LAUSR

RATIONALE Extremely preterm infants develop bronchopulmonary dysplasia (BPD), a chronic lung injury that lacks effective treatment. Thrombospondin-1 is an anti-angiogenic protein that activates TGF-β1, a cytokine strongly linked to both experimental and human BPD. OBJECTIVES 1) To examine effects of inhibiting thrombospondin-1-mediated TGF-β1 activation (LSKL) in neonatal rats with bleomycin-induced lung injury, 2) To examine effects of a thrombospondin-1-mimic (ABT-510) on lung morphology, and 3) To determine whether thrombospondin-1 and related signaling peptides are increased in lungs of human preterm infants at risk for BPD. METHODS From postnatal days 1-14, rat pups received daily i.p. bleomycin (1 mg/kg) or vehicle combined with daily s.c. LSKL (20 mg/kg) or vehicle. Separate animals were treated with vehicle or ABT-510 (30 mg/kg/d). Paraffin-embedded lung tissues from 47 autopsies (controls; death <28 days, n=30 and BPD at risk; death ≥28 days, n=17) performed on infants born <29 completed weeks' gestation were semi-quantified for injury markers (collagen, macrophages, 3-nitrotyrosine), thrombospondin-1 and TGF-β1. MEASUREMENTS AND MAIN RESULTS Bleomycin or ABT-510 increased lung TGF-β1 activity and macrophage influx, caused pulmonary hypertension and led to alveolar and microvascular hypoplasia. Treatment with LSKL partially prevented abnormal lung morphology secondary to bleomycin. Lungs from human infants at-risk for BPD had increased contents of thrombospondin-1 and TGF-β1 when compared to controls. TGF-β1 content correlated with markers of lung injury. CONCLUSIONS Thrombospondin-1 inhibits alveologenesis in neonatal rats, in part via up-regulated activity of TGF-β1. Observations in human lung suggest a similar pathogenic role for thrombospondin-1 in infants at-risk for BPD.