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Fike CD. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 297: L596 -L607, 2009. First published July 10, 2009 doi:10.1152/ajplung.90568.2008.-Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881-L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) ϩ polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F 2-isoprostanes, measured by gas chromatographymass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxiainduced pulmonary hypertension in newborn piglets. superoxide dismutase enzymes; SOD1; SOD2; NOX4; NOX1; p67phox; catalase; F 2-isoprostanes; M40403 SCIENTIFIC AND CLINICAL ADVANCES implicate disruption of enzymatic systems that produce and regulate reactive oxygen species (ROS) in the pathogenesis of a number of vascular diseases, including pulmonary hypertension (11,37,40,53,64,65). In particular, there is growing evidence that NADPH oxidase (NOX) family members are important sources for ROS generation in vascular diseases. Yet, compared with the systemic circulation, little is known about the role of the various NOX family members in the pulmonary circulation (10,22,28,39,45,62). Even less is known about the role of NOX family members in regulating vascular tone and reactivity in the neonatal compared with the adult pulmonary circulation. Fundamental differences in the regulation of pulmonary vascular tone in newborns and adults caution against extrapolation of findings regarding NOX signaling in adult lungs to the newborn (52, 74). Regulation of vascular tone is known to differ between larger (conduit-level) pulmonary arteries and smaller (resistance-level) pulmonary arteries (PRAs) (2...