Brittany Ann Ruschkowski, Yousef Esmaeil, Kate Daniel, Chantel Gaudet, Behzad Yeganeh, David Grynspan, Robert P. Jankov
Children’s Hospital of Eastern Ontario Research Institute. University of Ottawa.
Canada
American Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med 2022; 205: 685-699
DOI: 10.1164/rccm.202104-1021OC
Abstract
Rationale: Extremely preterm infants develop bronchopulmonary dysplasia (BPD), a chronic lung injury that lacks effective treatment. TSP-1 (thrombospondin-1) is an antiangiogenic protein that activates TGF-β1 (transforming growth factor-β1), a cytokine strongly linked to both experimental and human BPD.
Objectives:1) To examine effects of inhibiting TSP-1-mediated TGF-β1 activation (LSKL [leucine-serine-lysine-leucine]) in neonatal rats with bleomycin-induced lung injury; 2) to examine effects of a TSP-1 mimic (ABT-510) on lung morphology; and 3) to determine whether TSP-1 and related signaling peptides are increased in lungs of human preterm infants at risk for BPD.
Methods: From Postnatal Days 1 to 14, rat pups received daily intraperitoneal bleomycin (1 mg/kg) or vehicle and were treated with daily subcutaneous LSKL (20 mg/kg) or vehicle alone. Separate animals were treated with vehicle or ABT-510 (30 mg/kg/d). Paraffin-embedded lung tissues from 47 autopsies (controls; death <28 d, n = 30 and BPD at risk; death ⩾28 d, n = 17) performed on infants born <29 completed weeks’ gestation were semiquantified for injury markers (collagen, macrophages, and 3-nitrotyrosine), TSP-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 TSP-1 and TGF-β1 when compared with controls. TGF-β1 content correlated with markers of lung injury.
Conclusions: TSP-1 inhibits alveologenesis in neonatal rats, in part via the upregulated activity of TGF-β1. Observations in human lungs suggest a similar pathogenic role for TSP-1 in infants at risk for BPD.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class III. Pulmonary Hypertension Associated with Lung Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes