Mechanical Ventilation During Neonatal Hyperoxia Causes Thrombospondin-1 Dependent Lung Remodeling in Mice.

Extremely premature infants are simultaneously exposed to hyperoxia (O2) and mechanical ventilation (MV) as a life-saving intervention, but these stimuli increase their risk of developing Bronchopulmonary Dysplasia (BPD). Passive O2 models have traditionally been used to model BPD, however, these models do not account for superimposed mechanical stretch responses in the developing lung. To address this gap, we engineered a novel, non-invasive rodent model of combined O2-MV wherein mice are exposed to cyclic positive pressure with either room air (RA) or hyperoxia (100% O2) for 6 hours per day from postnatal days (PND) 1-4 and then recovered in room air. Pulmonary function testing revealed that O2-control mice had decreased resistance and increased compliance, consistent with expected findings in a distensible, simplified lung. In contrast, function studies in O2-MV mice were partially normalized, with persistent remodeling of collagen and elastin fiber networks and less alveolar simplification than O2-controls. Transcriptomic analyses at PND4 revealed several extracellular matrix (ECM) genes induced by combined O2-MV, including glycoprotein Thrombospondin-1 (Thbs1), confirmed by immunohistochemistry and qRT-PCR. To test the contribution of Thbs1 to lung remodeling, exposure of neonatal Thbs1 -/- mice to O2-MV led to growth failure, alveolar simplification, and reversal of lung function and collagen remodeling changes at PND 28, suggesting that O2-MV remodels the lung collagen fiber networks through Thbs1 expression. Our findings establish a mechanistic link between Thbs1 and ECM remodeling and emphasize the need to better understand how MV in the setting of neonatal hyperoxia contributes to the pathogenesis of BPD.