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INFLAMMATION AND CYTOKINES

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

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

Submitted 18 March 2004 ; accepted in final form 25 October 2004

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

tumor necrosis factor- receptors; mouse; cardiac contractile function; knockout

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