Effects of inhibitors of the activity of cyclo‐oxygenase‐2 on the hypotension and multiple organ dysfunction caused by endotoxin: A comparison with dexamethasone

Leach, Mary; Hamilton, Lorna; Olbrich, Antje; Wray, Gillian M.; Thiemermann, Christoph

doi:10.1038/sj.bjp.0701869

Cited by 53 publications

(37 citation statements)

References 37 publications

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“…2 ). The ED 50 for PEinduced contraction in ring segments of LPS-treated rats was 459 ± 83 nM compared with 57 ± 6 nM for vehicle-treated controls ( P < 0.001). 4F administration in the absence of LPS treatment did not alter the response to PE (ED 50 = 69 ± 8 nM).…”

Section: Chromatographic Colocalization Of 4f and Lps In Hdlmentioning

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: Chromatographic Colocalization Of 4f and Lps In Hdlmentioning

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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“…The present results are also the first demonstration that both COX isoforms are required for the hypotensive response to LPS to develop. With a single exception (33), all previous studies found that COX-2 is not required for the development of LPS hypotension (47,87), and one study (87) found that COX-1 is also uninvolved in this response. However, it should be considered that all previous studies were performed in anesthetized rats receiving fluid resuscitation.…”

Section: Effects Of Cox-1 and Cox-2 Inhibitors On Lps-induced Responsesmentioning

confidence: 99%

“…However, it should be considered that all previous studies were performed in anesthetized rats receiving fluid resuscitation. Under these conditions, rats respond to high doses of LPS with a slowly developing, progressive fall in blood pressure (47,87). The present study was conducted in unanesthetized rats not receiving fluid resuscitation, conditions under which rats respond to high doses of LPS with a rapid drop in blood pressure that corresponds in time to the first phase of the hypothermic response (70).…”

Section: Effects Of Cox-1 and Cox-2 Inhibitors On Lps-induced Responsesmentioning

confidence: 99%

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Steiner

Hunter²,

Phipps³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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DL, Romanovsky AA. Cyclooxygenase-1 or -2-which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol Regul Integr Comp Physiol 297: R485-R494, 2009. First published June 10, 2009 doi:10.1152/ajpregu.91026.2008.-Systemic inflammation is associated with either fever or hypothermia. Fever, a response to mild systemic inflammation, is mediated by cyclooxygenase (COX)-2 and not by COX-1. However, it is still disputed whether COX-2, COX-1, neither, or both mediate(s) responses to severe systemic inflammation, and, in particular, the hypothermic response. We compared the effects of SC-236 (COX-2 inhibitor) and SC-560 (COX-1 inhibitor) on the deep body temperature (Tb) of rats injected with a lower (10 g/kg iv) or higher (1,000 g/kg iv) dose of LPS at different ambient temperatures (Tas). At a neutral Ta (30°C), the rats responded to LPS with a polyphasic fever (lower dose) or a brief hypothermia followed by fever (higher dose). SC-236 (2.5 mg/kg iv) blocked the fever induced by either LPS dose, whereas SC-560 (5 mg/kg iv) altered neither the febrile response to the lower LPS dose nor the fever component of the response to the higher dose. However, SC-560 blocked the initial hypothermia caused by the higher LPS dose. At a subneutral T a (22°C), the rats responded to LPS with early (70 -90 min, nadir) dose-dependent hypothermia. The hypothermic response to either dose was enhanced by SC-236 but blocked by SC-560. The hypothermic response to the higher LPS dose was associated with a fall in arterial blood pressure. This hypotensive response was attenuated by either SC-236 or SC-560. At the onset of LPS-induced hypothermia and hypotension, the functional activity of the COX-1 pathway (COX-1-mediated PGE2 synthesis ex vivo) increased in the spleen but not liver, lung, kidney, or brain. The expression of splenic COX-1 was unaffected by LPS. We conclude that COX-1, but not COX-2, mediates LPS hypothermia, and that both COX isoforms are required for LPS hypotension. body temperature; thermoregulation; fever; inflammation SO STRONGLY IS SYSTEMIC INFLAMMATION associated with changes in deep body temperature (T b ) that every clinical definition of the systemic inflammatory response syndrome includes a change in T b (11,48). Whereas the majority (ϳ90%) of patients with systemic inflammation have an increased T b , a number of them (ϳ10%) have a lowered T b (6, 17). Thermoregulatory manifestations are also present in animal models of systemic inflammation. In a rat model of systemic inflammation induced by bacterial LPS, the pattern of T b change depends on the ambient temperature (T a ) and the LPS dose. At a neutral or supraneutral T a (warm environment), fever is the prevailing response; the fever is monophasic when the dose of LPS is low (just suprathreshold), but it turns polyphasic as the dose increases (66, 68, 69, 71, 79); a mild hypothermia may precede the polyphasic fever when the dose of LPS is high (68). At a subneutral T a (cool environment), hypothermia followed by fever is the predominant response; th...

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“…Moreover, COX-2 inhibition has been shown to ameliorate liver I/R injury (21)(22)(23) and to reduced liver injury and hepatic microcirculatory dysfunction in response to LPS (24). In contrast, inhibition of COX-2 failed to attenuate hepatocellular injury in rats with endotoxemia (25), and COX-2-deficient mice showed more susceptibility to Con A-induced hepatitis (26). Furthermore, it has been reported that COX-2 inhibition blocked the effect of arachidonic acid, but not of ethanol, on the induction of collagen type I gene expression by stellate cells (27).…”

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confidence: 99%

Cyclooxygenase-2 Deficiency Enhances Th2 Immune Responses and Impairs Neutrophil Recruitment in Hepatic Ischemia/Reperfusion Injury

Hamada

Tsuchihashi

Avanesyan

et al. 2008

The Journal of Immunology

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Cyclooxygenase-2 (COX-2) is a prostanoid-synthesizing enzyme that is critically implicated in a variety of pathophysiological processes. Using a COX-2-deficient mouse model, we present data that suggest that COX-2 has an active role in liver ischemia/reperfusion (I/R) injury. We demonstrate that COX-2-deficient mice had a significant reduction in liver damage after I/R insult. The inability of COX-2−/− to elaborate COX-2 products favored a Th2-type response in these mice. COX-2−/− livers after I/R injury showed significantly decreased levels of IL-2, as well as IL-12, a cytokine known to have a central role in Th1 effector cell differentiation. Moreover, such livers expressed enhanced levels of the anti-inflammatory cytokine IL-10, shifting the balance in favor of a Th2 response in COX-2-deficient mice. The lack of COX-2 expression resulted in decreased levels of CXCL2, a neutrophil-activating chemokine, reduced infiltration of MMP-9-positive neutrophils, and impaired late macrophage activation in livers after I/R injury. Additionally, Bcl-2 and Bcl-xL were normally expressed in COX-2−/− livers after injury, whereas respective wild-type controls were almost depleted of these two inhibitors of cell death. In contrast, caspase-3 activation and TUNEL-positive cells were depressed in COX-2−/− livers. Therefore, our data support the concept that COX-2 is involved in the pathogenic events occurring in liver I/R injury. The data also suggest that potential valuable therapeutic approaches in liver I/R injury may result from further studies aimed at identifying specific COX-2-derived prostanoid pathways.

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Effects of inhibitors of the activity of cyclo‐oxygenase‐2 on the hypotension and multiple organ dysfunction caused by endotoxin: A comparison with dexamethasone

Cited by 53 publications

References 37 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-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Cyclooxygenase-2 Deficiency Enhances Th2 Immune Responses and Impairs Neutrophil Recruitment in Hepatic Ischemia/Reperfusion Injury

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