Inhibition of Cyclooxygenase-2 by NS-398 Following Hemorrhage and Subsequent Sepsis: No Beneficial Effects in Either Gender

Kahlke, Volker; Seidel, Mirja; Stapela, Sietje; Brötzmann, K.; Schafmayer, Clemens; Schröder, Jörg

doi:10.1089/109629604773860282

Cited by 6 publications

(8 citation statements)

References 28 publications

(51 reference statements)

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“…These doses of 1400W and NS-398 have been shown to maximally inhibit NOS2 and COX-2 activities in septic rats ( 38,39 ). Separate control groups received vehicle injection, 4F, or 1400W, but no LPS.…”

Section: Vessel Reactivity Studiesmentioning

confidence: 99%

The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

Dai

Datta

Zhang

et al. 2010

Journal of Lipid Research

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Sepsis is a major cause of death in hospitalized patients. Approximately 50% of patients in intensive care units develop sepsis, and the overall mortality rate is 29% ( 1 ). Mortality is due, in large part, to the cytotoxic actions of lipopolysaccharide (LPS), an endotoxic component of the outer membrane of Gram-negative bacteria. LPS is released from bacterial membranes and activates Toll-like receptors (TLR) on monocytes, neutrophils, and other target cells ( 2-5 ). TLRs transduce LPS action by activating nuclear factor (NF)-B-dependent signaling ( 4-6 ). By this mechanism, LPS stimulates the synthesis/release of infl ammatory cytokines, which play an important role in the innate immune response ( 7,8 ). Dysregulation of this infl ammatory response can lead to intravascular coagulation and multiple organ failure. LPS-induced cytokine production also increases expression of nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX-2), thus enhancing the synthesis of nitric oxide (NO) and arachidonic acidderived vasoactive prostanoids. These products have been implicated in hemodynamic disturbances in sepsis by reducing peripheral vascular resistance ( 9-14 ). Cardiovascular (CV) failure, characterized by severe hypotension and cardiac dysfunction, is linked to increased mortality in patients with severe sepsis ( 15-17 ).Lipoproteins are thought to play a role in the neutralization/detoxifi cation of endotoxin (18)(19)(20). Low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) bind to LPS and direct it to the liver for metabolism and excretion (18)(19)(20). HDL is most effective in clearing endotoxin, a property attributed to its relatively high phospholipid content compared with LDL and VLDL ( 18,21 ). With increasing Abstract High density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) reduce infl ammatory responses to lipopolysaccharide (LPS). We tested the hypothesis that the apoA-I mimetic peptide 4F prevents LPS-induced defects in blood pressure and vascular reactivity. Systolic blood pressure (SBP) was measured in rats at baseline and 6 h after injection of LPS (10 mg/kg) or saline vehicle. Subgroups of LPStreated rats also received 4F (10 mg/kg) or scrambled 4F (Sc-4F). LPS administration reduced SBP by 35% compared with baseline. 4F attenuated the reduction in SBP in LPStreated rats (17% reduction), while Sc-4F was without effect. Ex vivo studies showed a reduced contractile response to phenylephrine (PE) in aortae of LPS-treated rats (ED 50 = 459 ± 83 nM) compared with controls (ED 50 = 57 ± 6 nM). This was associated with nitric oxide synthase 2 (NOS2) upregulation. 4F administration improved vascular contractility (ED 50 = 60 ± 9 nM), reduced aortic NOS2 protein, normalized plasma levels of NO metabolites, and reduced mortality in LPS-treated rats. These changes were associated with a reduction in plasma endotoxin activity. In vivo administration of , , GM-082952 (C.R.W. and G.D.) and HL-85282 (H.G.) Abbreviations: apoA-I, apolipoprotein A-I; COX-2,...

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Section: Vessel Reactivity Studiesmentioning

confidence: 99%

The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

Dai

Datta

Zhang

et al. 2010

Journal of Lipid Research

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“…In total, the studies identified for this paper demonstrated that COX inhibition, and genetic COX-2 deletion [12], improved survival in 21 of 29 studies (72.4%) [3, 7, 9, 11, 12, 14, 18–21, 24, 27, 32, 34, 37, 39, 40, 42, 44, 45], caused no change in survival in 7 studies (24.3%) [15, 23, 33, 38, 43, 46, 47], and reduced survival in a single mouse study (3.4%) [35]. …”

Section: Resultsmentioning

confidence: 99%

“…Seventeen studies were identified in 16 manuscripts that examined the impact of either pharmacological or genetic inhibition of COX enzymes and infection-induced sepsis [46–61]. There were three publications that did not report mortality data and were excluded from analysis [51, 52, 56].…”

Section: Resultsmentioning

confidence: 99%

“…The models of sepsis used in these studies included three mouse CLP studies [46, 53, 60], three rat studies involving the introduction of feces into the peritoneal cavity [49, 57, 61], two rat studies using systemic infection with live E. coli [48, 57], one rat study with systemic infection with live Group B Streptococcus [58], two canine studies with systemic infection with live E. coli [50, 51], three porcine studies with systemic infection with live Group B Streptococcus [47, 56, 59], one mouse study with systemic infection with live Vibrio vulnificus [55], one mouse study using live Group A Streptococcus [54], and one sheep study of infection with live E. coli [48]. …”

Section: Resultsmentioning

confidence: 99%

“…This included one of the two COX-2 knockout mouse studies [54]. Two studies showed no effect on mortality of COX inhibition [46, 47] and two mouse studies revealed increased death in either COX-inhibitor-treated mice [55] or a COX-2 knockout mouse model [53]. …”

Section: Resultsmentioning

confidence: 99%

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Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?

Aronoff

2012

Mediators of Inflammation

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Prostaglandins are important mediators and modulators of the inflammatory response to infection. The prostaglandins participate in the pathogenesis of hemodynamic collapse, organ failure, and overwhelming inflammation that characterize severe sepsis and shock. In light of this, cyclooxygenase (COX) inhibiting pharmacological agents have been extensively studied for their capacity to ameliorate the aberrant physiological and immune responses during severe sepsis. Animal models of sepsis, using the systemic administration of pathogen-associated molecular patterns (PAMPs) or live pathogens, have been used to examine the effectiveness of COX inhibition as a treatment for severe sepsis. These studies have largely shown beneficial effects on mortality. However, human studies have failed to show clinical utility of COX inhibitor treatment in severely septic patients. Why this approach “worked” in animals but not in humans might reflect differences in the controlled nature of animal investigations compared to human studies. This paper contrasts the impact of COX inhibitors on mortality in animal models of sepsis and human studies of sepsis and examines potential reasons for differences between these two settings.

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Eicosanoid production varies by sex in mesenteric ischemia reperfusion injury

Rowe

Fleming

2020

Clinical Immunology

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Inhibition of Cyclooxygenase-2 by NS-398 Following Hemorrhage and Subsequent Sepsis: No Beneficial Effects in Either Gender

Abstract: Despite a significant reduction of PGE(2) concentration, NS-398 treatment has no beneficial effects on cytokine release and survival in this model of hemorrhage and subsequent sepsis.

Cited by 6 publications

References 28 publications

The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats

Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?

Eicosanoid production varies by sex in mesenteric ischemia reperfusion injury

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