Chantal Gaudet, Kathrine L. Daniel, Sophie Holcik, Ali Hamraghani, Behzad Yeganeh, Robert P Jankov
Children’s Hospital of Eastern Ontario. University of Ottawa.
Canada
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2026;
DOI: 10.1152/ajplung.00090.2026
Abstract
Bronchopulmonary dysplasia (BPD) is a neonatal lung injury characterized by inflammation, and alveolar and vascular hypoplasia that currently lacks effective treatment. Thrombospondin (TSP)-1 is an angiostatic and pro-inflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. In order to gain further insight into the relative importance of downstream effects of TSP-1, our objective in a neonatal rat model of hyperoxia-intermittent hypoxia (H-IH)-induced lung injury was to compare effects of inhibiting: 1) TSP-1-mediated TGF-β1 activation alone (LSKL) or 2) global TSP-1 signaling (soluble CD47 receptor ligand trap; sCD47r). From postnatal days (PND) 1-21, rat pups were exposed to air or to H-IH (PND 1-7 85% O2, PND 7-14 60% O2 and PND 14-21 air with intermittent exposure to 10% O2 for 10 min every 4 hours) while either receiving daily s.c. LSKL (20 mg/kg) or third daily sCD47r (3 mg/kg). Controls were treated with vehicle or were continuously exposed to normoxia. Exposure to H-IH increased lung contents of TSP-1 and active TGF-β1, and caused macrophage influx, alveolar and pulmonary vascular hypoplasia, and pulmonary hypertension (PH). Both strategies prevented H-IH-mediated effects on active TGF-β1 content, macrophage influx, abnormal lung morphology and PH, while only sCD47r increased lung NO content and signaling. These observations in a clinically-relevant model indicate that multiple strategies aimed at suppressing TSP-1 signaling are effective in preventing lung injury and that targeting TSP-1-mediated activation of TGF-β1 is sufficient to achieve these effects.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access Free PDF File or Full Text Article Available Through PubMed or DOI: Yes