Changes in Vascular Responsiveness to a Thromboxane Mimetic in Endotoxin Tolerance

Tempel, G; Brown, Alan N.; Morinelli, Thomas A.; Halushka, Perry V.; Cook, James A.

doi:10.1097/00024382-200116050-00012

Cited by 3 publications

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“…In rats rendered tolerant to lethal doses of endotoxin by repeated sublethal doses of endotoxin, the pressor response to phenylephrine was attenuated, but a higher peak response to U46619 was observed compared with controls (Coffee et al, 1991), although in the same model, the sensitivity of the response to U46619 in isolated aortic rings was reduced (Temple et al, 2001). The reason for these differences between the contractile agents is unclear, but one possibility is differences between their signaling pathways.…”

Section: Downloaded Frommentioning

confidence: 97%

Effects of in Vivo Lipopolysaccharide Infusion on Vasoconstrictor Function of Rat Isolated Mesentery, Kidney, and Aorta

Farmer

Roberts²,

Gardiner³

et al. 2003

J Pharmacol Exp Ther

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Continuous infusion of lipopolysaccharide (LPS) into conscious rats elicits regionally selective cardiovascular disturbances. The aim of the present study was to assess contractile function in different vascular preparations (renal, mesenteric, and thoracic aorta) taken from rats infused with LPS for 2 or 24 h. Sustained responses to continuous infusion of methoxamine but not to KCl were reduced in the aorta (at 2 and 24 h LPS) and mesentery (at 24 h LPS) but not in the renal vascular bed. In contrast, transient responses to bolus doses of methoxamine were unchanged in the mesentery. In Ca 2ϩ -imaging experiments with fura-2, challenge with a single concentration of methoxamine (10 M, which showed an impaired contractile response at 24 h LPS) induced a rise in intracellular Ca 2ϩ in the mesenteric artery that was not different from the control. Furthermore, in the aorta, the contractile response to caffeine was attenuated only in the 2 h LPS group. These results show that there is regional heterogeneity in in vitro vascular responsiveness in preparations taken from LPS-infused rats. Thus, in mesenteric beds and aortae, but not renal beds, there is hypocontractility to methoxamine that is not due to a generalized inability of the smooth muscle to contract, which is evident with sustained but not transient application of agonist (mesentery) and which, in late endotoxemia (24 h LPS), does not appear to involve abnormalities in Ca 2ϩ mobilization or entry.

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Section: Downloaded Frommentioning

confidence: 97%

Effects of in Vivo Lipopolysaccharide Infusion on Vasoconstrictor Function of Rat Isolated Mesentery, Kidney, and Aorta

Farmer

Roberts²,

Gardiner³

et al. 2003

J Pharmacol Exp Ther

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“…Our previous studies demonstrated that in peritoneal macrophages from LPS-tolerant rat, GTPase activity, GTP g S binding, and protein content of G i3a and G i2a were significantly decreased. [61][62][63] In the same model, it was found that G i3a mRNA expression was also decreased. 64 Thus decreases of G i protein content and function in LPS-tolerant rat may be another manifestation of LPS tolerance.…”

Section: Proximal Post-receptor Signaling Protein Alterations In Endotoxin Tolerancementioning

confidence: 99%

Review: Molecular mechanisms of endotoxin tolerance

Cook

2004

Journal of Endotoxin Research

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The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti-inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased G i protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-kB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kB (IkB) isoforms. Also at the nuclear level, increase in the NF-kB subunit p50 homodimer expression and increased activation of peroxisome-proliferatoractivated receptors-g (PPARg) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.

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Molecular mechanisms of endotoxin tolerance

Fan¹,

Cook²

2004

J. Endotoxin Res.

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377

344

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The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti-inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased Gi protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kappaB (IkappaB) isoforms. Also at the nuclear level, increase in the NF-kappaB subunit p50 homodimer expression and increased activation of peroxisome-proliferator-activated receptors-gamma (PPARgamma) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.

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Changes in Vascular Responsiveness to a Thromboxane Mimetic in Endotoxin Tolerance

Cited by 3 publications

References 0 publications

Effects of in Vivo Lipopolysaccharide Infusion on Vasoconstrictor Function of Rat Isolated Mesentery, Kidney, and Aorta

Effects of in Vivo Lipopolysaccharide Infusion on Vasoconstrictor Function of Rat Isolated Mesentery, Kidney, and Aorta

Review: Molecular mechanisms of endotoxin tolerance

Molecular mechanisms of endotoxin tolerance

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