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.

17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension

“…1. Maximal aerobic capacity (V O2max, expressed relative to body mass) was determined before Su5416 administration and at the end of the 7-wk SuHx period via an indirect open-circuit calorimetric system, as described previously (7,11,16). V O2max was identified using standard criteria for rats, including three consecutive failures to return to running after contacting the shock stimulus at the rear of the treadmill and a respiratory exchange ratio Ͼ 1.015 (4).…”

Increased Cardiac Output and Preserved Gas Exchange Despite Decreased Alveolar Surface Area in Rats Exposed to Neonatal Hyperoxia and Adult Hypoxia

“…We have previously shown that animals initially exposed to neonatal hyperoxia respond to adult hypoxia with increased RVH and RVSP, suggesting a more severe pulmonary hypertensive phenotype (16). In addition, we showed that compared with adult animals exposed to Hypoxia (wk [10][11][12] Re co ve ry Figure 1.…”

“…All procedures were approved by the Indiana University Animal Care and Use Committee, as previously described (16,17). SpragueDawley rat pups were exposed to either room air (RA) or continuous hyperoxia (>90% oxygen) for the first 10 postnatal days, corresponding to the period of saccular and early alveolar lung development (18), and were then returned to RA.…”

“…To understand how neonatal hyperoxic lung injury alters the response to a secondary insult, from 10 to 12 weeks of age, animals were subsequently exposed to either RA or hypobaric hypoxia (H) (P atm = 362 mm Hg, equivalent to FI O 2 of 0.1 at sea level). At the end of the 2-week hypoxia exposure, cardiac output was assessed by echocardiography (VisualSonics Inc., Toronto, ON, Canada), followed by assessment of functional gas exchange by DF CO , as previously described (see Figure 1 for experimental timeline) (16,17).…”

“…Using rodent models that closely resemble the pathological features of premature chronic lung disease, we recently demonstrated that briefly exposing the developing lung to hyperoxia was associated with alveolar simplification, reduced pulmonary arterial density, elevated RV systolic pressure (RVSP), and impaired gas exchange (16,17). In addition, when adult rats were subsequently exposed to the secondary insult of hypoxia, previous exposure to neonatal hyperoxia significantly increased RVSP and RVH yet, surprisingly, maintained cardiac output, suggesting that animals exposed to neonatal hyperoxia respond to the secondary insult of hypoxia with a more adaptive RV phenotype.…”