Oxidant stress caused by pathological elevation of
reactive oxygen species (ROS) production in the endothelial cells lining the vascular lumen is an important component of many vascular and
pulmonary disease conditions.
NADPH oxidase (NOX) activated by pathological mediators including
angiotensin and
cytokines is a major source of endothelial ROS. In order to intercept this pathological pathway, we have encapsulated an indirect NOX inhibitor,
MJ33, into immunoliposomes (Ab-
MJ33/IL) targeted to endothelial marker platelet endothelial cell adhesion molecule (PECAM-1). Ab-
MJ33/IL, but not control
IgG-
MJ33/IL are specifically bound to endothelium and attenuated
angiotensin-induced ROS production in vitro and in vivo. Additionally, Ab-
MJ33/IL inhibited endothelial expression of the inflammatory marker
vascular cell adhesion molecule (VCAM) in cells and animals challenged with the
cytokine TNF. Furthermore, Ab-
MJ33/IL alleviated pathological disruption of endothelial permeability barrier function in cells exposed to
vascular endothelial growth factor (
VEGF) and in the lungs of mice challenged with
lipopolysaccharide (LPS). Of note, the latter beneficial effect has been achieved both by prophylactic and therapeutic injection of Ab-
MJ33/IL in animals. Therefore, specific suppression of ROS production by NOX in endothelium, attainable by Ab-
MJ33/IL targeting, may help deciphering mechanisms of vascular oxidative stress and
inflammation, and potentially improve treatment of these conditions.