis of Variance↗
PubMed1995

Mast cell distribution and neutral protease expression in acute and chronic allergic conjunctivitis.

Allergic eye disease has a variety of clinical manifestations including seasonal atopic conjunctivitis (SAC), perennial atopic conjunctivitis (PAC), atopic keratoconjunctivitis (AKC), and atopic blepharoconjunctivitis (ABC). We have investigated the number, distribution and protease expression of mast cells in normal and diseased conjunctiva with the use of immunohistochemistry in water-miscible resin sections. The median mast cell densities in normal subjects were 17 mm-2 in the bulbar substantia propria and 9 mm-2 in tarsal substantia propria. Mast cells were absent from the normal conjunctival epithelium at both sites. Mast cell densities were increased in the bulbar substantia propria in SAC, AKC and ABC. Tarsal substantia propria showed a significant increase in mast cells in ABC and AKC disease states. Mast cells express a range of proteases which varies according to their anatomic site. Mast cells in connective tissue are described to contain tryptase, chymase, cathepsin-G and carboxypeptidase-A, whereas mucosal mast cells contain only tryptase. In the diseased conjunctiva there was a marked reduction in proteases other than tryptase in the intraepithelial mast cells. There were also significant reductions in protease expression other than tryptase in the bulbar substantia propria in AKC and ABC. There appear to be specific alterations in the distribution of mast cells in the sub-categories of allergic eye disease. The distinction between mucosal and connective tissue mast cell phenotypes is not clear-cut and may depend on the functional state of the mast cells in relation to the microenvironment.

Acute Disease↗
PubMed1995

Oligoclonal activation of CD4+ T lymphocytes in posterior uveitis.

Several lines of evidence support an important role for activated T lymphocytes in the perpetuation of autoimmune intraocular inflammatory disease (posterior uveitis). In this study peripheral blood lymphocytes (PBL) were examined by three-colour flow cytometry to assess the distribution of IL-2 receptors (IL-2R) among CD4+ and CD8+ T cell subsets in patients with active posterior uveitis and control subjects. Patients with uveitis (n = 70) showed a significant increase in PBL expressing the alpha-chain (Tac) of the IL-2R compared with controls (n = 28) (34.2% versus 29.6%) (P < 0.05). This increased Tac expression was present on both the CD4+ subset (25.7% versus 20.9%) (P < 0.05) and the CD8+ subset (2.5% versus 1.8%) (P < 0.05) of lymphocytes. We also examined whether the activated CD4+ PBL from uveitis patients (n = 30) showed a dominant pattern of T cell receptor (TCR) gene rearrangement, suggestive of an oligoclonal response to a small number of antigenic peptides. A significant increase in the usage of the V alpha 2.3 TCR family by activated but not by non-activated CD4+ PBL was detected in patients (3.9% versus 3.4%) (P < 0.05) compared with controls. There was evidence of oligoclonal activation of CD4+ PBL in 11/30 patients (36.7%) but in none of the controls (n = 10). However, different V alpha or V beta TCR families were selectively activated among and even within individual patients. The heterogeneity in TCR expression among patients with active intraocular inflammatory disease is discussed.

Autoimmune Diseases↗
PubMed1995

Nucleotides as extracellular signalling molecules.

There is now wide acceptance that ATP and other nucleotides are ubiquitous extracellular chemical messengers. ATP and diadenosine polyphosphates can be released from synaptosomes. They act on a large and diverse family of P2 purinoceptors, four of which have been cloned. This receptor family can be divided into two distinct classes: ligand-gated ion channels for P2X receptors and G protein-coupled receptors for P2Y, P2U, P2T and P2D receptors. The P2Y, P2U and P2D receptors have a fairly wide tissue distribution, while the P2X receptor is mainly found in neurons and muscles and the P2T and P2Z receptors confined to platelets and immune cells, respectively. Inositol phosphate and calcium signalling appear to be the predominant mechanisms for transducing the G-protein linked P2 receptor signals. Multiple P2 receptors are expressed by neurons and glia in the CNS and also in neuroendocrine cells. ATP and other nucleotides may therefore have important roles not only as a neurotransmitter but also as a neuroendocrine regulatory messenger.

Amino Acid Sequence↗
PubMed1995

Inhibition of hypothalamic nitric oxide synthase gene expression in the rat paraventricular nucleus by food deprivation is independent of serotonin depletion.

We have investigated the effects of food deprivation on nitric oxide synthase (NOS) transcript levels in the rat paraventricular (PVN) and supraoptic nuclei (SON), using in situ hybridization histochemistry. Food deprivation for 48 h significantly and consistently reduced NOS transcript prevalence by approximately 50% in both sites. Since there is considerable evidence for an important role of 5-HT in feeding behaviour, we then examined the effect of food deprivation on NOS gene expression in the PVN following para-chlorophenylalanine (PCPA)-induced hypothalamic 5-HT depletion. As starvation causes central down-regulation of the thyroid axis, changes in thyrotropin-releasing hormone (TRH) and pituitary thyrotrophin (TSH) transcript prevalence were used as internal controls. PCPA pretreatment (200 mg/kg body weight as a single daily dose ip for 2 days) had no significant effect on basal levels of NOS, TRH or TSH transcripts, or on the effect of a subsequent 48 h fast, which significantly reduced all three. These results show for the first time, that food deprivation for 48 h significantly reduces NOS gene expression in the rat PVN and SON. Secondly, that basal levels and the fasting-induced reductions in the prevalence of NOS, TRH and TSH transcripts were not affected by PCPA-induced hypothalamic 5-HT depletion. Therefore, at least under the experimental conditions used here, 5-HT does not appear to be involved in setting baseline levels- or in the starvation-induced inhibition of NOS or thyroid axis gene expression in the PVN.

Animals↗
PubMed1995

S-100 antigen-positive folliculostellate cells are not the source of IL-6 gene expression in human pituitary adenomas.

We have investigated the expression of IL-6 in a random selection of 27 human pituitary adenomas, comprising 8 somatotroph, 5 corticotroph, 3 mammotroph and 11 endocrinologically inactive adenomas, using a 35S-labelled 1.1kb riboprobe complementary to human IL-6. Positive and negative IL-6 transcript controls were generated from the IL-6-secreting human bladder carcinoma cell line T24/83. Tissue from a malignant melanoma was used as a positive S-100 immunocytochemical control tissue. Of the 27 human pituitary adenomas examined by in situ hybridization, 7 (26%) contained IL-6 transcripts: these were 3 of 5 corticotroph adenomas, 2 of 8 somatotrophinomas and 2 of 11 endocrinologically inactive adenomas. In each case, IL-6 transcript-positive cells constituted less than 1% of the total pituitary tissue mass examined. Alternate wax embedded 3 microns thick sections from 5 of the 7 IL-6 transcript positive tumours were examined immunocytochemically for S-100 antigen, or by in situ hybridization for IL-6 transcripts. Immunocytochemistry for S-100 antigen was completely negative in 3 of the 5 tumours and in the remaining 2, there was no evidence of IL-6 transcripts and S-100 antigen co-localization in any of the sections examined. This suggests that in pituitary adenomas, cells other than classical folliculostellate cells are responsible for IL-6 production.

Adenoma↗
PubMed1995

Evidence for arginine vasopressin as the primary activator of the HPA axis during adjuvant-induced arthritis.

1. Adjuvant-induced arthritis (AA) is an experimental inflammation of the joints that results in chronic activation of the hypothalamo-pituitary-adrenal (HPA) axis. 2. In this study the role of hypothalamic corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) in the regulation of the HPA axis in this condition both in Sprague-Dawley (SD), and Piebald-Viral-Glaxo (PVG) rats has been further characterized. 3. The increase in AVP peptide content of portal blood (as early as day 11), just prior to the onset of arthritis is confirmed and further increases, peaking at day 16 are shown, coincident with the progression of inflammation in the PVG rats. 4. The increase in AVP is associated with a significant increase in the expression of AVP but not CRF mRNAs in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN) of arthritic SD rats. 5. In the presence of maximal inflammation of SD rats there was a significant decrease in the maximum binding of [125I]-Tyr-oCRF to anterior pituitary membranes, whereas AVP receptor concentration in anterior pituitary membranes from both PVG and SD rats showed a significant increase with respect to controls. 6. The basal adrenocorticotrophin (ACTH) secretion in vitro was similar in both control and arthritic SD rats but that from arthritic PVG rat pituitaries was significantly greater than the respective controls (436 +/- 91 v 167 +/- 23 pg/tube). The ACTH response of pituitaries of arthritic PVG rats to CRF or the combination of CRF and AVP was significantly higher compared with the controls, although the ACTH response of arthritic SD rat pituitaries was unchanged. 7. The results are consistent with the view that activation of the parvocellular vasopressin system has an important role in the adaptation of the HPA axis to experimentally-induced chronic stress of arthritis.

Adrenocorticotropic Hormone↗