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Cytokine. 2010 Jan;49(1):30-8. doi: 10.1016/j.cyto.2009.10.006. Epub 2009 Nov 13.

Blockade of multiple but not single cytokines abrogates downregulation of angiotensin II type-I receptors and anticipates septic shock.

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Department of Anesthesiology, University of Regensburg, Franz-Josef-Strauss Allee 11, 93042 Regensburg, Germany.


In this prospective, randomized animal study, the role of proinflammatory cytokines in the pathogenesis sepsis-induced circulatory failure with downregulation of angiotensin-II-type-I-(AT(1))-receptors was investigated. Sepsis in wild-type mice and in mice with deficiencies for TNF-alpha, IL-1beta, IFN-gamma or IL-6 was induced by cecal ligation and puncture (CLP) and wild-type mice were injected with cytokines. Animals were treated with glucocorticoids or small interfering RNA (siRNA) targeting single or multiple cytokines or NF-kappaB. Vascular smooth muscle cells (VSMCs) were incubated with cytokines. CLP resulted in circulatory failure and a significant downregulation of AT(1)-receptors. Injection of single proinflammatory cytokines also strongly downregulated AT(1)-receptors paralleled by a markedly endogenous liberation of further cytokines, whereas, simultaneous blockade of these endogenously activated cytokines by dexamethasone prevented downregulation of AT(1)-receptors. Furthermore, inhibition of multiple but not single cytokines by treatment with siRNA against multiple cytokines or NF-kappaB significantly attenuated CLP-induced AT(1)-receptor downregulation and prevented septic circulatory failure. Our data demonstrate that downregulation of AT(1)-receptors during sepsis is due to multiple but not single cytokines and define a relevant role for NF-kappaB in the pathogenesis of septic shock.

[Indexed for MEDLINE]

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