Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Posttranslational processing of the adrenomedullin gene product results in the formation of at least two biologically active peptides, adrenomedullin (AM) and proadrenomedullin N-20 terminal peptide (PAMP). Produced predominantly in the vasculature, both peptides are potent hypotensive agents, albeit via unique mechanisms of action. The gene is transcribed in a variety of other tissues including brain, pituitary, and kidney. Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, AM is diuretic and natriuretic, and both AM and PAMP inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion, again by apparently differing mechanisms. Additionally, AM antagonizes CRH-stimulated ACTH release. The peptides are produced in numerous brain sites, including hypothalamus and brainstem. Inhibition of AVP release has been reported and the physiologic significance of AM's ability to inhibit water drinking and salt appetite has been established. Thus the peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in the blood vessel. Interestingly, direct cardiac effects (positive inotropism and chronotropism) and CNS actions (sympathostimulation) have been reported, leading to the hypothesis that these peptides also can exert important cardioprotective effects, helping to prevent vascular collapse during states of high AM secretion such as sepsis.
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PMID:Proadrenomedullin-derived peptides. 957 82

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

A 64-year-old woman was hospitalized because of poor general condition, gastrointestinal upset, unexplained fever, electrolyte imbalances, and an incidental finding of bilateral huge adrenal masses on computerized tomography (CT) of the abdomen. Non-Hodgkin's lymphoma (NHL) of B-cell origin was proven by ultrasound-guided aspiration biopsy of the left adrenal gland. Meanwhile, primary adrenal insufficiency was confirmed by her low serum cortisol level, high ACTH level, and inadequate adrenal response to the rapid ACTH stimulation test. The diagnosis of primary adrenal NHL was supported by detailed physical examinations, bone marrow examination, and such imaging studies as CT scan and sonography. She received three courses of chemotherapy with cyclophosphamide, vincristine, and prednisolone and there was an initial transient response, but she died of sepsis and progression of NHL three and a half months later.
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PMID:Adrenal insufficiency caused by primary aggressive non-Hodgkin's lymphoma of bilateral adrenal glands: report of a case and literature review. 1021 58

Because high circulating levels of glucocorticoids impair immunity and predispose to infections, we evaluated whether indices of cortisol (F) production could predict infections in patients with Cushing syndrome (CS) caused by ectopic production of ACTH (EA). Charts of 54 consecutive patients with untreated EA, without underlying diagnosis of small cell carcinoma of the lung, were reviewed, and types of infections, white blood cell (WBC) count, fever, as well as the glucocorticoid indices [0800 h F, daily urine F excretion (UFC), and daily urine 17-hydroxysteroid/g creatinine excretion (17OHS)], were recorded. Thirty-five patients had no or clinically mild infection; the remaining 19 patients had severe, systemic infection (n = 13) and/or sepsis (n = 6), including either bacterial or opportunistic pathogens or both (73.7%, 42.1%, and 13.8%, respectively). The latter group of patients had significantly higher indices of hypercortisolism (F, UFC, and 17OHS) than those with mild or no infections, but these indices did not correlate with temperature or WBC count. Thresholds for identifying severe infection were selected for maximal positive predictive value and were: F, 43.1 microg/dL; UFC, 2000 microg/day; and 17OHS, 35 mg/g creatinine. The most accurate discriminator for severe infection was 17OHS, based on a positive predictive value of 64.7%. Our data strongly suggests that the likelihood for a bacterial or opportunistic infection in CS patients, even without underlying small cell carcinoma of the lung, is greatest in patients with extreme hypercortisolism. The predictive value of total WBC count or the presence of an elevated temperature is not sufficient to identify patients with severe, life-threatening infection.
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PMID:Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. 1115 75

Two recent small randomized trials evaluating a 5- to 12-day course of low dose hydrocortisone in patients with septic shock have reported a significant clinical improvement and a reduction in mortality. Recent studies indicate that an overaggressive and unregulated systemic inflammatory response is a major determinant of outcome in sepsis. In septic shock, nonsurvivors as opposed to survivors have over time: (1) significantly higher NF-kB activity in peripheral mononuclear cells, (2) persistent elevation in circulating inflammatory cytokine levels, and (3) elevated ACTH and cortisol levels. Current research recognizes that cytokines can cause a concentration-dependent resistance to endogenous glucocorticoids (GC). It is postulated that an excess of cytokine-induced transcription factors, such as NF-kB, may form complexes with activated glucocorticoid receptors (GCR), preventing GCR interaction with DNA. When T cells are incubated with a combination of cytokines, GC resistance is induced in a cytokine concentration-dependent fashion and reversed by removal of cytokines. Prolonged treatment with physiological doses of exogenous GCs may be necessary to compensate adequately for the inability of target organs to respond to endogenous cortisol and for the inability of the host to produce appropriately elevated levels of GCs. This hypothesis is supported by the laboratory findings of a recent randomized study of patients with unresolving acute respiratory disease.
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PMID:New rationale for glucocorticoid treatment in septic shock. 1067 98

Neuroendocrine-immune interactions are vital for the individual's survival in certain physiopathological conditions such as sepsis and tissular injury. It is known that several snake venoms (SV) are potent neurotoxic compounds and that their main component is a specific phospholipase type 2 (PLA2). It has been recently described that the venom from crotalus durissus terrificus (SV) possesses a cytotoxic effect in different in vitro and in vivo animal models. In the present study we investigated whether SV is able to stimulate both TNFalpha and neuroendocrine functions in a sexual dimorphic fashion. For this purpose the modulatory role of endogenous sex steroids during neurotoxemia was evaluated. Our results indicate that SV (25 microg/animal) stimulates the hypothalamo-pituitary-adrenal axis and TNFalpha secretion when administered (ip) to adult male mice, such responses were characterized by a time-related enhance in plasma glucose, ACTH, corticosterone and TNFalpha levels. SV-stimulated glycemia, corticosteronemia and adrenal glucocorticoid were sexually dimorphic. Twenty-day gonadectomized mice showed a similar sexual dimorphism to that found in intact animals, however, they additionally showed a sexual dimorphic pattern in cytokine release in plasma 30 min post-SV. Estradiol (E2) treatment, in gonadectomized mice, abolished some characteristics of the sexual dimorphism, such as hyperglycemia, hypercorticosteronemia and hypercytokinemia. Finally, in vitro experiments indicate that: a) gonadectomy increased spontaneous and SV-stimulated cytokine output by incubated peripheral mononuclear cells (PMNC), regardless of the sex; and b) despite E2 treatment, in gonadectomized, did not modify the pattern of basal and SV-elicited TNFalpha secretion induced by orchidectomy, fully reversed the enhance in basal and SV-stimulated cytokine release found after ovariectomy alone. Our results further indicate that neurotoxemia, due to SV challenge, induces several symptoms common to those of inflammatory stress; they also strongly support that both gender and endogenous sex steroids are responsible for neuroendocrine-immunological sexual dimorphism.
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PMID:Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFalpha responses to phospholipase A2-related neurotoxin (from crotalus durissus terrifcus) challenge. 1100 68

To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission. On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18). Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs. 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs. 231 ng/L). Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs. 17), TSH (0.97 vs. 0.29 mE/L), T3 (0.53 vs. 0.38 nmol/L), reverse T3 (rT3) (0.75 vs. 1.44 nmol/L), C-reactive protein (34 vs. 78 mg/L), nonesterified fatty acids (0.32 vs. 0.95 mmol/L), and lactate (7.3 vs. 3.2 mmol/L). In those who survived, the most important changes within 48 h were seen in a normalization of cortisol and ACTH levels, but without a circadian rhythm; a decrease of rT3 and an increase in the T3/rT3 ratio; and a decrease in the levels of the nonesterified free fatty acids and an unaltered high urinary nitrogen excretion. At this moment, it is yet unknown whether the hormonal abnormalities are determining factors in the outcome of acute meningococcal sepsis or merely represent secondary effects. Understanding the metabolic and endocrine alterations is required to design possible therapeutic approaches. The striking difference between nonsurvivors and survivors calls for reconsideration of corticosteroid treatment in children with meningococcal sepsis.
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PMID:Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. 1106 34

Septic shock in animals and humans is associated with thymic atrophy and generalized lymphocyte apoptosis that impairs T cell responses. Injection of animals with E. coli lipopolysaccharide (LPS) mimics bacterial sepsis-induced thymic atrophy. Leukemia inhibitory factor (LIF) induces pituitary ACTH release in vivo, and LIF administration to mice induces acute thymic atrophy. We have investigated the role of LIF in LPS-induced thymic atrophy. LPS significantly elevated serum LIF within 1 h and induced thymic LIF mRNA within 6 h. Moreover, pretreatment of mice with anti-LIF antibody significantly reduced LPS-induced thymic atrophy. Using adrenalectomized mice and 17-day fetal thymic organ cultures treated with the steroidogenic enzyme inhibitor metyrapone, we demonstrated that LIF induced both systemic and intrathymic corticosteroid production. These data demonstrate systemic and intrathymic pathways of E. coli LPS-induced acute thymic atrophy mediated by LIF and corticosteroids.
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PMID:Leukemia inhibitory factor is a mediator of Escherichia coli lipopolysaccharide-induced acute thymic atrophy. 1238 26

Leptin, which plays a key role in regulating energy homeostasis, may also modulate the inflammatory response. An inflammatory challenge with endotoxin has been shown to stimulate leptin release in the rodent. This finding has not been reproduced in humans or in nonhuman primates, although leptin levels have been reported to increase in septic patients. We have therefore examined the effects of endotoxin injection on plasma leptin levels in nine ovariectomized monkeys and four postmenopausal women. In an initial study in five monkeys, mean leptin levels did not increase during the first 5 h after endotoxin treatment, but did increase significantly from 6.4 +/- 2.1 ng/ml at baseline to 12.3 +/- 4.4 ng/ml at 24 h (P = 0.043). In a second study, a significant increase in leptin over time was noted after endotoxin treatment (P < 0.001); leptin release during the 16- to 24-h period after endotoxin injection was 48% higher than during the control period (P = 0.043). A similar stimulatory effect of endotoxin on leptin was observed when monkeys received estradiol replacement. In a third study, repeated injections of endotoxin over a 3-d period stimulated IL-6, ACTH, cortisol, and leptin release (P < 0.001). Leptin increased during the first day of treatment in all animals, but only monkeys with baseline plasma leptin levels greater than 10 ng/ml exhibited a sustained increase in leptin throughout the 3-d period. There was a significant correlation (r = 0.81; P = 0.008) between the mean baseline leptin level and the percent increase in leptin over baseline on the last day of treatment. In the human subjects, plasma leptin concentrations did not change significantly during the 7-h period after endotoxin injection. However, leptin increased in all four women from a mean baseline of 8.34 +/- 3.1 to 13.1 +/- 4.3 ng/ml 24 h after endotoxin (P = 0.038). In summary, endotoxin stimulates the release of leptin into peripheral blood in the human and nonhuman primate, but the time course is different from that reported in the rodent. These results are consistent with previous reports of increased blood leptin levels in patients with sepsis. The significance of these findings and the potential role of leptin in modulating the response to inflammation in the human require further study.
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PMID:Endotoxin stimulates leptin in the human and nonhuman primate. 1262 20

After a period of initial enthusiasm, several trials cast serious doubts on the usefulness of corticosteroids for the treatment of patients with severe sepsis. Short course with high doses of steroides should not be given in patients with severe sepsis. The attention is now addressed to low-dose of corticosteroides. The rational for a replacement therapy with hydrocortisone in patients with cathecolamines-dependent septic shock is based on the concept that this may be complicated by an occult adrenal insufficiency and a glucocorticoid peripheral resistance syndrome. Low doses of hydrocortisone has been shown to reproduce the normal effects of cortisol: anti-inflammatory properties and an increased in the vasoconstrictor response to cathecolamines. There is no concordance in literature about the role of replacement therapy with hydrocortisone on survival in patients with septic shock. Waiting for the results of the European confirmatory phase III trial, and based on the results of the French phase III trial, one may recommended to treat septic shock patients who have a cortisol increment after ACTH of less than 9 micro g/dl with 50 mg of hydrocortisone every 6 hours for seven days combined with 50 micro g of fludrocortisone once a day for seven days.
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PMID:Sepsis clinical knowledge: a role of steroid treatment. 1276 16


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