A study led by Robert Sackstein, MD, PhD, director, BWH/Harvard Program of Excellence in Glycosciences, demonstrates that a clinically used growth factor causes sugar-coating of an enzyme, thereby provoking vascular injury.
Myeloperoxidase (MPO) is a toxic enzyme normally housed inside white blood cells called leukocytes. Sackstein and his team observed that granulocyte-colony stimulating factor, or G-CSF, causes modification of MPO with specific sugar molecules, moving MPO from inside the leukocyte to the surface. This sugar-decorated enzyme, called myeloperoxidase E-selectin ligand (or MPO-EL), possesses dual function in promoting leukocyte trafficking to sites of inflammation and in damaging blood vessels at those sites. Specifically, MPO-EL causes attachment of leukocytes to the cells lining blood vessels (endothelial cells), and production of toxic oxidizing agents by MPO-EL kills the endothelial cells, thereby inducing vascular injury.
According to the researchers, MPO-EL is not only expressed on leukocytes of patients treated with G-CSF, it is also naturally expressed on blood leukocytes in patients with fever and increased circulating leukocytes.
“Previous studies have noted that G-CSF administration induces various forms of vascular inflammation in patients. This study sheds light on how MPO-EL may play a role in such inflammatory exacerbations,” said Sackstein.
The researchers note that the work provides new insights on how interrupting MPO-EL interactions may help prevent vascular complications associated with G-CSF administration, as well as sickle cell crises, ischemic vascular events, sepsis-related vascular compromise, and systemic vasculitic syndromes.
The study was published online July 7, 2014 in Proceedings of the National Academy of Sciences.