Inhibition of thrombospondin-1 signaling prevents experimental bronchopulmonary dysplasia

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 proinflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. 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 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 h) while either receiving daily subcutaneous 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.NEW & NOTEWORTHY Thrombospondin (TSP)-1, an angiostatic and proinflammatory protein recently implicated in bronchopulmonary dysplasia (BPD) pathogenesis, activates transforming growth factor (TGF)-β1 and suppresses nitric oxide signaling via separate receptor-mediated pathways. In a rat model of BPD, treatment with LSKL (targeting TSP-1-mediated TGF-β1 activation alone) had equivalent preventive effects on inhibited alveolarization, inflammation, and pulmonary hypertension to global inhibition of TSP-1 (soluble ligand trap). We conclude that limiting TSP-1-mediated activation of TGF-β1 appears sufficient to prevent experimental BPD.