| First Author | Meng X | Year | 2005 |
| Journal | Am J Physiol Regul Integr Comp Physiol | Volume | 288 |
| Issue | 3 | Pages | R600-6 |
| PubMed ID | 15514106 | Mgi Jnum | J:96316 |
| Mgi Id | MGI:3530164 | Doi | 10.1152/ajpregu.00182.2004 |
| Citation | Meng X, et al. (2005) Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-alpha receptor. Am J Physiol Regul Integr Comp Physiol 288(3):R600-6 |
| abstractText | Hemorrhagic shock causes myocardial contractile depression. Although 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 effects of TNF-alpha. 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-alpha response to hemorrhagic shock and TLR4's role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-alpha production to 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 increased plasma and myocardial TNF-alpha (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-alpha 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-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. |
