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.

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

2020 ◽  
Vol 19 (3) ◽  
pp. 541-547
Author(s):  
Junzuo Liao ◽  
Wenying Liu ◽  
Libin Zhang ◽  
Qin Li ◽  
Fang Hou
Keyword(s):  
Body Weight ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Lung Development ◽  
Vascular Remodeling ◽  
Hippo Pathway ◽  
Histological Evaluation ◽  
Pulmonary Vascular Remodeling

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

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

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.

Fetal tracheal occlusion in the rat model of nitrofen-induced congenital diaphragmatic hernia

1999 ◽  
Vol 87 (2) ◽  
pp. 769-775 ◽  
Author(s):  
Yoshihiro Kitano ◽  
Paul Davies ◽  
Daniel von Allmen ◽  
N. Scott Adzick ◽  
Alan W. Flake
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rat Model ◽  
Weight Ratio ◽  
Lung Parenchyma ◽  
Lung Hypoplasia ◽  
Lung Growth ◽  
Lung Weight ◽  
Pregnant Rats ◽  
Tracheal Occlusion

Prenatal tracheal occlusion (TO) consistently accelerates lung growth in the sheep model of congenital diaphragmatic hernia (CDH). However, significant variability in lung growth has been observed in early clinical trials of TO. We hypothesized that lung hypoplasia created at relatively late stages of lung development may not be equivalent to human CDH-induced lung hypoplasia, which begins early in gestation. To test this hypothesis, we performed TO in the rat model of nitrofen-induced CDH. Left-sided CDH was induced by administering 100 mg of nitrofen to timed pregnant rats on day 9 of gestation. On day 19 of gestation, four to five fetuses per dam underwent surgical ligation of the trachea. At death ( day 21.5), lungs from non-CDH (non-CDH group), left-CDH (CDH group), and trachea-occluded left-CDH fetuses (CDH-TO group) were harvested and compared by weight, DNA and protein content, and stereological morphometry. Wet and dry lung weight-to-body weight ratio, total lung DNA and protein contents, the volume of lung parenchyma, and the total saccular surface area of the CDH-TO group were significantly increased relative to the CDH group and were either greater than or comparable to the non-CDH controls. We conclude that TO accelerates lung growth and increases lung parenchyma in an early-onset model of CDH-induced lung hypoplasia.

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 nitrofen in the final stages of development of the diaphragm muscle in rats

2013 ◽  
Vol 28 (suppl 1) ◽  
pp. 13-18 ◽  
Author(s):  
Frances Lilian Lanhellas Gonçalves ◽  
Fábio Santana de Oliveira ◽  
Augusto Frederico Schmidt ◽  
Luís Antônio Violin Dias Pereira ◽  
Rodrigo Melo Gallindo ◽  
...  
Keyword(s):  
Body Weight ◽  
Congenital Diaphragmatic Hernia ◽  
Olive Oil ◽  
Diaphragmatic Hernia ◽  
Muscle Fibers ◽  
Diaphragm Muscle ◽  
External Control ◽  
Stages Of Development ◽  
Pregnant Rats ◽  
Histological Staining

PURPOSE: To evaluate the expression of myosin in muscle fibers of the diaphragm in experimental congenital diaphragmatic hernia (CDH). METHODS: Fetuses of pregnant rats were divided into four groups: External Control (EC), composed of non-manipulated rats; Nitrofen, composed of pregnant rats that received 100 mg of nitrofen (2,4-dichloro-4'nitrodiphenyl ether) diluted in olive oil on gestational day (GD) 9.5, whose fetuses developed CDH (N+) or not (N-), and Olive Oil Placebo (OO), composed of pregnant rats that received the oil on the same GD. The fetuses were collected on GD 18.5, 19.5, 20.5 and 21.5 (term = 22 days). We obtained body weight (BW) and photographed the diaphragm area (DA), hernia area (HA) and subsequent calculated the HA/DA ratio in N+ group. Samples of Diaphragm muscle were processed for histological staining with H/E and immunohistochemistry (IHQ) for myosin.} RESULTS: The fetuses of N- and N+ groups had decreased BW and DA compared to EC and OO groups (p <0.001). HA was decreased on GD 18.5 compared to 21.5 (p <0.001) and the HA/DA ratio showed no difference. IHQ showed decreased expression of myosin in nitrofen groups. CONCLUSION: CDH induced by nitrofen model contributes to the understanding of muscularization in the formation of the diaphragm where the myosin expression is decreased.

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