title: Toll-like receptor 4 plays a central role in cardiac dysfunction during trauma hemorrhage shock.
abstract: Cardiac dysfunction is a major consequence that contributes to the high mortality of trauma-hemorrhage (TH) patients. Recent evidence suggests that innate immune and inflammatory responses mediated by Toll-like receptors (TLRs) play a critical role in the pathophysiologic mechanisms of acute organ dysfunction during TH. This study investigated the role of TLR4 in cardiac dysfunction following TH. Toll-like receptor 4-deficient (TLR4-/-, n = 7/group) and age-matched wild-type (WT, n = 8/group) mice were subjected to TH that was induced by soft tissue injury and blood withdrawal from the jugular vein to a mean arterial pressure of 35 ± 5 mmHg. Cardiac function and mean arterial pressure were measured with a Millar system before, during, and after blood withdrawal. Sham surgical-operated mice served as control (WT, n = 9/group; TLR4-/-, n = 10/group). Cardiac function in WT mice was significantly reduced following TH. However, cardiac function was well preserved in TLR4-/- mice. Administration of a TLR4 antagonist (3 mg/kg) to WT mice also significantly attenuated TH-induced cardiac dysfunction. Western blot showed that either TLR4-/- or TLR4 antagonist markedly attenuated TH-induced decreases in the levels of phosphorylated-Akt in myocardium. In addition, inhibition of TLR4 attenuated TH-induced myocardial nuclear factor κB-binding activity as well as lung myeloperoxidase activity and tumor necrosis factor α production. The data indicate that TLR4 plays a central role in TH-induced cardiac dysfunction. Toll-like receptor 4 deficiency or TLR4 inhibition attenuated cardiac dysfunction following TH, which may involve activation of the phosphoinositide 3-kinase/Akt signaling and decrease in nuclear factor κB-binding activity. Toll-like receptor 4 antagonism may be a new and novel approach for the treatment and management of cardiac dysfunction in TH patients.
authors.affiliation: Departments of *Surgery and †Biometry and Medical Computing, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Xinyun
authors.initials: X
authors.lastname: Cao
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: John H
authors.initials: JH
authors.lastname: Kalbfleisch
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008050:Lipid A / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D017695:Soft Tissue Injuries / Q000150:complications; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C404742:E5564; D008050:Lipid A; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt