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

Abstract

Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-α (TNF-α), the role of TNF-α as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-α receptor mediates the myocardial depressive effects of TNF-α. 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-α response to hemorrhagic shock and TLR4’s role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-α production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-α production and myocardial depression, and determined the roles of TNF-α and TNF-α receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-α (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-α 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-α KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-α KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-α response during hemorrhagic shock and that TNF-α through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-α receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.