Role of reactive oxygen species in chronic hypoxia-induced pulmonary hypertension and vascular remodeling.

Pulmonary hypertension is a life-threatening disease process that affects adults and children. Pediatric patients with lung diseases that can be complicated by alveolar hypoxia, such as bronchopulmonary dysplasia (BPD), are at risk for developing pulmonary hypertension, which leads to right heart failure and greatly increases morbidity and mortality. We review the evidence that reactive oxygen species (ROS) are generated by pulmonary vascular wall cells in response to a hypoxic exposure, and that this response contributes to chronic hypoxic pulmonary hypertension. We summarize the accumulating data implicating NADPH oxidase as a major source of O2 responsible for vascular remodeling and hypertension. We also consider the effects of chronic hypoxia on the clearance of O2 by superoxide dismutases, specifically extracellular superoxide dismutase, which is highly expressed in the pulmonary artery. We review the role of the activated vascular adventitial fibroblast in the generation of ROS and in the pathogenesis of vascular remodeling, and provide a rationale to consider the role of the activated fibroblast and ROS in hypoxic pulmonary hypertension using a clinically relevant bovine model of neonatal chronic hypoxic pulmonary hypertension.