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Superoxide and Chronic Hypoxia-Induced Pulmonary Hypertension in Newborn Piglets* FREE TO VIEW

Candice D. Fike, MD; Judy L. Aschner, MD; Yongmei Zhang; Daniela Salvemini, PhD; Mark R. Kaplowitz
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*From the Department of Pediatrics (Drs. Fike and Aschner, Mr. Zhang, and Mr. Kaplowitz), Wake Forest University School of Medicine, Winston-Salem, NC; and Metaphore Pharmaceuticals (Dr. Salvemini), St. Louis, MO.

Correspondence to: Candice D. Fike, MD, Department of Pediatrics, Vanderbilt University Medical School, 2215 B Garland Ave, 1125 MRBIV, Nashville, TN 37232-0656

Chest. 2005;128(6_suppl):555S-556S. doi:10.1378/chest.128.6_suppl.555S
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Free radicals, including superoxide, O2, have been implicated in the pathogenesis of certain types of pulmonary hypertension. Yet, the role of O2 in chronic hypoxia-induced pulmonary hypertension in newborns is unknown. Moreover, there is little information regarding the influence of chronic hypoxia on the expression of O2 enzymatic scavenging systems, such as the cytosolic copper/zinc containing enzyme, superoxide dismutase (SOD)-1 or mitochondrial manganese SOD (SOD-2). Our purpose was to determine whether O2 is involved with the abnormal constrictor responses that develop in resistance pulmonary arteries (RPAs) of newborn pigs exposed to 3 days of hypoxia. We also evaluated whether 3 days of exposure to hypoxia alters the expression of either SOD-1 or SOD-2 in RPAs. Newborn pigs, 2 to 3 days old, were placed in normoxic (control) or hypoxic (11% O2) chambers. After 3 days in the respective chambers, the piglets were euthanized and RPAs (100 to 300 μm in diameter) were dissected from the lungs. Some RPAs were cannulated and pressurized to measure the effect of the cell-permeable SOD mimetic, M40401, on responses to acetylcholine. Other RPAs were homogenized for determination of SOD-1 and SOD-2 levels by immunoblot technique. We found that untreated RPAs from hypoxic piglets constricted to acetylcholine; whereas after M40401 treatment, RPAs from hypoxic piglets dilated to acetylcholine. Although SOD-2 abundance was unaltered, SOD-1 was diminished by 20% in RPAs from hypoxic as compared to control piglets. Thus, O2 contributes to the constrictor response to acetylcholine that develops in RPAs of piglets exposed to 3 days of hypoxia. Moreover, chronic in vivo hypoxia inhibits the expression of one of the most important intracellular antioxidant enzymes, SOD-1. O2 generation, exaggerated by the inhibition of SOD-1, contributes to the development of chronic hypoxia-induced pulmonary hypertension in newborn pigs.

Abbreviations: RPA = resistance pulmonary artery; SOD = superoxide dismutase




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