Endotoxin-induced liver hypoxia: Defective oxygen delivery versus oxygen consumption

In vivo EPR was used to investigate liver oxygenation in a hemodynamic model of septic shock in mice. Oxygen-sensitive material was introduced either (i) as a slurry of fine particles which localized at the liver sinusoids (pO₂ = 44.39 ± 5.13 mmHg) or (ii) as larger particles implanted directly into liver tissue to measure average pO₂ across the lobule (pO₂ = 4.56 ± 1.28 mmHg). Endotoxin caused decreases in pO₂ at both sites early (5-15 min) and at late time points (6 h after endotoxin; sinusoid = 11.22 ± 2.48 mmHg; lobule = 1.16 ± 0.42 mmHg). The overall pO₂ changes observed were similar (74.56% versus 74.72%, respectively). Blood pressures decreased transiently between 5 and 15 min (12.88 ± 8% decrease) and severely at 6 h (59 ± 9% decrease) following endotoxin, despite volume replacement with saline. Liver and circulatory nitric oxide was elevated at these times. Liver oxygen extraction decreased from 44% in controls to only 15% following endotoxin, despite severe liver hypoxia. Arterial oxygen saturation, blood flow (hepatic artery), and cardiac output were unaffected. Pretreatment with L-NMMA failed to improve endotoxin-induced oxygen defects at either site, whereas interleukin-13 preserved oxygenation. These site-specific measurements of pO₂ provide in vivo evidence that the principal cause of liver hypoxia during hypodynamic sepsis is reduced oxygen supply to the sinusoid and can be alleviated by maintaining sinusoidal perfusion.