Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep.

Introduction: Acute kidney injury (AKI) is a common and feared complication of sepsis. The pathogenesis of sepsis-induced AKI is largely unknown, and therapeutic interventions are mainly supportive. In the present study, we tested the hypothesis that pharmacological inhibition of Toll-like receptor 4 (TLR4) would improve renal function and reduce renal damage in experimental sepsis, even after AKI had already developed.

Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs.

Background: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors.

Methods And Findings: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours.

Toll-like receptor 4 inhibitor TAK-242 attenuates acute kidney injury in endotoxemic sheep.

Background: This study was conducted to investigate the role of toll-like receptor 4 (TLR4) in mediating acute kidney injury in endotoxemic sheep using the selective TLR4 inhibitor TAK-242.

Methods: A randomized, controlled, experimental study was performed with 20 adult Texel crossbred sheep. Before an Escherichia coli lipopolysaccharide infusion (3 μg · kg(-1) · h(-1) for 24 h), sheep were randomized to receive a bolus dose (2 mg/kg), followed by a continuous infusion (4 mg · kg(-1) · 24 h(-1)) of either TAK-242 (n = 7) or vehicle (n = 7).

Mixed endothelin receptor antagonism with tezosentan improves intestinal microcirculation in endotoxemic shock.

Background: Microcirculatory dysfunction is a common feature of sepsis. The potent vasoconstrictor endothelin (ET) is released in sepsis and endotoxemia, potentially contributing to sepsis-induced microcirculatory failure. In this study we tested the hypothesis that mixed ET receptor antagonism with tezosentan would improve splanchnic microcirculatory blood flow in acute porcine endotoxemia.