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FG-4592, a prolyl hydroxylase inhibitor, improves long-term pulmonary outcomes in a murine model of bronchopulmonary dysplasia
Lumeng J. Yu, Scott C. Fligor, Victoria H. Ko, Savas T. Tsikis, Jordan D. Secor, Amy Pan, Mark Puder
Vascular Biology Program, Department of Surgery, Boston Children"s Hospital, Boston, Massachusetts, United States

OBJECTIVE
Bronchopulmonary dysplasia (BPD) affects up to 40% of infants born before 28 weeks" gestation. In these patients, prematurity, oxygen toxicity, and barotrauma lead to deficiency of pulmonary parenchyma and alveolar simplification. Decreased pulmonary expression of vascular endothelial growth factor (VEGF) is observed in BPD. FG-4592, a prolyl hydroxylase inhibitor, increases endogenous VEGF by stabilizing upstream regulatory factors. We investigated FG-4592 as treatment for BPD in a murine model.

DESIGN
Newborn C57Bl/6J mouse littermates were exposed to normoxia (21% O2) or hyperoxia (75% O2) for 10 days.
Cohort 1: Pulmonary function testing (PFT), morphometric analysis on postnatal day 10 (PNd10)
Cohort 2: 12 doses of 10mg/kg FG-4592 or vehicle control (VC) every other day via orogastric gavage; treadmill exercise tolerance testing (TETT), PFT, morphometric analysis at postnatal week 5 (PNw5)

SETTING
Laboratory.

PARTICIPANTS
C57Bl/6J mice.

INTERVENTIONS
Hyperoxia: 75% O2.
Treatment: 10mg/kg FG-4592.

MAIN OUTCOME MEASURES
TETT: Distance, time running.
PFT: Compliance, inspiratory capacity (IC).
Morphometric analysis: Alveolar count (AC), mean linear intercept (MLI), mean septal thickness (MST).

RESULTS
PNd10:
Hyperoxia increased compliance, IC, MLI, decreased AC.
PNw5:
Hyperoxia/VC exposure decreased running distance and time relative to normoxia/VC. FG-4592 improved TETT, although not reaching statistical significance.
Hyperoxia/VC significantly increased compliance and IC compared to normoxia/VC. FG-4592 significantly attenuated hyperoxia-induced increased compliance and decreased IC.
Hyperoxia significantly decreased AC, increased MST, and slightly increased MLI. FG-4592 significantly improved MST.

CONCLUSIONS
FG-4592 has potential to attenuate long-term deficits in pulmonary function testing, exercise tolerance, and lung histology in a murine model of neonatal hyperoxia-induced bronchopulmonary dysplasia. Further investigation of the use of FG-4592 in BPD, including dose-response and optimal treatment duration, is warranted, as it is currently safe in phase III clinical trials as treatment for anemia.


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