Effect of antenatal tetrandrine administration on endothelin-1 and epidermal growth factor levels in the lungs of rats with experimental diaphragmatic hernia.
OBJECTIVE
The aim of this study was to evaluate the effect of the traditional Chinese medicine tetrandrine (Tet) and to determine its possible mechanism on expression of endothelin-1 (ET-1) and epidermal growth factor (EGF) in the lung of a rat model of nitrofen-induced congenital diaphragmatic hernia (CDH).


METHODS
A single oral dose (115 mg/kg) of nitrofen on day 9.5 of pregnancy was maternally administered to induce CDH. Pregnant rats were divided into 4 groups on day 18.5: control (n = 5), CDH (n = 5), CDH+dexamethasone (Dex) (n = 5), and CDH+Tet (n = 5). All fetuses were delivered by cesarean delivery on day 21.5. Accordingly, there were 4 groups of fetuses: control (n = 38), CDH (n = 25), CDH+Dex (n = 21), and CDH+Tet (n = 22). Lung tissue weight (LW) and body weight (BW) of each fetus were recorded, lung histologic evaluations and ET-1 and EGF immunohistochemistry staining were performed, and image analysis was performed after lung processing.


RESULTS
Five female rats in the control group produced 38 fetuses without CDH. CDH was observed in 68 of the 128 rat fetuses (53.1%) among the other 3 groups. The LW/BW ratio of the CDH group was significantly lower than those of the Dex and EGF groups (P < .05). The lungs of fetuses with CDH showed marked abnormal structure such as pulmonary hypoplasia and vascular remodeling, in contrast to improved pulmonary structure in lungs of fetuses in the CDH+Dex and CDH+Tet groups. Statistical differences in morphologic parameters (radial alveolar counts, percentage of alveoli, percentage of medial wall thickness, and vascular volume) were found (P < .05). The immunoreactivity of EGF and ET-1 in the CDH group was markedly stronger than that in the control, CDH+Dex, and CDH+Tet groups (P < .01). In addition, EGF and ET-1 expression in the CDH+Dex and CDH+Tet groups was stronger than that in the control group (P < .05). There was no difference in lung EGF and ET-1 immunoreactivity between CDH+Dex and CDH+Tet groups (P > .05).


CONCLUSIONS
Antenatal treatment with Tet may improve lung growth and vascular remodeling, and its mechanism seems to be involved in decreasing EGF and ET-1 expression. Tet administered maternally may be a hopeful new therapeutic option in the treatment of CDH and may be effective in helping to avoid the side effects of Dex.
Lin
Han
H
Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, PR China.
Wang
Yonggang
Y
Xiong
Zhongxun
Z
Tang
Yunman
Y
Liu
Wenying
W
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D044182:Benzylisoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001724:Birth Weight / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000032:analysis*; D004815:Epidermal Growth Factor / Q000032:analysis*; D005260:Female; D005325:Fetal Organ Maturity / Q000187:drug effects*; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000188:drug therapy*; D008168:Lung / Q000002:abnormalities / Q000737:chemistry / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010647:Phenyl Ethers / Q000008:administration & dosage / Q000633:toxicity; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000470:Alkaloids; D044182:Benzylisoquinolines; D004365:Drugs, Chinese Herbal; D019332:Endothelin-1; D010647:Phenyl Ethers; C009438:tetrandrine; D004815:Epidermal Growth Factor; D003907:Dexamethasone; C007350:nitrofen