Endothelial barrier dysfunction and oxidative stress: roles for nitric oxide?
Endothelial dysfunction has an important role to play in the pathophysiology of human vascular disease. The maintenance of barrier function is critical to the role of vascular endothelium in cardiovascular haemostasis and this function can be compromised by inflammatory mediators, cytokines or oxidants. Under conditions of oxidative stress a variety of reactive oxygen species (ROS) may be generated, which increase the permeability of the endothelial monolayer to fluid, macromolecules and inflammatory cells. The endothelium-derived nitric oxide radical (NO), whose physiological actions include effects on vascular smooth muscle, is normally inactivated by the superoxide radical anion. While large amounts of NO have cytotoxic potential, it is now becoming clear that combinations of NO with ROS can produce either cytotoxic or cytoprotective effects, depending on the relative amounts of each which are present in the target cell or its environment at a particular time. The contribution of NO to oxidant-mediated endothelial barrier dysfunction can be assessed in vitro in endothelial monolayers grown on porous membrane supports. In this model, using hydrogen peroxide (H2O2) as the oxidant, H2O2-induced losses of barrier function can be enhanced or partially offset by NO donor drugs, depending on the concentration of NO donor used. Furthermore, the injurious or cytoprotective effects of these agents appear to be determined by the quantity of NO generated. Since NO is administered clinically by inhalation in conditions such as pulmonary hypertension or the adult respiratory distress syndrome, which are themselves associated with generation of ROS, it is likely that low concentrations of NO may protect the pulmonary vascular endothelium while high concentrations might be expected to combine with ROS to yield intermediates capable of causing further endothelial injury or loss of barrier function.
McQuaid
K E
KE
Department of Pharmacology, University College Dublin, Ireland.
Keenan
A K
AK
D000818:Animals; D015824:Blood-Air Barrier / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000503:physiopathology*; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D014652:Vascular Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D016877:Oxidants; D009569:Nitric Oxide