Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia

Abstract

Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p < 0.01), increased lung volume (p < 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p < 0.05, and PCO2 ; p < 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright © 2016 John Wiley & Sons, Ltd.

Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114)

“…We thus considered a strategy to ameliorate CDH when diagnosed in utero . ( 32 ) Based on the previous report that non-CDH affected lungs in the newborns of nitrofen-induced CDH models are also hypoplastic, we hypothesized that there are direct effects of nitrofen to the lung in addition to indirect effects on the retinoid and thyroid signalling pathways as reported previously. ( 11 – 13 ) Saireito, a Japanese herbal drug, has been registered and used for pregnant patients in Japan to reduce edema.…”

“…( 30 , 31 ) We recently showed in the rat CDH model that antenatal Saireito increased the lung volume and alveolarization and respiratory functions while decreasing endothelin-1 expression and vascular remodelling, thus lowering the incidence of CDH. ( 32 ) Here, we focused on iron metabolism and oxidative stress in nitrofen-induced rat CDH and its prevention by Saireito.…”

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

“…Lungs of nitrofen-exposed rats with CDH had increased levels of ET-1, ECE, and both receptors as early as E15. 9,51,[73][74][75][76][77][78] The increase in receptors was confirmed in a study showing that arterioles from nitrofen-exposed CDH lungs constricted more than those in controls in response to ET-1. 79 Interestingly, administering an inhibitor of ECE prenatally to dams exposed to nitrofen was reported to increase the survival rate of pups with CDH.…”

Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia

“…Pregnant rats were randomly divided into three groups (Figure 6): control, Nitrofen, and Nitrofen + HW. The nitrofen-induced rat CDH models were prepared as previously reported [54,55]. One hundred milligrams of nitrofen (2,4-dichlorophenyl-p-nitrophenylether, Sigma-Aldrich, Inc., St. Louis, MO, USA) dissolved in 1 mL of olive oil was administered using a gastric tube on embryonic day 9 (E9) in the Nitrofen and Nitrofen + HW groups.…”