15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and nitrofen

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Airway Obstruction; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Isoenzymes; Membrane Proteins; Muscle, Smooth; Pesticides; Phenyl Ethers; Potassium Chloride; Pregnancy; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vasoconstrictor Agents; Vasodilator Agents

Infants born with congenital diaphragmatic hernias (CDH) frequently die as a result of pulmonary hypertension and persistent fetal circulation. The pulmonary vessels of infants with CDH have decreased total cross-sectional area, increased muscle content, and muscularization of intra-acinar arterioles that are normally not muscularized. These structural alterations are believed to result in exaggerated responses to normal vasoconstrictor stimuli.. The authors used the nitrofen-induced CDH model in rats to determine whether the vasoconstrictor responses of pulmonary arterioles are exaggerated in this animal model of CDH. The authors compared the responses of isolated third-generation pulmonary arterioles from normal rats and from rats with nitrofen-induced CDH to K+-induced depolarization, phenylephrine, angiotensin II, serotonin, and the thromboxane A2 agonist, U46619.. It was found that the intraluminal diameter of third-generation pulmonary arterioles from CDH rats was significantly less than in controls (129 +/- 5 micron v 152 +/- 9 micron, respectively). In addition, the ratio of wall thickness to vessel internal diameter was increased in the third-generation pulmonary arterioles of rats with nitrofen-induced CDH (0.62 +/- 0.4 v 0.50 +/- 0.5 for controls). Responses to K+-induced depolarization, phenylephrine, angiotensin II, serotonin, and U46619, however, were not different for pulmonary arterioles from control and CDH rats.. These data suggest that the structural alterations of the pulmonary vasculature observed in infants with CDH may not cause exaggerated vasoconstrictor responses to normal vasoconstrictor stimuli.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Angiotensin II; Animals; Arterioles; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fetus; Herbicides; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Phenyl Ethers; Phenylephrine; Pregnancy; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Serotonin; Vasoconstriction; Vasoconstrictor Agents