Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

2012 ◽  
Vol 302 (11) ◽  
pp. L1159-L1166 ◽  
Author(s):  
Ya-Ting Chang ◽  
Andreas Ringman Uggla ◽  
Cecilia Österholm ◽  
Phan-Kiet Tran ◽  
Ann-Christine Eklöf ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Wall Thickness ◽  
Rat Model ◽  
Pulmonary Arteries ◽  
Medial Wall ◽  
Imatinib Treatment ◽  
Lumen Area ◽  
Medial Wall Thickness

The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-β were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-α remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.

scholarly journals Effect of antenatal tetramethylpyrazine on lung development and YAP expression in a rat model of experimental congenital diaphragmatic hernia

2019 ◽  
Author(s):  
Junzuo Liao ◽  
Wenying Liu ◽  
Libin Zhang ◽  
Qin Li ◽  
Fang Hou
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Lung Development ◽  
Vascular Remodeling ◽  
Low Cost ◽  
Underlying Mechanism ◽  
Therapeutic Effects ◽  
Pregnant Rats ◽  
Medial Wall Thickness

AbstractTetramethylpyrazine (TMP) is a chemical compound found in extracts derived from the Chinese medicinal plant. Due to its remarkable therapeutic effects, availability, and low cost and toxicity, TMP has been used to treat cardiovascular diseases and pulmonary hypertension in China. The aim of this study was to investigate the therapeutic effects and underlying mechanism of TMP on lung development using a rat model of nitrofen-induced congenital diaphragmatic hernia (CDH). Pregnant rats were divided into three groups: control, CDH, and CDH+TMP. Nitrofen was used to induce CDH. In the CDH and CDH+TMP, Fetuses only with left diaphragmatic hernias were chosen for analysis. Lung and body weight were recorded and lung histologic evaluations, image analysis, and western blot analysis of YAP, p-YAP and LATS1 were performed after lung processing. A marked abnormal structure was observed, as evidenced by pulmonary hypoplasia and vascular remodeling, in the CDH. These abnormalities were improved in the CDH+TMP. There were significant differences between the CDH and CDH+TMP in percentage of medial wall thickness, arteriole muscularization, radial alveolar counts, AA%, and alveolar septal thickness. YAP expression was markedly increased in the CDH compared to the control, which was not affected by antenatal TMP administration. However, prenatal TMP intervention significantly increased expression of LATS1 and phosphorylation of YAP in the CDH fetuses. Our results demonstrate that antenatal TMP administration improved vascular remodeling and promoted lung development in a rat model of CDH, potentially through increasing expression of LATS1 and phosphorylation of YAP.

Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia

2014 ◽  
Vol 49 (12) ◽  
pp. 1749-1752 ◽  
Author(s):  
Kohei Sakai ◽  
Osamu Kimura ◽  
Taizo Furukawa ◽  
Shigehisa Fumino ◽  
Koji Higuchi ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Lung Development

scholarly journals Nitrofen rat model of congenital diaphragmatic hernia demonstrates increased lung stiffness using shear wave elastography

2022 ◽  
Vol 226 (1) ◽  
pp. S592
Author(s):  
Felix R. De Bie ◽  
Ryne A. Didier ◽  
Christopher Halline ◽  
Anush Sridharan ◽  
Abby Larson ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Shear Wave ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Shear Wave Elastography

scholarly journals Prenatal tracheal ligation or intra-amniotic administration of surfactant or dexamethasone prevents some structural changes in the pulmonary arteries of surgically created diaphragmatic hernia in rabbits

2002 ◽  
Vol 57 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Consuelo J. Rodrigues ◽  
Uenis Tannuri ◽  
Ana Cristina A. Tannuri ◽  
João Maksoud-Filho ◽  
Aldo J. Rodrigues Junior
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Structural Changes ◽  
Elastic Fiber ◽  
Pulmonary Arteries ◽  
External Diameter ◽  
Cell Nuclei ◽  
Fiber Density ◽  
Positive Effects ◽  
Tracheal Ligation

PURPOSE: Characterization of the structural changes occurring in the pulmonary arteries resulting from surgically produced congenital diaphragmatic hernia in rabbits, with particular emphasis on the preventive effects of prenatal tracheal ligation or administration of intra-amniotic dexamethasone or surfactant. METHODS: Twenty rabbit fetuses underwent surgical creation of a left-sided congenital diaphragmatic hernia on the 24th or 25th gestational day. They were divided according to the following procedures: congenital diaphragmatic hernia (n = 5), congenital diaphragmatic hernia plus tracheal ligation (n = 5), congenital diaphragmatic hernia plus intra-amniotic administration of dexamethasone 0.4 mg (n = 5) or surfactant (Curosurf 40 mg, n = 5). On gestational day 30, all the fetuses were delivered by caesarean section and killed. A control group consisted of five nonoperated fetuses. Histomorphometric analysis of medial thickness, cell nuclei density, and elastic fiber density of pulmonary arterial walls was performed. RESULTS: Arteries with an external diameter > 100 mum have a decreased medial thickness, lower cell nuclei density, and greater elastic fiber density when compared with arteries with external diameter <= 100 mum. Congenital diaphragmatic hernia promoted a significant decrease in medial thickness and an increase in cell nuclei density in artery walls with external diameter > 100 mum. Prenatal treatments with tracheal ligation or intra-amniotic administration of dexamethasone or surfactant prevented these changes. In arteries with external diameter <= 100 mum, congenital diaphragmatic hernia promoted a significant increase in medial thickness and in cell nuclei density and a decrease in elastic fiber density. The prenatal treatments with tracheal ligation or intra-amniotic administration of dexamethasone or surfactant prevented these changes, although no effect was observed in elastic fiber density in the congenital diaphragmatic hernia plus dexamethasone group. CONCLUSIONS: Congenital diaphragmatic hernia promoted different structural changes for large or small arteries. The prenatal intra-amniotic administration of dexamethasone or surfactant had positive effects on the lung structural changes promoted by congenital diaphragmatic hernia, and these effects were comparable to the changes induced by tracheal ligation.

scholarly journals The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia

2015 ◽  
Vol 79 (5) ◽  
pp. 766-775 ◽  
Author(s):  
Thomas H. Mahood ◽  
Dina R. Johar ◽  
Barbara M. Iwasiow ◽  
Wayne Xu ◽  
Richard Keijzer
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Pulmonary Hypoplasia

Decreased expression of miR-33 in fetal lungs of nitrofen-induced congenital diaphragmatic hernia rat model

2016 ◽  
Vol 51 (7) ◽  
pp. 1096-1100 ◽  
Author(s):  
Shibo Zhu ◽  
Qiuming He ◽  
Ruizhong Zhang ◽  
Yong Wang ◽  
Wei Zhong ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Fetal Lungs

Pathogenesis of nitrofen-induced congenital diaphragmatic hernia in fetal rats

1997 ◽  
Vol 83 (2) ◽  
pp. 338-347 ◽  
Author(s):  
Douglas W. Allan ◽  
John J. Greer
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Phrenic Nerve ◽  
Lung Development ◽  
Primary Role ◽  
Primary Defect ◽  
Myotube Formation ◽  
Fetal Rats ◽  
Weight Protein

Allan, Douglas W., and John J. Greer. Pathogenesis of nitrofen-induced congenital diaphragmatic hernia in fetal rats. J. Appl. Physiol. 83(2): 338–347, 1997.—Congenital diaphragmatic hernia (CDH) is a developmental anomaly characterized by the malformation of the diaphragm and impaired lung development. In the present study, we tested several hypotheses regarding the pathogenesis of CDH, including those suggesting that the primary defect is due to abnormal 1) lung development, 2) phrenic nerve formation, 3) developmental processes underlying diaphragmatic myotube formation, 4) pleuroperitoneal canal closure, or 5) formation of the primordial diaphragm within the pleuroperitoneal fold. The 2,4-dichloro-phenyl- p-nitrophenyl ether (nitrofen)-induced CDH rat model was used for this study. The following parameters were compared between normal and herniated fetal rats at various stages of development: 1) weight, protein, and DNA content of lungs; 2) phrenic nerve diameter, axonal number, and motoneuron distribution; 3) formation of the phrenic nerve intramuscular branching pattern and diaphragmatic myotube formation; and 4) formation of the precursor of the diaphragmatic musculature, the pleuroperitoneal fold. We demonstrated that previously proposed theories regarding the primary role of the lung, phrenic nerve, myotube formation, and the closure of pleuroperitoneal canal in the pathogenesis of CDH are incorrect. Rather, the primary defect associated with CDH, at least in the nitrofen rat model, occurs at the earliest stage of diaphragm development, the formation of the pleuroperitoneal fold.

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