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Neonatal Hyperoxic Lung Injury Alters adult Right Ventricular Remodeling Responses to Hypoxia Exposure in Rats

Kara Goss


Shawn Ahlfeld


Anthony Cucci


Margie Albrecht

Amanda Fisher


Jordan Wood

Roziya Tursunova


Robert Tepper

Tim Lahm


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Conference: 2014 International PHA Conference and Scientific Sessions

Release Date: 06.22.2014

Presentation Type: Abstracts

The development of pulmonary hypertension (PH) is thought to require multiple pulmonary vascular insults. Oxygen therapy is frequently required to support the immature lung following preterm birth, but its role in the postnatal development of PH is unknown.

Background: The development of pulmonary hypertension (PH) is thought to require multiple pulmonary vascular insults. Oxygen therapy is frequently required to support the immature lung following preterm birth, but its role in the postnatal development of PH is unknown. We hypothesized that neonatal hyperoxia (O2) exposure to the immature, developing lung predisposes to the development of more pronounced hypoxia-induced PH (HPH) and right ventricular (RV) remodeling in the mature animal exposed to hypobaric hypoxia (H).

Methods: Male and female Sprague-Dawley pups were continuously exposed to 90% O2 during postnatal days 0-4 (4d O2) or 0-10 (10d O2). Control pups remained in room air (RA). All pups were then allowed to mature in room air. At 10 weeks of age, rats from each group were exposed to 2 weeks of hypoxia (Patm=362 mmHg), resulting in the following experimental groups: 1) RA-RA control; 2) RA-H (n=16); 3) 4d O2-H (n=18); 4) 10d O2-H (n=8). At 12 weeks, RV function (echocardiography), hemodynamics (RV systolic pressure [RVSP]), RV hypertrophy (RVH, measured by RV/left ventricle plus septum ratio [RV/LV+S]), RV capillarization (capillary to myocyte ratio), and RV fibrosis (Trichrome staining) were assessed.

Results: Hypoxia exposure led to an expected robust HPH phenotype characterized by increased RVSP, RVH, and decreased cardiac output (CO). Compared to RA-H rats, 4d O2-H and 10d O2-H rats developed significantly more RVH (p<0.05). Elevation in RVSP was comparable in RA-H and 4d O2-H rats, but markedly increased in 10d O2-H rats (p<0.01). Surprisingly, despite the elevated RVSP and RVH, the CO was higher in both 4d O2-H and 10d O2-H animals compared to RA-H rats (p<0.05). This was associated with an increase in RV capillarization and a decrease in RV fibrosis scores in both groups of O2-H rats, consistent with a more adaptive remodeling response to chronic hypoxia following neonatal hyperoxia. 

Conclusions: Neonatal hyperoxia exposure appears to predispose to more profound RVH associated with significant elevations in RVSP, yet more preserved CO. We speculate that the relative increase in CO may signify early priming of the cardiac myocytes by hyperoxia, resulting in a more adaptive RV remodeling response with increased capillarization and decreased fibrosis. The molecular mechanisms underlying these responses are currently under investigation. 

Abstract type: Basic science

Funding: NIH T32 (KG), Showalter Foundation Grant (SA), VA Merit 1I01BX002042-01A2 (TL)