Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune and neuroendocrine systems communicate and maintain homeostasis through various mechanisms, including the use of common signal and recognition molecules and the use of similar processes. This type of integrated network has profound effects on the onset and outcome of certain disease states, including endotoxic shock, in which a cascade of mediators influence the pathophysiologic responses. We have found that some of the common signal molecules shared between the immune and neuroendocrine systems are the peptide hormones adrenocorticotropin (ACTH) and endorphins (END). Our investigations have shown that these molecules are produced in vitro by cells of the immune system treated with various stimuli, including immunological stimuli such as bacterial lipopolysaccharide (LPS; endotoxin), virus infection (Newcastle virus; NDV), and the more classical neuroendocrine stimuli corticotropin-releasing hormone (CRH). We have proposed that the production of END by the peripheral immune system contributes to the pool of opioid peptides associated with the pathophysiology of endotoxic shock. Lymphocytes from LPS-sensitive C3HeB/FeJ mice but not LPS-resistant C3H/HeJ mice produce END and ACTH both in vitro and in vivo after treatment with LPS. Purification of the in vitro produced LPS-induced END from B-lymphocyte spleen cells followed by injections into both LPS-sensitive and -resistant mice elicits changes in body temperature and respiration rate. The spleen cells from the LPS-sensitive mice process ACTH and END differently depending on the stimulus for induction and the cell type in which the processing takes place. CRH or virus induce ACTH 1-39 and beta-END, whereas inductions with LPS yield major products of ACTH 1-22 to 1-26 and gamma-END, products that are for the most part unique to the immune system. We have shown that LPS induces a novel protease that functions optimally at pH 5 to cleave ACTH 1-39 into ACTH 1-22 to 1-26. This enzyme is present in LPS, but not mock or CRH-induced B cells from LPS-sensitive mice. The LPS-resistant mice did not possess this enzyme and therefore produced only the high-molecular-weight pro-opiomelanocortin (POMC)-like molecule. The inability to produce ACTH and END, presumably by their inability to process the precursor, may account, in part, for their lack of response to the LPS. The POMC peptides also may play an indirect role in orchestrating the pathophysiologic response, since both ACTH and END were shown to induce tumor necrosis factor (TNF). Our data strongly suggest that lymphocyte POMC peptides ACTH and END are important mediators in the overall response to endotoxin.
 ...
PMID:Role of leukocyte-derived pro-opiomelanocortin peptides in endotoxic shock. 166 42

Current research suggests that the secretion of beta-endorphin from the pituitary gland may be associated with the refractory hypotension seen in patients with septic shock. Extensive animal research and a few clinical studies have demonstrated that naloxone, a narcotic antagonist, can increase MAP, cardiac output, and cardiac contractility and improve survival in victims of endotoxic shock. The ability of naloxone to improve MAP, however, appears to decrease with prolonged persistent hypotension (greater than eight hours). Studies also suggest that a synergistic effect exists between naloxone and the steroid methylprednisolone in improving the hemodynamics of these patients. In the future, naloxone may prove to be essential in the management of patients in the early stages of septic shock, but more complete clinical trials are warranted. It is imperative that nurses be involved in this type of clinical research.
 ...
PMID:Naloxone and its use in neonatal septic shock. 214 Aug 71

We have discovered that the immune system processes proopiomelanocortin (POMC) products differently depending on the stimulus for induction. We have shown that corticotropin-releasing factor (CRF) induces the lymphocytes from C3HeB/FeJ lipopolysaccharide (LPS)-sensitive mice to produce adrenocorticotropin (ACTH) 1-39 and beta-endorphin, whereas LPS induces these lymphocytes to produce ACTH 1-23 to 26 and alpha- or gamma-endorphin. We have proposed that the smaller species of ACTH and endorphin are proteolytic cleavage products from ACTH 1-39 and beta-endorphin. Analysis of C3HeB/FeJ LPS-treatment B lymphocyte lysates showed an enzymatic activity at pH 5 but not pH 7 that cleaved ACTH 1-39 into a smaller ACTH 1-23 to 26. The B lymphocytes from C3H/HeJ (LPS-resistant) mice expressed but did not process proopiomelanocortin after LPS or CRF treatment, nor did their B cells express the aforementioned enzymatic activity. Taken together, these data suggest a unique processing pathway in LPS-treated B lymphocytes and one in which immunoreactive (ir)-endorphins may play a role in the pathophysiology of endotoxic shock.
 ...
PMID:Novel processing pathway for proopiomelanocortin in lymphocytes: endotoxin induction of a new prohormone-cleaving enzyme. 282 3

Using the opiate receptor antagonist naloxone, we tested the hypothesis that endorphins act on opiate receptors to cause cardiovascular depression in primate shock. Mean arterial pressure (MAP), cardiac output, and left ventricular contractility (LV dP/dtmax) were measured in 34 anesthetized cynomolgus monkeys. Hemorrhagic shock was induced by bleeding into a heparinized reservoir to achieve (t = 0) and maintain MAP at 45 mm Hg. At t = 60 min, the reservoir was clamped and the animals were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 5) or 0.9% NaCl as a control (n = 5). There were no significant differences in the cardiovascular responses to naloxone and saline when acid-base balance and core body temperature were not controlled. Pressor responses to naloxone, however, were present in proportion to arterial pH and body temperature. When these factors were controlled, naloxone (n = 6) significantly increased MAP and LV dP/dtmax by 48% and 83%, respectively, whereas saline (n = 6) had no significant effect. Blood was reinfused at t = 120 min, and survival rate at 72 h was significantly (p = .01) higher with naloxone (3/6) than saline controls (0/6). In the endotoxic shock model, cynomolgus monkeys were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 6) or 0.9% NaCl (n = 6) when MAP reached 75 mm Hg or its nadir 60 to 90 min after Escherichia coli endotoxin, 5 mg/kg iv. Naloxone significantly increased MAP and LV dP/dtmax by 24% and 22%, respectively, whereas saline had no effect. Survival rate at 48 h was significantly (p = .01) higher with naloxone (6/6) than saline (1/6). Plasma beta-endorphin and beta-lipotropin concentrations rose three to five-fold in both shock models and were not affected by treatment. We conclude that endorphins are activated in primate shock and act on opiate receptors to contribute to the cardiovascular depression found with hemorrhage and endotoxemia.
 ...
PMID:Evidence for a role of endorphins in the cardiovascular pathophysiology of primate shock. 296 36

The opioid peptides beta-endorphin and [met]enkephalin are present in the peripheral circulation. Plasma beta-endorphin originates from the pituitary gland and its cosecretion with ACTH is stimulated by a variety of noxious stimuli. Although the adrenal medulla contains high concentrations of [met]enkephalin-containing polypeptides which are costored with catecholamines, and although the adrenal gland appears to secrete [met]enkephalin into the adrenal vein, the relative adrenal contribution to plasma [met]enkephalin appears to be negligible. Plasma concentrations of immunoreactive [met]enkephalin may be increased by insulin and by endotoxic shock, but they are not significantly altered by acute haemorrhagic stress nor by surgical stress. Thus blood plasma concentrations of beta-endorphin, but not of [met]enkephalin, are generally increased during acute stress. The physiological significance of endogenous opioids in the circulation is not known. It is unlikely that transient increases in the concentrations of opioid peptides in peripherally circulating blood modulate nociception, since the peptides do not enter ventricular cerebrospinal fluid in detectable amounts under these conditions. Recent evidence has raised the possibility that circulating opioids may be involved in regulating blood glucose and in activating the immune system. It is also possible that circulating beta-endorphin and related polypeptides have non-opioid actions on a variety of peripheral tissues.
 ...
PMID:Opioid peptides in blood and cerebrospinal fluid during acute stress. 332 99

The effects of naloxone on endotoxic hypotension in adrenalectomized and selectively adrenal demedullated rats were evaluated. In sham-operated rats, naloxone administered intracerebroventricularly (ICV) and intravenously (IV) produced an elevation of arterial pressure in this conscious rat model of endotoxemia. By contrast, both adrenalectomy and selective adrenal demedullation (wherein cortical function remained) not only enhanced the sensitivity to endotoxin-induced hypotension at least 10- to 15-fold, but also completely prevented the pressor response to ICV or IV naloxone. These results indicate that 1) adrenal enkephalins are probably not the endogenous opiates responsible for shock hypotension since their removal enhances shock susceptibility; 2) pituitary-derived endorphins in the circulation also appear to be uninvolved since naloxone fails to reverse shock hypotension despite reported elevations of circulating beta-endorphin in adrenalectomized rats; 3) since evidence indicates that naloxone acts centrally in intact endotoxemic rats and fails to do so following adrenal demedullation, we suggest that endotoxic shock results in an endogenous opiate inhibition of central autonomic sites regulating sympatho-medullary outflow. Naloxone, by reversing these actions, may result in the increased release of pressor substances from the adrenal medulla.
 ...
PMID:Adrenalectomy blocks pressor responses to naloxone in endotoxic shock: evidence for sympathomedullary involvement. 631 25

It is well recognized that the reciprocal interaction established between the immune and neuroendocrine systems is crucial for the homeostatic adaptation of individuals during septicemia. In the present study, using an in vivo rat model, we investigated the degree of participation of central and peripheral epinergic systems in the modulation of the hypothalamic-pituitary-adrenal and immune axes' functions during endotoxemia. For this purpose, acute endotoxemia was induced in adult male rats pretreated intraperitoneally with either different inhibitors of phenylethanolamine-N-methyltransferase (PNMT) [which are active either peripherally (SKF 29661) or both peripherally and centrally (SKF 64139), thus lowering epinephrine (EPI) synthesis] or vehicle only (CTRL). Twelve hours after pretreatment, animals were intraperitoneally injected with vehicle alone (basal) or vehicle containing bacterial lipopolysaccharide (LPS) and sacrificed 2 h later. A significant (p < 0.05 vs. the respective basal value) hypoglycemia was found in all groups studied. No pretreatment modified basal plasma adrenocorticotropic hormone (ACTH), glucocorticoid and cytokine concentrations. Endotoxin-stimulated ACTH secretion was severalfold (p < 0.05) higher than the respective basal value in CTRL and in SKFs-pretreated rats; however, the plasma ACTH levels after LPS were significantly (p < 0.05 vs. CTRL and SKF-29661 values) reduced in SKF-64139-pretreated rats. All groups studied showed an appropriate adrenal response to endotoxin challenge. Although no differences were found in basal anterior pituitary (AP) ACTH content among groups, LPS treatment significantly (p < 0.05 versus the respective basal value) decreased AP ACTH in CTRL and SKF 29661 groups. No pretreatment modified the basal medial basal hypothalamus (MBH) corticotropin-releasing hormone (CRH) content. Conversely, SKF 64139 pretreatment significantly (p < 0.05 vs. CTRL and SKF 29661 values) reduced basal median eminence (ME) CRH content, and LPS administration significantly (p < 0.05) decreased ME CRH in CTRL and SKF-29661-pretreated rats. SKF 64139 pretreatment significantly (p < 0.05) enhanced basal MBH and ME arginine vasopressin (AVP) contents. LPS administration significantly (p < 0.05) decreased MBH AVP in CTRL and SKF-29661-pretreated rats and diminished (p < 0.05 vs. basal values) ME AVP in all groups. The plasma tumor necrosis factor alpha (TNFalpha) concentrations were enhanced severalfold (p < 0.05 vs. basal values) after LPS treatment in CTRL rats, but not in SKFs-treated animals. In order to explore the reduced cytokine release after LPS in PNMT-inhibited rats, additional ex vivo experiments were performed by using peripheral mononuclear cells (PMNC) from both CTRL and SKF-29661-pretreated rats. The results of these experiments confirmed an immune dysfunction after inhibition of peripheral EPI synthesis; in fact, basal and concanavalin-A-stimulated TNFalpha secretions were significantly (p < 0.05) lower in SKF-29661-treated than in CTRL PMNC, while, interestingly, addition of EPI (10(-7) M) to the medium fully restored these effects. These data demonstrate that: (1) the mechanism whereby LPS-induced hypoglycemia was independent of epinergic activity; (2) selective central inhibition of epinergic function reduced endotoxin-stimulated ACTH secretion, an effect that could mainly be due to a decrease in CRH-ergic activity; (3) the central epinergic system positively and negatively modulates CRH- and AVPergic functions, respectively, and (4) inhibition of peripheral PNMT activity reduced immune system function in vivo and ex vivo. It is further suggested that low peripheral levels of EPI could be beneficial for the body's defense mechanisms during endotoxic shock.
 ...
PMID:Modulatory role of the epinergic system in the neuroendocrine-immune system function. 1096 35

Targeted mutagenesis of the glucocorticoid receptor has revealed an essential function for survival and the regulation of multiple physiological processes. To investigate the effects of an increased gene dosage of the receptor, we have generated transgenic mice carrying two additional copies of the glucocorticoid receptor gene by using a yeast artificial chromosome. Interestingly, overexpression of the glucocorticoid receptor alters the basal regulation of the hypothalamo-pituitary-adrenal axis, resulting in reduced expression of corticotropin-releasing hormone and adrenocorticotrope hormone and a fourfold reduction in the level of circulating glucocorticoids. In addition, primary thymocytes obtained from transgenic mice show an enhanced sensitivity to glucocorticoid-induced apoptosis. Finally, analysis of these mice under challenge conditions revealed that expression of the glucocorticoid receptor above wild-type levels leads to a weaker response to restraint stress and a strongly increased resistance to lipopolysaccharide-induced endotoxic shock. These results underscore the importance of tight regulation of glucocorticoid receptor expression for the control of physiological and pathological processes. Furthermore, they may explain differences in the susceptibility of humans to inflammatory diseases and stress, depending on individual prenatal and postnatal experiences known to influence the expression of the glucocorticoid receptor.
 ...
PMID:Mice with an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock. 1107 99