• Lihua Ao, Yong Song, David A Fullerton, Charles A Dinarello, and Xianzhong Meng.
• Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorando, USA.
• Cytokine. 2007 Jun 1;38(3):124-9.

UnlabelledMultiple pro-inflammatory mediators contribute to cardiac dysfunction caused by bacterial lipopolysaccharide (LPS). The rapid TNF-alpha response is likely involved in the induction of down-stream myocardial depressant factors. Studies by our laboratory and others indicate an important role for ICAM-1 in endotoxemic cardiac dysfunction through leukocyte-independent mechanisms. The purpose of this study was to determine: whether ICAM-1 knockout improves cardiac function during endotoxemia and whether TLR4 and TNF-alpha regulate LPS-induced myocardial ICAM-1 expression.Methods And ResultsMice were treated with Escherichia coli LPS (0.5mg/kg iv). Myocardial ICAM-1 levels were analyzed by immunoblotting and left ventricular developed pressure (LVDP) was assessed by the Langendorff technique. In wild-type mice, peak ICAM-1 levels were observed at 4h when myocardial contractility was depressed. Myocardial contractility was improved following LPS in mice lacking functional TLR4, TNF-alpha or ICAM-1. TLR4 mutation abolished ICAM-1 expression with abrogation of precedent TNF-alpha response. Similarly, TNF-alpha knockout reduced myocardial ICAM-1 level following LPS treatment.ConclusionsICAM-1 contributes to the mechanism of endotoxemic cardiac dysfunction. TNF-alpha is involved in the regulation of myocardial ICAM-1 expression by TLR4.

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