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Am J Physiol Regul Integr Comp Physiol (October 28, 2004). doi:10.1152/ajpregu.00182.2004
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Submitted on March 18, 2004
Accepted on October 25, 2004

Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and the p55 TNF-{alpha} receptor

Xianzhong Meng1*, Lihua Ao1, Yong Song1, Christopher D Raeburn1, David A Fullerton1, and Alden H Harken1

1 Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA

* To whom correspondence should be addressed. E-mail: xianzhong.meng{at}uchsc.edu.

Hemorrhagic shock causes myocardial contractile depression. While this myocardial disorder is associated with increased expression of tumor necrosis factor-alpha (TNF-{alpha}), the role of TNF-{alpha} as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-{alpha} receptor mediates the myocardial depressive effect of TNF-{alpha}. Toll-like receptor 4 (TLR4) regulates cellular expression of pro-inflammatory mediators following lipopolysaccharide stimulation and may be involved in tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-{alpha} response to hemorrhagic shock as well as the role of TLR4 in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-{alpha} production with myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-{alpha} production and myocardial depression, and determined the roles of TNF-{alpha} and TNF-{alpha} receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in an increase in plasma and myocardial TNF-{alpha} (4.9 folds and 4.5 folds, respectively) at 30 min, while it induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-{alpha} response and attenuated myocardial depression (left ventricular developed pressure 43.0 ± 6.2 mmHg in TLR4 mutant vs. 30.0 ± 3.6 mmHg in wild type, P<0.05). TNF-{alpha} KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-{alpha} KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-{alpha} response during hemorrhagic shock and that TNF-{alpha} through the p55 receptor activates a pathway leading to myocardial depression. Thus, TLR4 and the p55 TNF-{alpha} receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.




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