Cardiomyocytes express most known Toll-like receptors. Of these, TLR2, TLR4 and TLR5 signal via NF-kappaB, resulting in decreased contractility and a concerted inflammatory response.

Inherent in the remote organ injury caused by sepsis is a profound maldistribution of microvascular blood flow. Using a 24-h rat cecal ligation and perforation model of sepsis, we studied O(2) transport in individual capillaries of the extensor digitorum longus (EDL) skeletal muscle. We hypothesized that erythrocyte O(2) saturation (SO(2)) levels within normally flowing capillaries would provide evidence of either a mitochondrial failure (increased SO(2)) or an O(2) transport derangement (decreased SO(2)). Using a spectrophotometric functional imaging system, we found that sepsis caused 1) an increase in stopped flow capillaries (from 10 to 38%, P < 0.05), 2) an increase in the proportion of fast-flow to normal-flow capillaries (P < 0.05), and 3) a decrease in capillary venular-end SO(2) levels from 58.4 +/- 20.0 to 38.5 +/- 21.2%, whereas capillary arteriolar-end SO(2) levels remained unchanged compared with the sham group. Capillary O(2) extraction increased threefold (P < 0.05) and was directly related to the degree of stopped flow in the EDL. Thus impaired O(2) transport in early stage sepsis is likely the result of a microcirculatory dysfunction.

The diverse physiological actions of the "biologic gases," O2, CO, NO, and H2S, have attracted much interest. Initially viewed as toxic substances, CO, NO, and H2S play important roles as signaling molecules. The multiplicity of gas actions and gas targets and the difficulty in measuring local gas concentrations obscures detailed mechanisms whereby gases exert their actions, and many questions remain unanswered. It is now readily apparent, however, that heme-based proteins play central roles in gas-generation/reception mechanisms and provide a point where multiple gases can interact. In this review, we consider a number of key issues related to "gas biology," including the effective tissue concentrations of these gases and the importance and significance of the physical proximity of gas-producing and gas-receptor/sensors. We also take an integrated approach to the interaction of gases by considering the physiological significance of CO, NO, and H2S on mitochondrial cytochrome c oxidase, a key target and central mediator of mitochondrial respiration. Additionally, we consider the effects of biologic gases on mitochondrial biogenesis and "suspended animation." By evaluating gas-mediated control functions from both in vitro and in vivo perspectives, we hope to elaborate on the complex multiple interactions of O2, NO, CO, and H2S.

The release of ATP from red blood cells (RBC) in response to low O2 levels is linked to ATP production and the oxygenation state of hemoglobin. Because O2 is unloaded from the RBC, the concentration of deoxygenated hemoglobin increases, displacing phosphofructokinase from the cytoplasmic domain of band 3. We hypothesize that the ATP molecules produced through this glycolytic stimulation at the membrane surface result in the release of ATP from the RBC. Rat whole blood exposed to 5 min of low PO2 in vitro increased plasma [ATP] by 1.0 miccroM (+45%). This increase was reduced to 0.1 microM (+12%, P < 0.05) after citrate incubation and reversed after fluoride treatment (both glycolytic inhibitors) by -0.2 microM (-23%, P < 0.05). Plasma [ATP] of control RBC decreased -0.3 microM (-12%) when 8% CO (P < 0.05) was added to the chamber. Because CO and O2 bind competitively to heme, these results support our hypothesis that the release of ATP from RBC is linked to ATP production through the oxygenation state of the hemoglobin molecule.