Elevated plasma 6-keto-prostaglandin F1α in patients in septic shock

Halushka, Perry V.; Reines, H. David; Barrow, Susan E.; Blair, Ian A.; Dollery, C. T.; Rambo, William M.; Cook, James A.; Wise, W. C.

doi:10.1097/00003246-198506000-00001

Cited by 76 publications

(14 citation statements)

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“…Due to the thickness of the smooth muscle layer compared with the endothelium, the output of PGI 2 after COX-2 induction became massive and could explain the high 6-keto-PGF 1α serum levels of shock patients and their extreme hypotension (27). Most such studies were performed with rats, in which • NO dominates as a vasodilator (51).…”

Section: Discussionmentioning

confidence: 99%

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COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

Schildknecht¹,

Bachschmid²,

Baumann³

et al. 2004

FASEB j.

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High levels of prostacyclin (PGI2; measured as 6-keto-PGF1alpha) have been reported in patients under septic shock. Because this was at variance with our previous findings of nitration and inhibition of PGI2 synthase by endotoxin (LPS) in the endothelium, we examined the role of vascular smooth muscle as an alternative source of PGI2. Bovine aortic smooth muscle cells (SMC) in passage 1 contained high levels of PGI2 synthase but no activity and no detectable levels of COX-1 or COX-2. LPS exposure for 3 h caused COX-2 mRNA and protein levels to rise during 8 h together with a large increase in PGI2 synthase activity. In contrast, cytokines lead to only a moderate increase of both PGI2 and PGE2. Specific COX-2 inhibitors completely blocked PGI2 formation but PGE2 synthesis only partially. Unexpectedly, *NO formation remained low over 6-8 h, which may be a reason for the lack of nitration and inhibition of prostacyclin synthase in LPS exposed SMC. Our results can explain the clinical observation of severe hypotension in progressive stages of septic shock as a mechanism to compensate endothelial dysfunction. According to our data, the use of COX-2-specific inhibitors may not be advisable in septic patients. In contrast, administration of COX-1-specific blockers could prevent platelet aggregation during progressed stages of endotoxic shock.

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Section: Discussionmentioning

confidence: 99%

“…However patients in endotoxic shock release high amounts of 6-keto-PGF 1α , which may have originated from nonendothelial sources (27,28). In contrast to high amounts of PGI 2 synthase, COX activity was found to be low in smooth muscle of unstimulated vessels (29).…”

mentioning

confidence: 96%

COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

Schildknecht¹,

Bachschmid²,

Baumann³

et al. 2004

FASEB j.

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“…The apparent discrepancy that in septic patients high 6‐keto‐PGF 1α levels were observed (28) could be solved by the finding of a high output of PGI 2 from LPS‐treated bovine vascular smooth muscle cells (VSMC). This synthesis strictly depends on the induction of PGHS‐2, which exclusively provides PGH 2 to the constitutively present PGI 2 ‐synthase and could counterregulate the observed vasoconstriction resulting from an impaired endothelial PGI 2 synthesis (29).…”

mentioning

confidence: 99%

Peroxynitrite provides the peroxide tone for PGHS‐2‐dependent prostacyclin synthesis in vascular smooth muscle cells

2005

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Endotoxin-treated vascular smooth muscle cells (VSMCs) were recently shown to release high amounts of prostacyclin (PGI2) dependent on the induction of prostaglandin endoperoxide synthase-2 (PGHS-2). In contrast to endothelial PGI2-synthase, for which nitration and inhibition by peroxynitrite was reported, addition of SIN-1 as a peroxynitrite-generating system did not cause inhibition but rather doubled PGI2 release by VSMC. The hypothesis of peroxynitrite supplementing an unsaturated peroxide tone for PGHS-2 was supported by H2O2 exerting the same effect. Studies performed with purified PGHS-2 revealed maximal elevation of enzyme activity in the presence of equimolar concentrations of *NO and *O2-, which together form peroxynitrite, while excessive production of either one radical was inhibitory. Most importantly, 6-keto-PGF1alpha formation by intact VSMC depended on a nearly equimolar generation of *NO and *O2- for providing the endogenous peroxide tone. These findings, together with the observation that an excess of exogenously added *NO, as well as uric acid as a scavenger of peroxynitrite potently reduced PGI2 release, underlined the role of peroxynitrite as the dominating and rate-limiting intracellular mediator of peroxide tone in VSMC. The results allow us to postulate a new cross-talk between the *NO and the prostanoid pathways with a crucial role for peroxynitrite in providing the peroxide tone for a continuous activation of PGHS-2.

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“…The vascular hyporeactivity that occurs in septic shock involves a variety of factors, including cytokines, platelet activating factor [69], prostacyclin [70], complement-derived C5a anaphylatoxin [71] and nitric oxide (NO) [72,73]. ATPsensitive potassium (KATP) channels have been implicated in vascular hyporeactivity [74].…”

Section: Corticosteroid Effects On Vascular Reactivitymentioning

confidence: 99%

Corticosteroids in Sepsis: Pathophysiological Rationale and the Selection of Patients

Salluh¹,

Bozza²,

Japiassú³

et al. 2010

EMIDDT

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Corticosteroids have been proposed for decades as adjunctive therapy of severe infections. These drugs have complex mechanisms of action involving anti-inflammatory and vasoactive properties. However, due to discordant results from clinical studies, the use of corticosteroids to treat patients with severe infections is still a matter of intense debate in the scientific and medical community. In the present article, we review the underlying mechanisms related to the potential benefits of corticosteroids and their impact on clinical management of severe sepsis.

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Elevated plasma 6-keto-prostaglandin F1α in patients in septic shock

Cited by 76 publications

References 0 publications

COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

Peroxynitrite provides the peroxide tone for PGHS‐2‐dependent prostacyclin synthesis in vascular smooth muscle cells

Corticosteroids in Sepsis: Pathophysiological Rationale and the Selection of Patients

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