title: Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure.
abstract: The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Kara N
authors: KN
authors: Goss
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Anthony R
authors: AR
authors: Cucci
authors: Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Amanda J
authors: AJ
authors: Fisher
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Marjorie
authors: M
authors: Albrecht
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Andrea
authors: A
authors: Frump
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Roziya
authors: R
authors: Tursunova
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Yong
authors: Y
authors: Gao
authors: Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Mary Beth
authors: MB
authors: Brown
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
authors: Irina
authors: I
authors: Petrache
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Robert S
authors: RS
authors: Tepper
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Shawn K
authors: SK
authors: Ahlfeld
authors: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana tlahm@iu.edu.
authors: Tim
authors: T
authors: Lahm
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D005260:Female; D018496:Hyperoxia / Q000150:complications / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism; D055370:Lung Injury / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling
keywords: atrial natriuretic peptide; capillarization; prematurity; pulmonary hypertension; right ventricular adaptation