Properties of US Standard Endotoxin (EC-5) in human male volunteers

Hochstein, H D; Fitzgerald, Edward A.; McMahon, F. Gilbert; Vargas, Ramón

doi:10.1177/096805199400100109

Cited by 39 publications

(21 citation statements)

References 6 publications

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“…[7][8][9] However, few studies have looked at dose-effect and time-course parameters specifically, [46][47][48] and some studies evaluated the HPA response to human endotoxemia. 48 Vedder et al studied the effects of low-and high-doses of LPS in male volunteers.…”

Section: Human Studiesmentioning

confidence: 99%

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Beishuizen

Thijs

2003

Journal of Endotoxin Research

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Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-a) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroidreleasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-a and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-a and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges. demonstrate higher plasma levels of IL-1 and TNF-a. Elevation of plasma glucocorticoids results in suppression of cytokines such as IL-1, IL-6, and TNF-a and in up-regulation of other cytokines, such as IL-4 and IL-10, and cytokine receptors. Thus, by regulation of cytokine production and action, the HPA axis contributes to modulation of the response to inflammation/infection. In addition, the role of HPA activation has been suggested to be a negative feedback system provided by the immunosuppressive activity of glucocorticoids, limiting inflammatory responses and preventing the immune system from over-reacting and causing tissue damage or autoimmunity.As early as 1957, Wexler et al. suggested that LPS could induce ACTH release since they found a depletion of ascorbic acid and cholesterol in the adrenal glands. 10 Moreover, LPS was not able to cause these changes in hypophysectomized rats. ...

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Section: Human Studiesmentioning

confidence: 99%

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Beishuizen

Thijs

2003

Journal of Endotoxin Research

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“…Additional sources of endotoxins include the bladder, peritoneal cavity and sinuses. Immune responses to LPS in the circulation include nausea, vomiting, diarrhea, dizziness, fever (Van Leeuwen et al, 1994), muscle aches and pain (Hochstein et al, 1994;Lynn et al, 2003). The tendency for LPS to reduce forelimb grip force responses in mice (Kehl et al, 2004) provides us with a model of the muscular discomfort that patients report during endotoxemia.…”

Section: Discussionmentioning

confidence: 99%

Movement-evoked hyperalgesia induced by lipopolysaccharides is not suppressed by glucocorticoids

Kovács

Papic

Larson

2008

Pain

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Systemic exposure to lipopolysaccharides (LPS) produces a variety of effects, including movementevoked hyperalgesia that can be measured using the grip force assay in mice. Because both lethality and enhanced sensitivity to cutaneous pain following exposure to endotoxins have each been attributed to inflammatory mediators, we explored the possibility that LPS-induced movementevoked hyperalgesia is also sensitive to manipulations of glucocorticoids that regulate these other LPS responses. We found that the hyperalgesic effect of LPS (5 mg/kg s.c.) in mice that were adrenalectomized did not differ from that in control mice that were sham-operated, even though mortality after LPS was potentiated by adrenalectomy. The development of tolerance to the movement-evoked hyperalgesic effect of LPS also did not differ between adrenalectomized and sham-operated control mice. In addition, mifepristone (25 mg/kg s.c.), a glucocorticoid antagonist, did not attenuate the hyperalgesic effect of LPS (2 mg/kg s.c.), yet this dose of mifepristone was sufficient to enhance the incidence of lethality induced by LPS. Enhancement of glucocorticoid activity by two injections of dexamethasone (1 mg/kg s.c.) had no effect on the degree of hyperalgesia in mice injected with LPS (5 mg/kg s.c.), yet this dose of dexamethasone was sufficient to attenuate the incidence of mortality induced by LPS in adrenalectomized mice. Finally, morphine (10 mg/kg i.p.) reversed the decrease in grip force caused by LPS (5 mg/kg i.p.), supporting the interpretation that decreases in grip force produced by LPS reflect muscle hyperalgesia that is not sensitive to glucocorticoids.

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“…Just 1% of this amount crossing the membrane into the bloodstream would essentially represent twice the amount of endotoxin currently allowed for single doses of parenteral pharmaceuticals by the FDA [19]. In the area of parenteral medicines, the wisdom of permitting the presence of any endotoxin is still a debated issue [20].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the DialGuard<sup>TM</sup> Device for Endotoxin Removal in Hemodialysis

Szathmáry¹,

Hegyi²,

Amoureux³

et al. 2004

Blood Purif

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Bacterial pyrogens, capable of penetrating dialyzer membranes, are responsible for a systemic inflammatory reaction in hemodialysis patients. Dialyzer reuse, involving rinsing of the dialyzer with pyrogen-containing water, may exacerbate this situation. Studies of the mechanism of action of endotoxin suggest that it irreversibly damages the vascular endothelium. The novel endotoxin removal method described here, is based on affinity-binding of endotoxin by the adsorbent ClarEtox^TM, a USP Class VI-certified resin that is the active component of the medical device DialGuard^TM. Under standard hemodialysis operating conditions, challenge of DialGuard with Pseudomonas maltophilia supernatant-spiked dialysate, containing 35–193 EU/ml endotoxin, resulted in endotoxin levels below 0.05 EU/ml in the treated dialysate. DialGuard was able to decrease endotoxin concentrations in the dialysate from a range of 2.39–8.49 to <0.005 EU/ml. DialGuard supports high fluid velocities at low back pressures and can be sanitized using the heat sanitization cycle of hemodialysis machines. DialGuard offers a simple, user-friendly way to reduce the concentration of endotoxin in dialysate and water for dialysis at a low cost.

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Properties of US Standard Endotoxin (EC-5) in human male volunteers

Cited by 39 publications

References 6 publications

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Movement-evoked hyperalgesia induced by lipopolysaccharides is not suppressed by glucocorticoids

Characterization of the DialGuard<sup>TM</sup> Device for Endotoxin Removal in Hemodialysis

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