Neonatal Pulmonology II: Therapies and Emerging Therapies for BPD
432 - A Live Biotherapeutics Product Reverses Neutrophilic Inflammation and Disease Phenotype in Models of Bronchopulmonary Dysplasia
Monday, April 25, 2022
3:30 PM – 6:00 PM US MT
Poster Number: 432 Publication Number: 432.430
Teodora Nicola, Alveolus Bio, Birmingham, AL, United States; Luhua Qiao, uab, Vestavia Hls, AL, United States; Nancy Wenger, Alveolus Bio, Birmingham, AL, United States; Andrew E. O'Connor, Alveolus Bio, Birmingham, AL, United States; Amelia Freeman, University of Alabama at Birmingham, Birmingham, AL, United States; Kent A. Willis, The University of Alabama at Birmingham, Birmingham, AL, United States; Amit Gaggar, University of Alabama School of Medicine, Birmingham, AL, United States; Namasivayam Ambalavanan, University of Alabama School of Medicine, Birmingham, AL, United States; Charitharth Vivek Lal, University of Alabama at Birmingham, AL, Birmingham, AL, United States
Associate Professor University of Alabama at Birmingham, AL Birmingham, Alabama, United States
Background:
Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary disease of early infancy. Disease progression is characterized by changes in lung and gut microbiome populations, extracellular matrix (ECM) breakdown, and neutrophilic inflammation marked by increased matrix metalloproteinase 9 (MMP-9) pathway activity.
Objective: To develop microbiome-based gut-lung axis therapeutic for Bronchopulmonary Dysplasia. We hypothesized that administration of a high potency live biotherapeutics product (LBP) would attenuate MMP-9 pathway-mediated neutrophilic inflammation in models of BPD.
Design/Methods:
Drug product development: A commercial grade, high potency LBP blend product (RB 3000) was developed through University Alabama at Birmingham biotech startup ResBiotic, Inc., using proprietary probiotic strains RSB11, RSB12 and RSB13 and essential micronutrients.
Human bronchial epithelial cells (HBE) grown on collagen plates were exposed to E. coli and normoxia (21% O2) or hyperoxia (85% O2). Cells were dosed with RB 3000 vs control. Supernatants collected at 12 hours were tested for cytokines, MMP-9 and Ac-PGP.
Wild type C57BL/6 mice were exposed to LPS (E. coli 055:B5) or PBS control via intranasal instillation with four incremental doses on PN3, PN6, PN9, and PN12. The pups were randomized to be exposed to normoxic conditions (21% FiO2) or hyperoxic conditions (85% FiO2) from PN3-PN14. Mice were treated with either RB3000 or vehicle control. Lung histology done, lung and serum samples were analyzed for cytokines, MMP-9, sIgA, CRP, neutrophilic markers. 16S microbiome analysis of lungs and gut of mice were conducted.
Administration of a LBP based treatment mitigates lung inflammation and structural damage in models of BPD. Oral LBP supplementation may be an intervention to prevent lung injury in preterm infants, acting through the gut-lung axis.
Results: E. coli exposed HBE cells were dosed with RB3000 under normoxic and hyperoxic conditions showed decreased cytokines, Ac-PGP and MMP-9 levels compared to those without the live bacterial blend. Compared to controls, in the lung injury model mice treated with the RB3000, radial alveolar counts, pulmonary compliance were higher and MMP9, sIgA, MPO, IL6, IL8, IL1Beta, NE, CRP, pulmonary resistance were decreased. Statistical differences defined as p < 0.05. Conclusion(s): Administration of a LBP based treatment mitigates lung inflammation and structural damage in models of BPD. Oral LBP supplementation may be an intervention to prevent lung injury in preterm infants, acting through the gut-lung axis.