Untitled

Abstract

Introduction Sepsis may impair mitochondrial utilization of oxygen. Since hepatic dysfunction is a hallmark of sepsis, we hypothesized that the liver is more susceptible to mitochondrial dysfunction than the peripheral tissues, such as the skeletal muscle. We studied the effect of prolonged endotoxin infusion on liver, muscle and kidney mitochondrial respiration and on hepatosplanchnic oxygen transport and microcirculation in pigs.

Renal Oxygenation and Hemodynamics in Kidney Injury

“…Sodium transport was decreased in both, hence, renal oxygen consumption factored for sodium reabsorption was increased in both. In another study in pigs with endotoxin infusion for 24 hours, renal oxygen extraction increased at 12 hours and remained persistently elevated at 24 hours [17]. In the above studies, renal oxygen utilization was increased despite a reduction in GFR and the filtered tubular load.…”

Sepsis-induced myopathy

“…Whereas Porta et al reported no changes in skeletal muscle oxidative phosphorylation in prolonged endotoxemia (108), Trumbeckaite and Gellerich and colleagues showed significant reductions in complex I/III activity in the vastus lateralis of endotoxin-treated rabbits (109). Others have shown that, in the CLP model, sepsis decreases complex I activity and ATP levels in hind-limb muscle, mirroring previous findings reported in muscle biopsies from septic patients (77).…”

Microcirculation vs. Mitochondria—What to Target?

“…Several rodent studies that included resuscitation demonstrated hyperlactatemia despite unchanged or even increased tissue PO 2 , and this coincided with both reduced function and structural damage to mitochondria ( 74 , 82 – 85 ). Resuscitated models investigating higher species (cats, swine, baboons) and characterized by a normotensive and a normo- or even hyperdynamic circulation, confirmed these findings ( 20 , 86 – 89 ). In this context, studies simultaneously recording parameters of both microcirculation and cellular O 2 utilization assume particular importance: LPS-challenged, fluid-resuscitated swine showed a reduced efficiency of hepatic mitochondrial respiration despite maintained liver surface laser Doppler blood flow ( 20 ).…”

“…Resuscitated models investigating higher species (cats, swine, baboons) and characterized by a normotensive and a normo- or even hyperdynamic circulation, confirmed these findings ( 20 , 86 – 89 ). In this context, studies simultaneously recording parameters of both microcirculation and cellular O 2 utilization assume particular importance: LPS-challenged, fluid-resuscitated swine showed a reduced efficiency of hepatic mitochondrial respiration despite maintained liver surface laser Doppler blood flow ( 20 ). The same group however reported in a longer-term model, unchanged liver tissue mitochondrial resuscitation with a tendency toward enhanced microcirculatory blood flow ( 88 ).…”

“…In this context, the concept of cytopathic hypoxia (or, perhaps, more accurately, cytopathic dysoxia) attempts to reconcile the phenomenon that organ failure coincides with hardly any cell death, availability of oxygen at the cellular level, relatively minor inflammatory cell migration, and capacity of these failed organs to recover ( 72 , 73 ). Cytopathic dysoxia refers to impaired ATP formation despite normal [or even supra-normal ( 20 )] tissue PO 2 levels. It can result from several factors, for instance, diminished delivery of key substrates (e.g., pyruvate) into the tricarboxylic acid (TCA) cycle, inhibition of various TCA cycle or (in particular) electron transport chain enzymes such as Complexes I and IV ( 74 , 75 ), and uncoupling [“slipping” ( 76 )] of the electron transport chain with a decrease in the proton gradient across the inner mitochondrial membrane resulting in production of heat rather than generation of ATP.…”