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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The response of the adrenal cortex to corticotropin during sepsis is variable. We have previously demonstrated a significant decrease of corticosterone production by rat adrenocortical cells in response to corticotropin stimulation after incubation with septic shock plasma (SP) as compared with control plasma (CP). We have studied the mechanisms of this depression. The following defects were demonstrated. (1) Cells bound less radioiodinated corticotropin analog after SP treatment (2.9 +/- 0.4 femtomoles/50 micrograms DNA) than after CP treatment (6.4 +/- 0.3 fmole/50 micrograms DNA). (2) Cyclic adenosine monophosphate (cAMP) production was less after SP treatment (59.3 +/- 4 pmole per 10(5) cells per two hours) compared with CP treatment (110.3 +/- 11.3 pmole per 10(5) cells per two hours). (3) Exogenously added dibutyryl cAMP was unable to correct the defect in corticosterone production after SP treatment (4.96 +/- 0.7 micrograms/24 hr) as compared with CP treatment (6.99 +/- 0.5 micrograms/24 hr). Our studies suggest this defect is located in the synthesis of pregnenolone from cholesterol. These mechanisms may be responsible for the low cortisol levels previously observed in humans during septic shock.
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PMID:Mechanisms of adrenocortical depression during Escherichia coli shock. 632 Jul 64

When gram-negative bacterial lipopolysaccharides (LPS) are injected intravenously into the rabbit or rat, they bind to plasma lipoproteins, particularly high density lipoproteins (HDL). The present studies were performed to examine the mechanisms by which LPS-HDL complexes are removed from the circulation and taken up by various tissues. Our approach was to compare the sites of specific tissue binding and uptake of HDL and of LPS-HDL complexes in the rat and squirrel monkey. In the rat, binding of homologous 125I-HDL was demonstrated principally in the adrenal gland, ovary, liver, and spleen. [3H]LPS-HDL complexes (produced in vitro by incubating Salmonella typhimurium [3H]LPS with rat HDL and lipoprotein-free plasma) bound to the same tissues, but with apparently lower affinities. The specificity of binding of both 125I-HDL and [3H]LPS-HDL to these organs was demonstrated in two ways. First, tissue binding of both radiolabeled preparations was swamped out by raising the circulating levels of HDL-cholesterol from 32 to 140 mg/dl. Second, treatment of the animals with dexamethasone abolished specific binding of both HDL preparations to the adrenal gland while administration of adrenocorticotropin increased the specific adrenal binding of the two preparations. The steady-state plasma clearance rate for 125I-HDL equaled 774 +/- 29 microliters/h and was significantly lower (557 +/- 39 microliters/h) for the LPS-HDL complex, a finding that presumably reflected the lesser ability of the various tissues to bind the LPS-HDL complex. Binding studies were also done in the squirrel monkey, an animal that has the same level of circulating HDL cholesterol as the rat, but nearly three times more cholesterol in low density lipoproteins. Specific binding of homologous 125I-HDL and [3H]LPS-HDL was again found principally in the adrenal gland and liver. The results indicate that the sites of tissue uptake of bacterial LPS are strongly influenced by binding of LPS to HDL. In particular, LPS-HDL binding may be an important determinant of the extent to which LPS are taken up by the adrenal gland during bacterial sepsis.
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PMID:Sites of tissue binding and uptake in vivo of bacterial lipopolysaccharide-high density lipoprotein complexes: studies in the rat and squirrel monkey. 703 86

There is increasing evidence that the hypercortisolemia in inflammatory diseases suppresses the elaboration of proinflammatory cytokines, thus protecting the host from its own defence reactions. In severe sepsis and septic shock cortisol levels are usually elevated, but some patients may have relative adrenal insufficiency. This may contribute to the overwhelming systemic inflammatory response syndrome. We evaluated the impact of low-dose hydrocortisone infusion (10 mg/h) on the course of the systemic inflammatory response syndrome. This dose corresponds to a maximum secretory rate of cortisol achieved in corticotropin-stimulated healthy humans. In a prospective observational study 57 surgical patients with severe sepsis or septic shock were studied, of which in addition to the conventional treatment 12 patients were infused with low-dose hydrocortisone, and 45 were treated without any corticosteroid. In the longitudinal analysis the systemic inflammatory response--as judged by body temperature, cardiovascular response, and kinetics of inflammatory mediators such as phospholipase A2, C-reactive protein, and neutrophil elastase--started to differ in favor of the hydrocortisone-treated patients after 2 days of treatment (P < 0.05, Mann-Whitney U test). The difference disappeared after withdrawal of exogenous cortisol. Shock reversal was achieved in all patients treated with low-dose hydrocortisone. The data provide evidence that low-dose hydrocortisone infusion attenuates the systemic inflammatory response in human septic shock. From an immunological point of view a relative cortisol deficiency may contribute to the amplified immune response in systemic inflammatory diseases. A randomized clinical trial must clarify the impact of low-dose hydrocortisone infusion on the clinical course and outcome of septic shock patients.
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PMID:Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. The Phospholipase A2 Study Group. 786 82

Current knowledge about the pathophysiology of septic shock is reviewed, and biotechnology-based therapies under development are discussed. Patients with septic shock begin their clinical course with leukocytosis, fever, tachycardia, tachypnea, and organ hypoperfusion; shock ensues as immunologic and vasoactive mediators produce hypotension. There are many metabolic and cardiovascular responses, and single- or multiple-organ failure is common. Patients may experience adult respiratory distress syndrome. A multitude of endogenous and exogenous factors have been linked to the pathophysiology of sepsis and septic shock, including (1) endotoxin from gram-negative bacteria, (2) peptidoglycan and exotoxins from gram-negative bacteria, (3) endotoxin-binding proteins and receptors, (4) bactericidal proteases, (5) exotoxins from gram-positive bacteria, (6) acute-phase proteins and proteases, (7) cytokines, (8) arachidonic acid metabolites, (9) complement, (10) beta-endorphin, (11) histamine, (12) stimulation of intrinsic and extrinsic coagulation pathways and proteases, and (13) endothelium-derived factors and adhesion molecules. Molecular entities and strategies under development to combat septic shock include monoclonal antibodies to endotoxin, active immunization with lipid-A analogues, bactericidal permeability-increasing protein, interleukin inhibitors, and inhibitors of tumor necrosis factor-alpha. Successful treatment of septic shock will probably require a combination of agents, including antimicrobials. An ideal goal for biotechnology in the area of septic shock is to prevent invading pathogens from overstimulating the host's immune system and to systematically eliminate those pathogens. Biotechnology is opening new avenues to the treatment of septic shock.
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PMID:Pathophysiology of septic shock and implications for therapy. 816 70

Hyponatremia occurs frequently in patients with severe infections though its cause has not been established. Recent studies have reported that in some patients with septicemia, adrenocortical insufficiency is present. To ascertain whether occurrence of hyponatremia and adrenocortical insufficiency might be related, we studied 40 patients with septicemia (11 in septic shock). A short corticotropin test was used for assessing the adrenocortical function. Though both adrenocortical failure (in 5 patients) and hyponatremia (serum sodium concentration < 125 mmol/l in 3 patients) occurred, there was no apparent relationship between the entities.
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PMID:Hyponatremia and adrenocortical function in patients with severe bacterial infections. 846 Mar 33

We investigated the effects of the opiate antagonist naloxone on the release of beta-endorphin and cortisol in rats subjected to sepsis. Sepsis was induced in weanling male Wistar albino rats (3-4 weeks old, 75-90 g) by cecal ligation and double perforation (CLP). Forty animals were randomly allocated to four groups. Group 1 was given naloxone hydrochloride 0.5 mg/kg subcutaneously after CLP and this treatment was repeated at 2-h intervals until the rats were killed. Group 2 rats underwent a sham operation. Group 3 (control group) rats had CLP. Group 4 consisted of nonoperated animals used to establish normal reference values. Eighteen hours after CLP or sham operation, the rats were killed by cervical dislocation and a blood sample was drawn via cardiac puncture to determine the beta-endorphin and cortisol levels. The beta-endorphin levels were significantly higher in the control group than in the sham-operated, naloxone-treated (NT), and nonoperated rats (P < 0.05). However, there were no significant differences in plasma beta-endorphin levels between sham-operated, NT and nonoperated rats (P > 0.05). Plasma cortisol levels were significantly higher in the control group compared with the other three groups and this difference was more significant in sham-operated and nonoperated rats (P < 0.01). However, no difference existed between sham-operated, NT, and nonoperated rats (P > 0.05). This study demonstrates that the endogenous opioid system may play a role in the activation of the pituitary-adrenal axis following sepsis, and shows that the increase in beta-endorphin and cortisol could be blocked by naloxone.
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PMID:Effects of naloxone on beta-endorphin and cortisol release in sepsis. 890 1

Immune neuroendocrine interactions are vital for the individual's survival in certain physiopathological conditions, such as sepsis and tissular injury. It is known that several animal venoms, such as those from different snakes, are potent neurotoxic compounds and that their main component is a specific phospholipase A type 2 (PLA2). It has been described recently that the venom from Crotalus durissus terrificus [snake venom (SV), in the present study] possesses some cytotoxic effect in different in vitro and in vivo animal models. In the present study, we investigated whether SV and its main component, PLA2 (obtained from the same source), are able to stimulate both immune and neuroendocrine functions in mice, thus characterizing this type of neurotoxic shock. For this purpose, several in vivo and in vitro designs were used to further determine the sites of action of SV-PLA2 on the hypothalamo-pituitary-adrenal (HPA) axis function and on the release of the pathognomonic cytokine, tumor necrosis factor alpha (TNF alpha), of different types of inflammatory stress. Our results indicate that SV (25 microg/animal) and PLA2 (5 microg/animal), from the same origin, stimulate the HPA and immune axes when administered (i.p.) to adult mice; both preparations were able to enhance plasma glucose, ACTH, corticosterone (B), and TNF alpha plasma levels in a time-related fashion. SV was found to activate CRH- and arginine vasopressin-ergic functions in vivo and, in vitro, SV and PLA2 induced a concentration-related (0.05-10 microg/ml) effect on the release of both neuropeptides. SV also was effective in changing anterior pituitary ACTH and adrenal B contents, also in a time-dependent fashion. Direct effects of SV and PLA2 on anterior pituitary ACTH secretion also were found to function in a concentration-related fashion (0.001-1 microg/ml), and the direct corticotropin-releasing activity of PLA2 was additive to those of CRH and arginine vasopressin; the corticotropin-releasing activity of both SV and PLA2 were partially reversed by the specific PLA2 inhibitor, manoalide. On the other hand, neither preparation was able to directly modify spontaneous and ACTH-stimulated adrenal B output. The stimulatory effect of SV and PLA2 on in vivo TNF alpha release was confirmed by in vitro experiments on peripheral mononuclear cells; in fact, both PLA2 (0.001-1 microg/ml) and SV (0.1-10 microg/ml), as well as concavalin A (1-100 microg/ml), were able to stimulate TNF alpha output in the incubation medium. Our results clearly indicate that PLA2-dependent mechanisms are responsible for several symptoms of inflammatory stress induced during neurotoxemia. In fact, we found that this particular PLA2-related SV is able to stimulate both HPA axis and immune functions during the acute phase response of the inflammatory processes.
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PMID:A phospholipase A2-related snake venom (from Crotalus durissus terrificus) stimulates neuroendocrine and immune functions: determination of different sites of action. 944 33

A 3-day-old female Pinto was admitted with profuse watery diarrhea and severe hypovolemic shock. After 1 week of intensive care, the foal developed seizures associated with profound serum electrolyte abnormalities suggestive of hypoadrenocorticism. Treatment with prednisone and isotonic saline (0.9% NaCl) solution led to prompt clinical response. Premature withdrawal of prednisone resulted in relapse of clinical signs. A diagnosis of adrenal insufficiency was made on the basis of clinical signs, electrolyte abnormalities, low baseline cortisol concentration, and lack of response to administration of exogenous adrenocorticotropin. Two months later, adrenocortical function was normal and the foal was doing well clinically. Clinical signs of acute adrenal insufficiency in neonatal foals can be confused with other conditions, such as septicemia, enteritis, and ruptured urinary bladder. A persistently low serum sodium-to-potassium ratio associated with CNS malfunction should warrant investigation of adrenal gland function. Acute hypoadrenocorticism in foals may be reversible.
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PMID:Adrenal insufficiency in a neonatal foal. 960 31

Leukemia inhibitory factor (LIF) levels are elevated in sepsis and correlate with shock and poor prognosis. We have previously shown that lipopolysaccharide (LPS) administration induces hypothalamic and pituitary LIF expression in vivo, which is associated with the acute rise in circulating adrenocorticotrophic hormone (ACTH) levels. As AtT-20 cells respond to LIF, we established murine LIF (mLIF) stably transfected AtT-20 cell lines to study LIF regulation of pro-opiomelanocortin (POMC) expression and ACTH secretion. Our results show that mLIF transfectants accumulated mLIF (up to 15.6 +/- 3.2 ng/mL after 24 h) as well as increased ACTH secretion (up to 2.4-fold above control cells) in conditioned medium. The magnitude of ACTH induction correlated with mLIF concentrations in different transfectants (r = 0.75-0.88, p < 0.05). Moreover, mLIF transfectants showed a higher sensitivity to CRH stimulation with an increased ACTH production within 8 h (p < 0.05), whereas control cells were responsive to CRH at 24 h. Additionally, mLIF transfectants exhibited a maximum threefold ACTH induction, compared to 1.7-fold in control cells. Furthermore, mLIF transfectants have a blunted dexamethasone-mediated inhibition of ACTH (35% inhibition in control cells vs no inhibition in mLIF-transfected cells at 24 h). These findings support and extend the previous observations of LIF acting at the pituitary level, and indicate that mLIF stably-transfected AtT-20 cells are a useful model for studying mLIF-mediated gene regulation in pituicytes.
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PMID:Leukemia inhibitory factor (LIF) modulates pro-opiomelanocortin (POMC) gene regulation in stably transfected AtT-20 cells overexpressing LIF. 965 69

The function of the hypothalamic-pituitary-adrenal axis as related to the degree of severity of a septic process was assessed by measuring plasma levels of beta-endorphin, ACTH and cortisol. Sixty-one cases of postoperative patients treated at the intensive care unit were classified into four groups according to the severity of infection: Group 1 (control) included patients who did not show any sign of infection, group 2 patients with sepsis, group 3 patients with septic syndrome and group 4 patients with septic shock. Compared to G1 patients' ACTH values (4.16+/-2.6pg/ml), a statistically significant increase in ACTH values in various stages of septicemia (p < 0.005) with a noticeable difference also between G3 (7.11 +/-3.7pg/ml) and G4 (11.5+/-6.6pg/ml) (p<0.05) was found. Differences were also observed in beta-endorphin (with a level of significance between the several groups of p = 0.0001). Also, beta-endorphin values in G4 (40.6+/-30.3 pg/ml) differed significantly from each of G1 (17.5 +/-6.6 pg/ml), G2 (21.1+/-11.3 pg/ml) and G3 (23.5+/-12 pg/ ml) (p<0.05). A progressive hypercortisolemia was obvious, with values of G4 (37.2+/-15.6 microg/dl) differing significantly from those of G1 (18+/-4.6microg/dl) and G2 (24-/+8.4microg/dl) (p<0.05) and of G3 (28.5+/-12.3 microg/dl) from that of G1 (p < 0.05). Interestingly, a dissociation of ACTH, beta-endorphin and cortisol was observed, in that the increased values of beta-endorphin and cortisol, detected in the G3 were not associated with a parallel increase in ACTH. These findings might be interpreted in the sense of an impairment of the stress stimulation of the hypothalamic pituitary adrenal axis. Provided that such a situation can be lethal, our results further confirm the idea that a low-dose, steroid replacement might be beneficial to critical illness.
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PMID:Dissociation of ACTH, beta-endorphin and cortisol in graded sepsis. 980 26


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