title: Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-alpha receptor.
abstract: 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.
authors.affiliation: Dept. of Surgery, Box C-320, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA. xianzhong.meng@uchsc.edu
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.forename: Yong
authors.initials: Y
authors.lastname: Song
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Raeburn
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: Alden H
authors.initials: AH
authors.lastname: Harken
mesh_terms: D000818:Animals; D006321:Heart / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000172:deficiency
chemical_list: D011956:Receptors, Cell Surface; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha