| Dokumentenart: | Artikel | ||||
|---|---|---|---|---|---|
| Titel eines Journals oder einer Zeitschrift: | Shock | ||||
| Verlag: | LIPPINCOTT WILLIAMS & WILKINS | ||||
| Ort der Veröffentlichung: | PHILADELPHIA | ||||
| Band: | 32 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 3 | ||||
| Seitenbereich: | S. 239-246 | ||||
| Datum: | 2009 | ||||
| Institutionen: | Medizin > Lehrstuhl für Anästhesiologie Biologie und Vorklinische Medizin > Institut für Physiologie | ||||
| Identifikationsnummer: |
| ||||
| Stichwörter / Keywords: | SEPTIC SHOCK; GENE-EXPRESSION; ACTIVATION; ENDOTOXEMIA; MECHANISMS; CYTOKINES; RATS; HYDROCORTISONE; PROTECTS; MICE; Sepsis; proinflammatory cytokines; NF-kappa B; alpha(1)-adrenergic receptor | ||||
| Dewey-Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status: | Veröffentlicht | ||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden: | Ja | ||||
| Dokumenten-ID: | 66974 |
Web of ScienceZusammenfassung
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. ...
Zusammenfassung
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.
Metadaten zuletzt geändert: 19 Dez 2024 12:04
Altmetric