Dataset Information

Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension.

ABSTRACT: The majority of morbidity and mortality in sickle cell disease is caused by vaso-occlusion: circulatory obstruction leading to tissue ischemia and infarction. The consequences of vaso-occlusion are seen clinically throughout the vascular tree, from the relatively high-oxygen and high-velocity cerebral arteries to the relatively low-oxygen and low-velocity postcapillary venules. Prevailing models of vaso-occlusion propose mechanisms that are relevant only to regions of low oxygen and low velocity, leaving a wide gap in our understanding of the most important pathologic process in sickle cell disease. Progress toward understanding vaso-occlusion is further challenged by the complexity of the multiple processes thought to be involved, including, but not limited to 1) deoxygenation-dependent hemoglobin polymerization leading to impaired rheology, 2) endothelial and leukocyte activation, and 3) altered cellular adhesion. Here, we chose to focus exclusively on deoxygenation-dependent rheologic processes in an effort to quantify their contribution independent of the other processes that are likely involved in vivo. We take advantage of an experimental system that, to our knowledge, uniquely enables the study of pressure-driven blood flow in physiologic-sized tubes at physiologic hematocrit under controlled oxygenation conditions, while excluding the effects of endothelium, leukocyte activation, adhesion, inflammation, and coagulation. We find that deoxygenation-dependent rheologic processes are sufficient to increase apparent viscosity significantly, slowing blood flow velocity at arterial oxygen tension even without additional contributions from inflammation, adhesion, and endothelial and leukocyte activation. We quantify the changes in apparent viscosity and define a set of functional regimes of sickle cell blood flow personalized for each patient that may be important in further dissecting mechanisms of in vivo vaso-occlusion as well as in assessing risk of patient complications, response to transfusion, and the optimization of experimental therapies in development.

SUBMITTER: Lu X

PROVIDER: S-EPMC4919586 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension.

Lu Xinran X Wood David K DK Higgins John M JM

Biophysical journal 20160601 12

The majority of morbidity and mortality in sickle cell disease is caused by vaso-occlusion: circulatory obstruction leading to tissue ischemia and infarction. The consequences of vaso-occlusion are seen clinically throughout the vascular tree, from the relatively high-oxygen and high-velocity cerebral arteries to the relatively low-oxygen and low-velocity postcapillary venules. Prevailing models of vaso-occlusion propose mechanisms that are relevant only to regions of low oxygen and low velocity ...[more]

PMID: 27332133

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Project description:Although mechanical ventilation is a life-saving intervention in patients suffering from respiratory failure, prolonged mechanical ventilation is often associated with numerous complications including problematic weaning. In contracting skeletal muscle, inadequate oxygen supply can limit oxidative phosphorylation resulting in muscular fatigue. However, whether prolonged mechanical ventilation results in decreased diaphragmatic blood flow and induces an oxygen supply-demand imbalance in the diaphragm remains unknown.We tested the hypothesis that prolonged controlled mechanical ventilation results in a time-dependent reduction in rat diaphragmatic blood flow and microvascular PO2 and that prolonged mechanical ventilation would diminish the diaphragm's ability to increase blood flow in response to muscular contractions.Compared to 30 mins of mechanical ventilation, 6 hrs of mechanical ventilation resulted in a 75% reduction in diaphragm blood flow (via radiolabeled microspheres), which did not occur in the intercostal muscle or high-oxidative hindlimb muscle (e.g., soleus). There was also a time-dependent decline in diaphragm microvascular PO2 (via phosphorescence quenching). Further, contrary to 30 mins of mechanical ventilation, 6 hrs of mechanical ventilation significantly compromised the diaphragm's ability to increase blood flow during electrically-induced contractions, which resulted in a ~80% reduction in diaphragm oxygen uptake. In contrast, 6 hrs of spontaneous breathing in anesthetized animals did not alter diaphragm blood flow or the ability to augment flow during electrically-induced contractions.These new and important findings reveal that prolonged mechanical ventilation results in a time-dependent decrease in the ability of the diaphragm to augment blood flow to match oxygen demand in response to contractile activity and could be a key contributing factor to difficult weaning. Although additional experiments are required to confirm, it is tempting to speculate that this ventilator-induced decline in diaphragmatic oxygenation could promote a hypoxia-induced generation of reactive oxygen species in diaphragm muscle fibers and contribute to ventilator-induced diaphragmatic atrophy and contractile dysfunction.

Dataset Information

Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension.

Publications

Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension.

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