| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | Shock | ||||
| Publisher: | LIPPINCOTT WILLIAMS & WILKINS | ||||
| Place of Publication: | PHILADELPHIA | ||||
| Volume: | 32 | ||||
| Number of Issue or Book Chapter: | 3 | ||||
| Page Range: | pp. 239-246 | ||||
| Date: | 2009 | ||||
| Institutions: | Medicine > Lehrstuhl für Anästhesiologie Biology, Preclinical Medicine > Institut für Physiologie | ||||
| Identification Number: |
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| Keywords: | SEPTIC SHOCK; GENE-EXPRESSION; ACTIVATION; ENDOTOXEMIA; MECHANISMS; CYTOKINES; RATS; HYDROCORTISONE; PROTECTS; MICE; Sepsis; proinflammatory cytokines; NF-kappa B; alpha(1)-adrenergic receptor | ||||
| Dewey Decimal Classification: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 66974 |
Web of ScienceAbstract
The reduced pressure response to norepinephrine during sepsis has directed our interest to the regulation of alpha(1)-adrenergic receptors. Because nuclear factor (NF)-kappa B occupies a prominent role in the inflammatory cascade, we hypothesized that NF-kappa B downregulates alpha(1)-receptors by liberation of proinflammatory cytokines and thereby contributes to septic circulatory failure. ...
Abstract
The reduced pressure response to norepinephrine during sepsis has directed our interest to the regulation of alpha(1)-adrenergic receptors. Because nuclear factor (NF)-kappa B occupies a prominent role in the inflammatory cascade, we hypothesized that NF-kappa B downregulates alpha(1)-receptors by liberation of proinflammatory cytokines and thereby contributes to septic circulatory failure. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type mice and mice with deficiencies for proinflammatory cytokines, and mice were injected with TNF-alpha, IL-1 beta, IFN-gamma, or IL-6. Animals were treated with glucocorticoids or small interfering RNA (siRNA) targeting multiple cytokines and NF-kappa B. Vascular smooth muscle cells were incubated with cytokines and calcium mobilization, mRNA stability assays, and promoter studies with alpha(1)-promoter-luciferase constructs were performed. Cecal ligation and puncture treatment resulted in a hyperdynamic circulatory failure, diminished calcium response to norepinephrine, and a significant downregulation of alpha(1)-receptors. Proinflammatory cytokines also downregulated alpha(1)-receptors by suppressing promoter activity at the level of gene transcription. However, suppression of single proinflammatory cytokines in cytokine knockout mice did not diminish CLP-induced downregulation of alpha(1)-receptors. In contrast, blocking multiple cytokines via siRNA pretreatment or glucocorticoid administration attenuated CLP-induced cardiovascular failure and downregulation of alpha(1)-receptors. Furthermore, inhibiting NF-kappa B activity by siRNA reduced the production of cytokines, prevented circulatory failure and downregulation of alpha(1)-receptors, and improved survival of septic mice. Our findings indicate that NF-kappa B has a central role in augmenting proinflammatory cytokine production during sepsis, which in turn downregulates alpha(1)-receptor expression. Our data further define a critical role for NF-kappa B in the pathogenesis of septic shock, indicating that targeting NF-kappa B is a desired therapeutic strategy to treat septic vasoplegia.
Metadata last modified: 19 Dec 2024 12:04
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