Medical College of Georgia
Low levels of oxygen and nitric oxide have an unfortunate synergy in sickle cell disease (SCD), according to preclinical research published in Blood.
The study indicates that these conditions dramatically increase red blood cells’ adhesion to endothelial cells and intensify the debilitating pain crises that can result.
The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said study author Tohru Ikuta, MD, PhD, of the Medical College of Georgia at Georgia Regents University in Augusta.
The study also points to a potential therapeutic target—the self-adhesion molecule P-selectin, which the researchers found played a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin.
To understand the relationship between hypoxia and nitric oxide, the researchers infused sickled red blood cells into mice incapable of producing nitric oxide.
The cells immediately began sticking to blood vessel walls, while normal mice were unaffected. In the face of low oxygen levels, cell adhesion increased significantly in the nitric oxide-deficient mice.
“It’s a synergy,” Dr Ikuta said. “This shows that hypoxia and low nitric oxide levels work together in a bad way for sickle cell patients.”
When the researchers restored normal nitric oxide levels by having mice breathe in the short-lived gas, cell adhesion did not increase when oxygen levels decreased.
And there was no additional benefit from increasing nitric oxide levels beyond normal. Rather, restoring normal nitric oxide levels appears the most efficient, effective way to reduce red blood cell adhesion, the researchers said.
They noted that clinical trials of nitric oxide therapy to ease pain in SCD patients have yielded conflicting results, with some patients reporting increased pain.
These new findings and the fact that SCD patients have significant variability in their nitric oxide levels—even during a pain crisis—likely explains why, Dr Ikuta said. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels of nitric oxide.
“The answer is that some patients may not need this,” Dr Ikuta said. “And our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.”
