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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 19 recordsLinked to original sources
PubMed2003

The effect of oestradiol and progesterone on hypoglycaemic stress-induced suppression of pulsatile luteinizing hormone release and on corticotropin-releasing hormone mRNA expression in the rat.

Corticotropin-releasing hormone (CRH) is implicated in the suppression of pulsatile luteinizing hormone (LH) secretion by a variety of stressful stimuli; 17beta-oestradiol (E2) has been shown to modulate this inhibitory response. The present study in ovariectomized (OVX) rats was designed to investigate the effect of E2 and progesterone (P4) on hypoglycaemic stress-induced changes in pulsatile LH secretion and on the associated changes in both central and peripheral components of the hypothalamic-pituitary-adrenal axis. E2 enhanced the hypoglycaemic stress-induced suppression of LH pulses; P4 in addition to E2 further potentiated the inhibitory response. The rise in plasma corticosterone following insulin-induced hypoglycaemia (IIH) was highest in the E2 + P4 group. Nevertheless, when such levels were achieved by administration of corticosterone, the occurrence of LH pulses was completely unaffected, irrespective of ovarian steroid milieu. E2 and E2 + P4 up-regulated basal CRH mRNA expression in the paraventricular nucleus (PVN) as measured by in situ hybridization; this signal was also increased in the medial preoptic nucleus (MPN) following E2. IIH resulted in a rise in CRH mRNA in the PVN, but not in the MPN; this rise may reflect a more significant role for the PVN in the present context. Changes in neuropeptide mRNA expression may signal changes in neuronal activity; nevertheless, the profound differences in LH pulse suppression in OVX, E2 and E2 + P4 rats following IIH were not reflected in the concurrent changes in CRH mRNA in the PVN. The results suggest that while corticosterone has no acute effect on LH pulses in the rat, the up-regulation by ovarian steroids of basal CRH mRNA in the PVN and/or MPN may contribute to the central regulation of these pulses in response to stress.

Adrenocorticotropic Hormone↗
PubMed2002

What is the role of the insulin-like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated?

OBJECTIVE AND BACKGROUND: The cancer cachexia syndrome is characterized by anorexia, weight loss with muscle wasting and increased energy expenditure. It is associated with increased morbidity and mortality, but its aetiology is poorly understood and no effective therapeutic intervention is available. It may result from an imbalance between the activity or effect of anabolic and catabolic hormones, mediated by the inflammatory cytokines. IGF-I is a potent anabolic agent, with therapeutic potential. Our objective was to investigate the role and regulation of the IGF system in cancer cachexia. DESIGN AND PATIENTS: We set up a prospective study of 30 patients with newly diagnosed unresectable non-small cell lung cancer, together with a cross-sectional comparison group of healthy volunteers. MEASUREMENTS: We examined the relationship between aspects of the IGF system, including IGFBP-3 proteolysis (using Western ligand and immunoblotting and an in vitro IGFBP-3 protease assay); the inflammatory cytokines and their soluble receptors; and food intake and nutritional status (including biochemical and anthropometric assessments). RESULTS: Although we did not observe a marked reduction in food intake in the cancer patients, the majority lost weight and functionally important lean body mass. We observed GH resistance in the cancer patients, and intermittent proteolysis of IGFBP-3, which correlated with the circulating interleukin-6 (IL-6) concentration. The pattern of IGFBP-3 proteolysis was unusual, with a prominent 17-kDa fragment. Less IGFBP-3 proteolysis was associated with more weight loss, suggesting that this could be a protective counter-regulatory mechanism, increasing IGF-I bioavailability to the tissues. CONCLUSIONS: Cancer cachexia in humans is a complex condition. Patients tend to be GH resistant. The significance of the intermittent increases in IGFBP-3 proteolysis, which may be regulated by IL-6, remains uncertain. A better understanding of the pathophysiology should enable the development of novel therapeutic approaches.

Aged↗
PubMed2002

Habituation and cross-sensitization of stress-induced hypothalamic-pituitary-adrenal activity: effect of lesions in the paraventricular nucleus of the thalamus or bed nuclei of the stria terminalis.

Habituation of the hypothalamic-pituitary-adrenal (HPA) response to chronic intermittent restraint stress (30 min/day for 15 days) and the cross-sensitization to a heterotypic stress [i.p. lipopolysaccharide (LPS)] were investigated in intact male Sprague Dawley rats, and in rats bearing quinolinic acid lesions to the medial anterior bed nuclei of the stria terminalis (BST) or anterior region of the paraventricular nucleus of the thalamus (PVT). In intact animals, a single period of restraint increased plasma corticosterone levels at 30 min and led to an increase in corticotropin-releasing hormone (CRH) mRNA levels in the PVN at 3 h. LPS had a smaller effect on corticosterone and more variable effect on CRH mRNA. Chronic intermittent restraint stress caused a decrease in body weight and increase in adrenal weights, with concomitant increase in basal corticosterone levels. These animals also displayed marked habituation of the corticosterone and CRH mRNA responses to the homotypic stress of restraint, but no loss of the corticosterone response to the heterotypic stress of LPS and a cross-sensitization of the CRH mRNA response. This pattern of stress responses in control and chronically stressed animals was not significantly affected by lesions to the PVT or BST, two areas which have been implicated in the coping response to stress. Thus, these data provide evidence for independent adaptive mechanisms regulating HPA responses to psychological and immune stressors, but suggest that neither the medial anterior BST nor the anterior PVT participate in the mechanisms of habituation or cross-sensitization.

Animals↗
PubMed2002

New genomic avenues in behavioural neuroendocrinology.

Neuroendocrine systems play a key role not only in the maintenance of whole-body homeostasis but also as the link between behavioural, endocrine and autonomic responses to environmental stimuli. It is becoming increasingly clear that neuroendocrine regulatory mechanisms are under the control of a combination of factors including genetic background, environment and early-life programming. Patterns of gene expression are increasingly being used to provide information on the genotypes associated with particular behaviours, and modulation of specific parts of the genome allow investigation of the contribution of particular genes. The sequencing of the genome provides a unique opportunity to elucidate the genetic contribution to neuroendocrine and behavioural processes, and to investigate the interactions between genetic and environmental factors. Although drugs can be used to activate or inhibit neurotransmitters and receptors, they lack specificity. New technologies now permit the activation or inactivation of both neurotransmitters and receptors in specific areas of the brain for defined periods, including crucially important developmental windows when activation appears to have long-term consequences. The future challenges are to define the critical mechanisms through which the genetic constitution of an individual human or experimental animal interacts with environmental cues to result in altered physiological or even pathological behaviour and endocrine function.

Animals↗
PubMed2002

Hypothalamic-pituitary-adrenal function.

Basal hypothalamic-pituitary-adrenal (HPA) function is characterised by pulses of corticosterone secretion followed by a transient refractory period when the axis appears to be inhibited. In females pulses of corticosterone secretion occur approximately once per hour with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Pulsatility is altered by genetic programming, early life experiences and reproductive status. Activation of the HPA axis during adjuvant induced arthritis results in an increase in the pulse frequency. This is associated with a marked change in hypothalamic gene expression with a diminution of CRH mRNA and a marked increase of AVP mRNA which becomes the predominant HPA secretagogue.

Adrenal Glands↗
PubMed2001

Experimental autoimmune uveoretinitis in mice (Biozzi ABH and NOD) expressing the autoimmune-associated H-2A(g7) molecule: identification of a uveitogenic epitope.

To determine whether Biozzi ABH (H-2A(g7)) mice were susceptible to chronic experimental autoimmune uveoretinitis (EAU). Biozzi ABH were immunized with the two retinal antigens, interphotoreceptor retinoid binding protein (IRBP) and soluble antigen (S-Ag). Biozzi ABH mice were found to be susceptible to EAU induction with native bovine IRBP. Recombinant protein domains were used to identify IRBP domain 2 (EcR2) as the uveitogenic domain. Histopathological examination indicated that EcR2-induced disease was of a chronic, non-destructive nature in the Biozzi ABH. Using synthetic overlapping peptides corresponding to EcR2, a uveitogenic and immunogenic epitope was identified corresponding to human IRBP511-530. Non-obese diabetic (NOD) mice share the same MHC class II (H-2A(g7)) molecule as the Biozzi ABH, and were also found to be susceptible to EAU induction with EcR2. This study has identified a novel mouse model of EAU, whereby disease is of a chronic, non-destructive nature, which has potential to be used in immune manipulation and neuroprotection studies.

Animals↗
PubMed2001

Are adhesion molecules involved in stress-induced changes in lymphocyte distribution?

Acute psychological stress is associated with important changes in circulating cell populations and reductions in cell-mediated immune responses. However, the mechanisms underlying these phenomena are poorly understood. In this study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on peripheral lymphocyte subsets and (ii) adhesion molecule (beta2 integrins) expression and (iii) also determined whether glucocorticoids could underlie stress-related changes in cellular redistribution. We observed time-dependent changes in lymphocyte distribution including decreased (-21%) percentages of peripheral T helper cells and increased (88%) NK cell numbers following acute brief restraint. Acute stress was also found to overall upregulate beta2-integrin (CD11a and CD11b) expression on T cells and to raise (1049%) plasma corticosterone levels. However, this stress response was found habituated (-75% vs. acute) in the animals previously exposed to chronic restraint stress. Stress effects on circulating lymphocytes were not observed in animals previously exposed to chronic intermittent restraint stress or chronically stressed animals re-exposed to the same stressor. Our results indicate that 1) stress alters lymphocyte distribution, 2) that adhesion molecules may be involved in stress-induced alterations of T-cell distribution and 3) that these changes may be related to circulating glucocorticoids and subjected to adaptation with repeated stress exposure.

Acute Disease↗
PubMed2001

Hypothalamic and amygdaloid corticotropin-releasing hormone (CRH) and CRH receptor-1 mRNA expression in the stress-hyporesponsive late pregnant and early lactating rat.

This study investigated the expression of corticotropin releasing hormone (CRH) and its receptor CRHR-1, and arginine vasopressin (AVP) mRNAs during the stress hyporesponsive periods of late pregnancy and lactation (day-3) and in virgin stress-responsive females. In situ hybridization histochemistry showed that basal CRH mRNA in the paraventricular nucleus (PVN) decreased in pregnant and increased in lactating rats (compared with virgin controls), whereas it increased after restraint stress only in virgin rats. Basal PVN CRHR-1 mRNA increased markedly in all groups but reached lower levels in pregnant rats. Basal AVP mRNA in the parvocellular PVN was higher in lactating rats, and in contrast to CRH mRNA, it increased after stress in all groups. In medial preoptic area (MPOA) CRH mRNA levels were higher in lactating females compared with virgin and pregnant rats, and unexpectedly they decreased markedly after stress only in virgin rats. CRH mRNA levels in the central and medial nuclei of the amygdala were higher in lactating rats than in virgin or pregnant ones, and stress had no effect in either group. These data suggest that these stress hyporesponsive periods: (1) do not depend on basal CRH mRNA expression in the PVN; (2) appear to have intact stress-activated afferent pathways to the PVN, as shown by preservation of CRHR-1 and AVP responses to stress, but the information may be differently processed; (3) are associated with an alteration in a CRH mediated pathway from the MPOA.

Amygdala↗
PubMed2001

ATP-mediated killing of Mycobacterium bovis bacille Calmette-Guérin within human macrophages is calcium dependent and associated with the acidification of mycobacteria-containing phagosomes.

We previously demonstrated that extracellular ATP stimulated macrophage death and mycobacterial killing within Mycobacterium bovis Bacille Calmette-Guérin (BCG)-infected human macrophages. ATP increases the cytosolic Ca(2+) concentration in macrophages by mobilizing intracellular Ca(2+) via G protein-coupled P2Y receptors, or promoting the influx of extracellular Ca(2+) via P2X purinoceptors. The relative contribution of these receptors and Ca(2+) sources to ATP-stimulated macrophage death and mycobacterial killing was investigated. We demonstrate that 1) ATP mobilizes Ca(2+) in UTP-desensitized macrophages (in Ca(2+)-free medium) and 2) UTP but not ATP fails to deplete the intracellular Ca(2+) store, suggesting that the pharmacological properties of ATP and UTP differ, and that a Ca(2+)-mobilizing P2Y purinoceptor in addition to the P2Y(2) subtype is expressed on human macrophages. ATP and the Ca(2+) ionophore, ionomycin, promoted macrophage death and BCG killing, but ionomycin-mediated macrophage death was inhibited whereas BCG killing was largely retained in Ca(2+)-free medium. Pretreatment of cells with thapsigargin (which depletes inositol (1,4,5)-trisphosphate-mobilizable intracellular stores) or 1,2-bis-(2-aminophenoxy)ethane-N, N, N',N'-tetraacetic acid acetoxymethyl ester (an intracellular Ca(2+) chelator) failed to inhibit ATP-stimulated macrophage death but blocked mycobacterial killing. Using the acidotropic molecular probe, 3-(2,4-dinitroanilino)-3'-amino-N-methyl dipropylamine, it was revealed that ATP stimulation promoted the acidification of BCG-containing phagosomes within human macrophages, and this effect was similarly dependent upon Ca(2+) mobilization from intracellular stores. We conclude that the cytotoxic and bactericidal effects of ATP can be uncoupled and that BCG killing is not the inevitable consequence of death of the host macrophage.

Adenosine Triphosphate↗
PubMed2001

Glucocorticoids modulate the NGF mRNA response in the rat hippocampus after traumatic brain injury.

Nerve growth factor (NGF) expression in the rat hippocampus is increased after experimental traumatic brain injury (TBI) and is neuroprotective. Glucocorticoids are regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) and corticosterone (CORT) replacement on the expression of NGF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury and in situ hybridisation to evaluate the expression of NGF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomised rats (with or without CORT replacement). TBI increased expression of NGF mRNA in sham-ADX rats, but not in ADX rats. Furthermore, CORT replacement in ADX rats restored the increase in NGF mRNA induced by TBI. These findings suggest that glucocorticoids have an important role in the induction of hippocampal NGF mRNA after TBI.

Adrenalectomy↗
PubMed2001

Interphotoreceptor retinoid binding protein peptide-induced uveitis in B10.RIII mice: characterization of disease parameters and immunomodulation.

Experimental autoimmune uveoretinitis (EAU) can be induced in the B10.RIII mice following immunization with bovine interphotoreceptor retinoid binding protein (IRBP) and human IRBP(161--180)peptide. This study examines the value of the human IRBP(161--180)peptide model in the B10.RIII mice, as a suitable model of EAU in order to examine immunotherapies. Having established a reliable and consistent immunization protocol of 25 micro g peptide and no PTX, the time course of histopathology was performed, which graded both cellular and structural scores individually. Disease was typically of an acute nature, characterized by rapid onset of a massive inflammatory response, resulting in extensive damage to the rod outer segments (ROS) and neuronal layers. Treatment with potent immunosuppressive agents, CD4-specific monoclonal antibodies resulted in the inhibition of disease and a reduction in disease incidence. Treatment with p55-tumor necrosis factor receptor-Ig (p55-TNFR-Ig) fusion protein reduced structural damage to the retina despite a high level of cellular infiltration in the eye, suggesting that target organ damage in an acute model of EAU can be modulated.

Animals↗
PubMed2001

Restraint stress is associated with changes in glucocorticoid immunoregulation.

Psychological stress has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired cell-mediated immune (CMI) responses. There is also evidence suggesting that intermittent chronic stress differentially alters CMI across different immune compartments, but the mechanisms underlying this phenomenon have not been explored in detail. In the present study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on both peripheral blood lymphocyte (PBL) and splenocyte mitogen-induced proliferation and (ii) also determined whether differential stress effects within these immune compartments might reflect alterations in lymphocyte sensitivity to glucocorticoids. It was found that while acute stress exposure significantly raised plasma corticosterone levels (1048% vs. controls, P<.001), this response was attenuated in the animals previously exposed to chronic intermittent stress (-79.66% vs. acute; P<.001). Acute stress increased phytohemagglutinin (PHA)-induced lymphocyte proliferation in the spleen (69.04%, P=.01) and suppressed PBL proliferation (-45.52%, P<.001). Neither of these changes were observed following chronic stress. We also demonstrated that reexposure to the stressor rapidly increased splenocyte sensitivity to in vitro dexamethasone (P<.05) and corticosterone (P<.05) in chronically stressed rats. Our data (1) confirm that acute stress is associated with compartment-specific changes in CMI function, (2) indicate that chronic stress is associated with habituated endocrine and immune responses and (3) that stressor exposure rapidly alters splenocyte sensitivity to glucocorticoids and we suggest that the latter may contribute to differential stress effects across immune compartments.

Acute Disease↗
PubMed2001

Peripartum plasticity within the hypothalamo-pituitary-adrenal axis.

The hypothalamo-pituitary-adrenal (HPA) axis plays important roles in the adaptive changes in physiology that occur during pregnancy and lactation. Although the axis still exhibits a pulsatile pattern of secretion, the normal diurnal rhythm of pulse amplitude is lost during lactation, such that mean basal levels remain constant throughout the day. In addition, the peripartum period is associated with a remarkable plasticity in stress-induced HPA activity, in that the increase of HPA activity normally seen in response to either physical or psychological stresses in the non-reproductive state become severely attenuated or absent in the lactating animal. This stabilization of both basal and stress-induced HPA activity may be important for maintaining a constant endocrine environment, thereby preventing any programming effects on the developing offspring. Attenuation of the stress response is initiated in late pregnancy and is temporally associated with luteolysis, indicating possible steroid hormone involvement. Indeed, mimicking the luteolytic changes in oestrogen and progesterone levels in non-pregnant animals induces a similar attenuation of the stress response. Furthermore down-regulation of the stress response is, at least in part, centrally mediated since in the period following luteolysis rats will show a decreased level of stress-induced neuronal activation of the PVN, as measured by the expression of either c-fos or CRH mRNAs. Persistence of this adapted state is dependent upon the continued suckling stimulus, as removal of the offspring litter rapidly leads to resumption of HPA responses to and the appearance of an exaggerated diurnal rhythm. The underlying mechanisms responsible for this stress hyporesponsiveness may include plasticity of noradrenergic and oxytocin pathways. In view of its role in other reproductive behaviors, a stress-inhibiting effect of oxytocin may reflect a more widespread co-ordinating role in the peripartum animal.

Animals↗
PubMed2001

CRH in chronic inflammatory stress.

Corticotropin-releasing hormone (CRH) is an important regulator of inflammation at the central level through hypothalamo-pituitary-adrenal (HPA) axis control of glucocorticoid secretion. Integrity of the HPA axis during autoimmune disease is critical in controlling the severity of inflammation, but the evidence for an HPA axis defect in the etiology of autoimmune diseases is not compelling. CRH secreted from leukocytes and neuronal terminals in peripheral tissues also plays a role in mediating inflammation. Elucidating the pathways underlying the expression of CRH, both central and peripheral, and interactions of CRH with other inflammatory mediators such as substance P, confers great potential for the development of a new generation of anti-inflammatory agents.

Animals↗
PubMed2001

Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder.

ABCG1 encodes a transporter protein that may be involved in the cellular uptake of tryptophan. Tryptophan is the precursor for serotonin, which is implicated in the regulation of mood. The gene maps to chromosome 21q22.3, a region implicated in bipolar disorder I (BPI) in genetic linkage studies. ABCG1 is thus a suitable candidate gene for study in BP1. We screened all 15 exons and 700 bases of the 5' flanking region of ABCG1 for mutations, using Denaturing High Performance Liquid Chromatography (DHPLC). A total of 13 single nucleotide polymorphisms (SNPs) were identified. Ten of the SNPs were intronic, two lie within the 5' flanking region and one within the 3' UTR. We identified a GCC repeat within Exon 1 and two novel intronic VNTRs. Eight of the SNPs, the two VNTRs, the GCC repeat and two known microsatellite markers within the gene were tested for association with BP1 in a sample of 110 parent-offspring trios using the Extended Transmission Disequilibrium Test (ETDT). No alleles or haplotypes were significantly preferentially transmitted from parents to affected offspring. However, the trend for preferential transmission of markers in the 3'UTR is in the same direction as in a previous report for association with mood and panic disorders and therefore warrants attempts at replication. Marker-to-marker linkage disequilibrium (LD) showed that strong LD was present over relatively short distances of up to 20 kb and was present for SNPs as well as for polymorphic repeats. The polymorphisms identified in this study will be useful in examining the role of this gene in other neuropsychiatric disorders and behavioural traits.

3' Untranslated Regions↗
PubMed2001

Increased corticosterone pulse frequency during adjuvant-induced arthritis and its relationship to alterations in stress responsiveness.

Frequent blood sampling from males rats was used to study hypothalamic-pituitary-adrenal (HPA) axis activation during arthritis and its association with diminished responses to acute psychological stress. In control rats, corticosterone release occurred in a series of 13 +/- 1 pulses per 24 h. Induction of arthritis by Mycobacterium-adjuvant injection initially increased the rate of hormone release within each pulse and, by day 14 postinjection, when hind-paw inflammation was established, caused a marked increase in pulse frequency to 22 +/- 1 per 24 h leading directly to elevated circulating corticosterone levels. In both control and adjuvant-treated rats, there was a marked response to a 10-min noise stress when the stimulus coincided with a rising or interpulse phase of the endogenous corticosterone rhythm. However, when the noise stress coincided with a falling phase of this rhythm, the response was greatly diminished. Since corticosterone pulse frequency was markedly increased and hence interpulse interval decreased by day 14, there was an increased probability of the noise stress occurring during the nonstress responsive falling phase of the corticosterone secretory cycle. As a result, the group mean response to noise stress was significantly smaller in the arthritic than the controls (70.2 +/- 9.2 versus 107.8 +/- 13.0 ng/ml, respectively). In contrast to the differential response to noise stress, all rats showed similar responses to the acute immunological challenge with i.v. lipopolysaccharide. Thus, altered basal pulse frequency is a major factor influencing HPA activation during acute psychological stress.

Animals↗
PubMed2001

The hypothalamo-pituitary-adrenal axis response to experimental traumatic brain injury.

Alterations in the hypothalamo-pituitary-adrenal (HPA) axis following traumatic brain injury have not been documented in detail. We used fluid percussion injury (FPI) to evaluate the early changes in components of the HPA axis following experimental traumatic brain injury. Wistar rats were sacrificed at 2 or 4 h following sham or FPI surgery. In situ hybridization histochemistry was used to determine the expression of mRNAs of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus and pro-opiomelanocortin (POMC) in the pituitary. A group of animals undergoing no surgery were used as control. Repeated blood sampling from an indwelling catheter demonstrated that plasma corticosterone (CORT) levels peaked 30 min following surgery in sham and FPI animals but there was no significant difference in CORT concentration between these groups at any time. Pituitary POMC expression was increased following sham and FPI surgery (compared with control non-operated animals) but with no significant difference between the two groups undergoing surgery. Hypothalamic CRH mRNA expression was significantly higher in animals undergoing FPI compared with sham surgery. Hypothalamic AVP mRNA expression was not significantly increased when compared with control nonoperated animals. These data indicate that the anaesthesia and/or surgery associated with FPI or sham surgery induces a generalised activation of the HPA axis. The selective increase in CRH mRNA in animals undergoing FPI may be due to specific effects of traumatic brain injury rather than a general stress response and may suggest an additional neurotransmitter role for CRH following head injury. The absence of an AVP response suggests that the effects of FPI may be mediated through the CRH-alone-containing subpopulation of neurons.

Animals↗