title: Endothelin-1-Rho kinase interactions impair lung structure and cause pulmonary hypertension after bleomycin exposure in neonatal rat pups.
abstract: Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through Rho kinase (ROCK) activation, ET-1 impairs endothelial cell function; however, whether ET-1-ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intraperitoneal bleomycin with and without selective ETA(BQ123/BQ610) and ETB(BQ788) receptor blockers, nonselective ET receptor blocker (ETRB) (bosentan), or fasudil (ROCK inhibitor). At day 14, lungs were harvested for morphometrics, and measurements of Fulton's index (RV/LV+S), medial wall thickness (MWT), and vessel density. Lung ET-1 protein and ROCK activity (phospho-MYPT-1:total MYPT-1 ratio) were also measured by Western blot analysis. Bleomycin increased lung ET-1 protein expression by 65%, RV/LV+S by 60%, mean linear intercept (MLI) by 212%, and MWT by 140% and decreased radial alveolar count (RAC) and vessel density by 40 and 44%, respectively (P < 0.01 for each comparison). After bleomycin treatment, fasudil and bosentan partially restored RAC and vessel density and decreased MLI, RV/LV+S, and MWT to normal values. Bleomycin increased ROCK activity by 120%, which was restored to normal values by bosentan but not selective ETRB. We conclude that ET-1-ROCK interactions contribute to decreased alveolar and vascular growth and PH in experimental BPD. We speculate that nonselective ETRB and ROCK inhibitors may be effective in the treatment of infants with BPD and PH.
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; jason.gien@ucdenver.edu.|Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Jason
authors.initials: J
authors.lastname: Gien
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Nancy
authors.initials: N
authors.lastname: Tseng
authors.affiliation: Section of Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; and.|Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Gregory
authors.initials: G
authors.lastname: Seedorf
authors.affiliation: Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kuhn
authors.affiliation: Section of Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; and.|Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001761:Bleomycin; D001808:Blood Vessels / Q000187:drug effects; D000077300:Bosentan; D019332:Endothelin-1 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; D001761:Bleomycin; C086539:BQ 788; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: ETA-selective receptor antagonist; ETB-selective receptor antagonist; Rho kinase (ROCK) endothelin receptor antagonist (ERA); bronchopulmonary dysplasia (BPD); endothelin-1 (ET-1); pulmonary hypertension