Schmidt, Christoph and Kurt, Birguel and Hoecherl, Klaus and Bucher, Michael (2009) INHIBITION OF NF-kappa B ACTIVITY PREVENTS DOWNREGULATION OF alpha(1)-ADRENERGIC RECEPTORS AND CIRCULATORY FAILURE DURING CLP-INDUCED SEPSIS. SHOCK, 32 (3). pp. 239-246. ISSN 1073-2322,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SEPTIC SHOCK; GENE-EXPRESSION; ACTIVATION; ENDOTOXEMIA; MECHANISMS; CYTOKINES; RATS; HYDROCORTISONE; PROTECTS; MICE; Sepsis; proinflammatory cytokines; NF-kappa B; alpha(1)-adrenergic receptor |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Anästhesiologie Biology, Preclinical Medicine > Institut für Physiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Sep 2020 08:25 |
| Last Modified: | 09 Sep 2020 08:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28549 |
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