Involvement of YAP and LATS1 in lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia

Purpose: To investigate the role of Hippo pathway in lung development in congenital diaphragmatic hernia (CDH). Methods: One oral dose of nitrofen was maternally administered for induction of CDH on embryonic day 9.5 (E 9.5). Sildenafil was administered intragastrically at a dose of 100 mg/kg on E 11.5. Three rat groups were used: control, CDH, and CDH + sildenafil. Cesarean section was used for fetal delivery on E 21.5. Fetuses with left diaphragmatic hernia (except in control rats) were chosen for investigations. Fetal body weight and weight of lung tissue were recorded, and lung histological evaluation, western blot and PCR were carried out after lung processing. Results: There was markedly higher expression of YAP in CDH rats than in control rats was unaffected by antenatal sildenafil administration (p < 0.05). However, prenatal sildenafil intervention significantly increased LATS1 expression in the lung of CDH fetuses (p < 0.05). Conclusion: These results indicate that increased pulmonary YAP expression in CDH rat model might contribute to pulmonary vascular remodeling and suppression of lung development. Thus, antenatal sildenafil administration not only mitigates abnormal vascular remodeling but also promotes lung development, most likely via increased expression of LATS1. Keywords: Congenital diaphragmatic hernia (CDH), Hippo pathway, Lung development, Sildenafil

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Prenatal Imatinib Treatment Reduces Pulmonary Vascular Remodeling In A Rat Model Of Congenital Diaphragmatic Hernia

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a3414 ◽

2012 ◽

Author(s):

Karin Tran-Lundmark ◽

Andreas R. Uggla ◽

Ya-Ting Chang ◽

Cecilia O. Corbascio ◽

Ann-Christine Eklof ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Rat Model ◽

Vascular Remodeling ◽

Imatinib Treatment ◽

Pulmonary Vascular Remodeling

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

10.1101/848556 ◽

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.

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

Journal of Pediatric Surgery ◽

10.1016/j.jpedsurg.2014.09.015 ◽

2014 ◽

Vol 49 (12) ◽

pp. 1749-1752 ◽

Cited By ~ 7

Author(s):

Kohei Sakai ◽

Osamu Kimura ◽

Taizo Furukawa ◽

Shigehisa Fumino ◽

Koji Higuchi ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Rat Model ◽

Lung Development

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miR-200 family expression during normal and abnormal lung development due to congenital diaphragmatic hernia at the later embryonic stage in the nitrofen rat model

Pediatric Surgery International ◽

10.1007/s00383-020-04757-2 ◽

2020 ◽

Vol 36 (12) ◽

pp. 1429-1436

Author(s):

Drew Mulhall ◽

Naghmeh Khoshgoo ◽

Robin Visser ◽

Barbara Iwasiow ◽

Chelsea Day ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Rat Model ◽

Lung Development ◽

Embryonic Stage

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Pathogenesis of nitrofen-induced congenital diaphragmatic hernia in fetal rats

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.2.338 ◽

1997 ◽

Vol 83 (2) ◽

pp. 338-347 ◽

Cited By ~ 86

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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