eritoran and Endotoxemia

Lipopolysaccharide (LPS) or endotoxin can induce Toll-like receptor 4 signaling and cause microcirculatory dysfunction, which can lead to multiple organ dysfunction. The goal of this study was to investigate whether Toll-like receptor 4 antagonist, eritoran tetrasodium, can attenuate microcirculatory dysfunction in endotoxemic rats. Seventy-two male Wistar rats were divided into three groups as follows: control, LPS, and eritoran + LPS. These rats received laparotomy to exteriorize a segment of terminal ileum for microcirculation examination on intestinal mucosa, muscle, and Peyer patch. The rats in the eritoran + LPS group received 10 mg kg⁻¹ eritoran intravenously. The rats in the LPS and eritoran + LPS groups received 15 mg kg⁻¹ LPS intravenously. Microcirculatory blood flow intensity was measured by full-field laser perfusion imager. Total and perfused small-vessel densities, microvascular flow index, and heterogeneity index were investigated by sidestream dark-field video microscope. Our results revealed that eritoran restored the mean arterial pressure. At 240 min, the microcirculatory blood flow intensity was higher in the eritoran + LPS group than in the LPS group as follows: mucosa (1,094 [SD, 398] vs. 543 [SD, 163] perfusion unit [PU]; P < 0.001), muscle (752 [SD, 124] vs. 357 [SD, 208] PU; P < 0.001), and Peyer patch (961 [SD, 162] vs. 480 [SD, 201] PU; P < 0.001). Eritoran also attenuated endotoxin-induced elevation in the serum level of D-dimer. In conclusion, we have established a promising rat protocol to investigate the intestinal microcirculation in endotoxemia. Our data indicate that eritoran can reduce microcirculatory dysfunction in endotoxemic rats.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Disaccharides; Endotoxemia; Fibrin Fibrinogen Degradation Products; Intestinal Mucosa; Intestines; Lipopolysaccharides; Male; Microcirculation; Rats; Rats, Wistar; Sugar Phosphates; Toll-Like Receptor 4

Severe sepsis and septic shock are often accompanied by acute cardiovascular depression. Lipopolysaccharide (LPS) signaling via Toll-like receptor 4 (TLR4) can induce septic organ dysfunction. The aim of this study was to elucidate the in vivo impact of pharmacological TLR4 antagonism on LPS-induced cardiovascular depression using eritoran tetrasodium (E5564). To simulate sepsis, C3H/HeN mice were challenged i.p. with 2 mg/kg body weight LPS. With the intent to antagonize the LPS effects, eritoran was administered i.v. (4 mg/kg body weight). Physical activity, peripheral blood pressure, and heart frequency were recorded before and after LPS and eritoran injection. In addition, intracardiac hemodynamic parameters were analyzed with a pressure conductance catheter. After 2 and 6 h of LPS stimulation ± eritoran treatment, the hearts and aortae were harvested, and TLR as well as inflammatory mediator expression was measured using reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Lipopolysaccharide significantly decreased arterial blood pressure over time. Administration of eritoran partially prevented the LPS-dependent reduction in blood pressure and preserved cardiac function. In addition, LPS increased the expression of CD14 and TLR2 in cardiac and aortic tissue. In aortic tissue, eritoran attenuated this increase, whereas no significant reduction was observed in the heart. Furthermore, cardiac and aortic inducible nitric oxide synthetase mRNA levels were significantly increased 6 h after LPS application. This effect was reduced in the presence of eritoran. In summary, the beneficial influence of eritoran on cardiovascular function in vivo seems to rely mainly on reduction of LPS-induced inducible nitric oxide synthetase expression as well as on attenuated cytokine expression in the vascular wall.

Topics: Animals; Disaccharides; Endotoxemia; Female; Lipopolysaccharides; Male; Mice; Sepsis; Sugar Phosphates; Toll-Like Receptor 4

Topics: Animals; Disaccharides; Endotoxemia; Female; Male; Sepsis; Sugar Phosphates; Toll-Like Receptor 4