Novel Immunomodulatory Compounds to Prevent Bronchopulmonary Dysplasia

Abstract

Introduction: Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in preterm infants that disrupts the developmental program of the lung. The pathologic hallmarks of BPD are hyperoxia-induced pulmonary inflammation, increased cell death culminating in impaired alveolarization and dysregulated vascularization of the lung. To date, there is no specific and effective prevention or treatment of BPD. AyuVis Research has synthesized a series of proprietary novel immunomodulatory small molecules derived from food ingredients, which were tested in mice models of BPD. Methodology: To emulate the clinical BPD model in mice, newborn pups (postnatal or PN1-saccular stage of lung development) were exposed to either moderate (60%) or severe (100%) hyperoxia for 4 consecutive days (till PN4) followed by recovery in room air (alveolar stage of lung development) till PN14. On PN2 and PN4, the nanosuspension of the test compound (referred to as AVR-NP111) were administered intranasally at a dose of 20uM. We also tested AVR-48 administered intra-peritoneally. On PN14, the pups were euthanized to collect the bronchoalveolar lavage (BAL), lungs, heart and serum for morphometry, flow cytometry, biochemical and physiological assays. Result(s): AVR-NP111 had a promising effect on BPD pups as was evident by normalization of lung morphology (mean +/- SEM, chord length: 50+/-2 vs 60+/-2.5 mum; septal thickness: 9+/-1.8 vs 13+/-2.2 mum; radial alveolar count: 9+/-2 vs 12+/-3 in treated BPD versus control BPD, respectively; all p<0.05) and vasculature (vwF staining). Several pro-inflammatory cytokines (IL1beta, TNF-alpha, MIP2, IL6, IP10) were downregulated (all p<0.05) whereas the anti-inflammatory IL10 was upregulated (p<0.01) in both moderate and severe BPD models treated with AVR-NP111. There was significantly decreased BAL protein (4.5+/-3.0 vs 6.25+/-5 mug/ml; p<0.01) and total cell counts (4.2 +/- 4.7 vs 6 +/- 3.5 x 105; p<0.05) in the BAL fluid in the AVR-NP111 treated BPD versus control BPD group. We had similar results using AVR-NP48. Flow cytometry confirmed that the drug did not alter the innate immunity markers (CD3, CD4, CD45, CD19, NK1.1) of newborn pups, and blood gas measurements had significantly higher pO2 values (p<0.05) in the AVR-NP111 treated BPD lungs as compared to controls. Conclusion(s): AVR compounds are a promising therapeutic target for this pediatric disease for which no treatment is available. Detail toxicokinetic studies are in progress to test the efficacy and safety of AVR-NP compounds to be selected and tested in larger animal models for translational extrapolation.