Airway smooth muscle changes in the nitrofen-induced congenital diaphragmatic hernia rat model.
In the fetal rat, nitrofen induces congenital diaphragmatic hernia (CDH) and pulmonary vascular remodeling similar to what is observed in the human condition. Airway hyperactivity is common in infants with CDH and attributed to the ventilator-induced airway damage. The purpose of this study was to test the hypothesis that airway smooth muscle mechanical properties are altered in the nitrofen-induced CDH rat model. Lungs from nitrofen-exposed fetuses with hernias (CDH) or intact diaphragm (nitrofen) and untreated fetuses (control) were studied on gestation d 21. The left intrapulmonary artery and bronchi were removed and mounted on a wire myograph, and lung expression, content, and immunolocalization of cyclooxygenases COX-1 and COX-2 were evaluated. Pulmonary artery muscle in the CDH group had significantly (p < 0.01) lower force generation compared with control and nitrofen groups. In contrast, the same generation bronchial smooth muscle of the CDH and nitrofen groups developed higher force compared with control. Whereas no differences were found in endothelium-dependent pulmonary vascular muscle tone, the epithelium-dependent airway muscle relaxation was significantly decreased (p < 0.01) in the CDH and nitrofen groups. The lung mRNA levels of COX-1 and COX-2 were increased in the CDH and nitrofen groups. COX-1 vascular and airway immunostaining, as well as COX-1 and COX-2 lung protein content, were increased in the CDH group. This is the first report of airway smooth muscle abnormalities in the nitrofen-induced fetal rat model of CDH. We speculate that congenital airway muscle changes may be present in the human form of this disease.
Belik
Jaques
J
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada. Jaques.Belik@SickKids.ca
Davidge
Sandra T
ST
Zhang
Wei
W
Pan
Jingyi
J
Greer
John J
JJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000402:Airway Obstruction / Q000151:congenital / Q000503:physiopathology*; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D005260:Female; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000503:physiopathology*; D065630:Hernias, Diaphragmatic, Congenital; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D010575:Pesticides; D010647:Phenyl Ethers; D011189:Potassium Chloride / Q000494:pharmacology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D007527:Isoenzymes; D008565:Membrane Proteins; D010575:Pesticides; D010647:Phenyl Ethers; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; C007350:nitrofen; D000109:Acetylcholine