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: Xia Zhang, Chen Lu, Ming Gao, Xinyun Cao, Tuanzhu Ha, John H Kalbfleisch, David L Williams, Chuanfu Li, Race L Kao
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 42 Issue 1 Pg. 31-7 (Jul 2014) ISSN: 1540-0514 [Electronic] United States
• PMID: 24569510 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• E5564
• Lipid A
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Dose-Response Relationship, Drug
• Heart (physiopathology)
• Hemodynamics (drug effects, physiology)
• Lipid A (analogs & derivatives, pharmacology)
• Male
• Mice, Knockout
• NF-kappa B (metabolism)
• Neutrophil Infiltration (drug effects, physiology)
• Phosphorylation (drug effects, physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Shock, Hemorrhagic (etiology, metabolism, physiopathology)
• Soft Tissue Injuries (complications)
• Toll-Like Receptor 4 (antagonists & inhibitors, deficiency, physiology)
• Tumor Necrosis Factor-alpha (biosynthesis)