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Query: UMLS:C0019270 (hernia)
 15,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary hypoplasia (PH) is a leading contributor to the lethality of congenital diaphragmatic hernia (CDH). Studies now suggest that PH arises prior to visceral herniation. Growth factors (GF) are pivotal to this embryonic lung growth. With striking in-vitro effects on lung morphogenesis, GF are under investigation as therapies for PH. Heparin modulates the kinetics of heparan-sulphate binding ligands that drive lung development. We hypothesised that heparin may rescue PH by favourable alteration of endogenous pulmonary GF activity. Normal and hypoplastic lung primordia were microdissected on day 13.5 of gestation and cultured for up to 78 h in plain media with and without heparin. In-vitro morphological development was studied by serial measurements of terminal bud count, lung area, and lung perimeter. Nitrofen-exposed lungs cultured with heparin showed no significant improvements in terminal bud count, lung area, and lung perimeter at 30, 54, and 78 h compared to untreated hypoplastic lungs maintained in vitro. In normal lungs heparin demonstrated no sustained significant morphological effects compared to untreated control lungs. In this study, heparin did not stimulate branching morphogenesis of normal or hypoplastic lungs in our organ culture system. Known at higher concentrations to inhibit smooth-muscle proliferation, heparin may ameliorate pulmonary vascular hypermuscularisation with the prospect of benefiting CDH infants on extracorporeal membrane oxygenation. Future studies will address the impact of exogenous GF on hypoplastic lung development in organ culture.
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PMID:Heparin and in-vitro experimental lung hypoplasia. 1089 23

Nitrofen induces in rats diaphragmatic hernia (CDH) with heart and lung hypoplasia by a mechanism involving oxidation. The aim of this study was to examine if prenatal administration of the anti-oxidant agent vitamin E (VitE) prevents to some extent heart and lung hypoplasia. Pregnant rats received on E9.5 either 100 mg of nitrofen alone or followed by 150 IU of VitE on E16.5-E20.5. Control animals received either vehicle or VitE alone. The fetuses were recovered on E21. The hearts and lungs were weighed and DNA and proteins were measured. Sections of the heart and lung were immunohistochemically stained for ki-67, Tunel and TTF-1, and the proportions of proliferating, apoptotic and TTF-1-expressing cells were determined. Cultured human pneumocytes were exposed to the same agents and similarly processed. TTF-1 expression and the proportion of proliferating cells were quantitated. The ANOVA or Kruskall-Wallis tests were used for comparison with p<0.05 as threshold of significance. Nitrofen-exposed rats had decreased lung and heart weight/body weight ratios, lung and heart DNA and protein, lung TTF-1 expression and proportion of proliferating cells in lung and heart. Additional treatment with VitE ameliorated these decreases except for lung TTF-1 and heart weight. In cultured pneumocytes, TTF-1 expression was decreased by nitrofen and rescued by VitE. Cell proliferation followed the same pattern. Antioxidant VitE partially reverses the effects of nitrofen on the heart and lungs of exposed rats. The same effects are observed in cultured human pneumocytes. These results further substantiate the oxidative nature of the effects of nitrofen and suggest that anti-oxidant agents could have a potential clinical application.
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PMID:Prenatal vitamin E improves lung and heart hypoplasia in experimental diaphragmatic [correction of diaphragamatic] hernia. 1289 60

Reduced lung size (lung hypoplasia, LH) is the main cause of mortality in newborns with congenital diaphragmatic hernia (CDH). However, it is unclear which mechanisms lead to LH. To assess this, we analyzed the relationship of LH and liver mass in correlation to the size of the diaphragmatic defect in rats with nitrofen-induced CDH. A total of 266 newborn Sprague-Dawley rats (30 litters) were exposed to nitrofen on day 11.5 of pregnancy. After spontaneous delivery at term (22 days), all newborns were microdissected. Using a computerized morphometric device, the area of the thoracic cavity, the lung, the intrathoracic liver, and the diaphragmatic defect were measured. The lungs, the intrathoracic, and the extrathoracic portion of the liver were weighed. After nitrofen exposure, 160 newborn rats presented with CDH (60.2%). They were divided into five groups according to the intrathoracic content of intraabdominal organs. We observed a significant increase of the total liver and decrease of the lung weight in the severely affected groups. A significant correlation between the size of the defect and the weight of the intrathoracic part of the liver could be demonstrated. Nitrofen alone had no effect on liver weight. Our results indicate that (1) the presence of liver inside the thoracic cavity is not the result of dislocation but rather of growth of liver tissue through the defect, and (2) the observed correlation between the size of the defect and the intrathoracic liver weight may be part of the pathogenesis of LH in CDH.
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PMID:The relationship of diaphragmatic defect, liver growth, and lung hypoplasia in nitrofen-induced congenital diaphragmatic hernia in the rat. 1522 67

Recent studies suggest a role for antioxidants in the prevention of pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH). We studied the effects of vitamin E in the nitrofen-rat model of CDH. After an initial fast, timed-pregnant Sprague-Dawley rats were gavage-fed nitrofen at gestational day 11 (term is 22 d). On the same day, one group was given a s.c. injection of vitamin E in alcohol; a second group was given an injection of alcohol alone. A third group received no treatment (control). Fetuses were delivered on day 21, and static pressure-volume curves were measured by immersion. Lungs were analyzed for total DNA and protein content by standard methods. A total of 203 fetuses were studied. Of 151 nitrofen-exposed fetuses, 77% had CDH; 92% of these were right-sided. CDH was present in 82% of vehicle-treated fetuses and 71% of vitamin E-treated fetuses (p=0.17). Nitrofen-exposed fetuses not only were smaller than control fetuses but also had disproportionately smaller lungs and poorer lung function, even when CDH was absent; however, lung function was worse when CDH was present. Vitamin E treatment did not improve either lung growth or function, although there was a trend toward less CDH. We have shown, for the first time, that the lung hypoplasia seen in nitrofen-exposed rat fetuses is associated with a dramatic reduction in static lung function, even when CDH is not present. Finally, our findings support the notion that lung hypoplasia in the nitrofen-rat model is independent of CDH formation.
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PMID:Can maternal vitamin e supplementation prevent lung hypoplasia in the nitrofen-induced rat model of congenital diaphragmatic hernia? 1561 44

Rats with experimental congenital diaphragmatic hernia (CDH) have heart hypoplasia and conotruncal and great vessel malformations that are likely related to disturbed neural crest developmental control. Neural crest cells communicate through intercellular gap junctions whose main protein is Connexin 43 (Cx43). The migration and participation of neural crest cells in heart development is likely influenced by this protein which might be also directly involved in myocardial development. Vitamin A is beneficial for heart hypoplasia in CDH rats. The aims of this study were to examine the status of Cx43 in the heart of embryonal rats exposed to nitrofen and to assess if vitamin A reverts these effects. Pregnant rats received either 100 mg nitrofen or olive oil on E9.5. Each group was divided into two subgroups according to the subsequent treatment with intragastric vitamin A (15,000 i.u.) or vehicle on E10.5 and E11.5. The pups were recovered on E13, E15, and E21 and the hearts were dissected out and pooled. Cx43 mRNA expression was determined by quantitative real-time PCR. Comparisons among groups were made with ANOVA and Bonferroni post hoc tests with a threshold of significance of P<0.05. In control rats Cx43 mRNA was minimally expressed on E13 and E15 and fully expressed on E21. Nitrofen significantly increased Cx43 mRNA on E15. Additional treatment with vitamin A tended to moderate this increase on E15. Cx43 was overexpressed in the hearts of nitrofen-exposed embryonal rats on day E15 of gestation. Vitamin A tended to normalize this expression. The mechanism of action of Cx43 deserves further investigation.
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PMID:Expression of Connexin 43 in the hearts of rat embryos exposed to nitrofen and effects of vitamin A on it. 1629 52

Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by coarse facies, diaphragmatic hernia, distal limb hypoplasia and malformations of the cardiovascular, gastrointestinal, genitourinary and central nervous systems. Diaphragmatic hernia is a leading diagnostic feature in Fryns syndrome, recorded in more than 80% of cases. We report a newborn with clinical features of Fryns syndrome except the diaphragmatic hernia. Cases of Fryns syndrome without diaphragmatic hernia are reviewed. Even in the absence of diaphragmatic hernia, pulmonary anomalies are described in Fryns syndrome, especially pulmonary hypoplasia. Fetal mice, exposed to nitrofen, have a high incidence of congenital diaphragmatic hernia and other malformations similar to that seen in Fryns syndrome. Nitrofen might target molecular mechanisms similar to those involved in Fryns syndrome.
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PMID:Fryns syndrome without diaphragmatic hernia. Report on a new case and review of the literature. 1644 Aug 78

We hypothesized that abnormal fetal lung growth in experimental congenital diaphragmatic hernia after maternal nitrofen exposure alters lung structure due to impaired VEGF signaling, which can be reversed with VEGF or nitric oxide (NO) treatment. Timed-pregnant Sprague-Dawley rats were treated with nitrofen on embryonic day 9 (E9), and fetal lungs were harvested for explant culture on E15. Explants were maintained in 3% O2 for 3 days and were treated with NO gas or recombinant human VEGF protein for 3 days. To determine the effects of VEGF inhibition on lung structure, normal fetal lung explants were treated with SU-5416, a VEGF receptor inhibitor, with or without exogenous NO or VEGF. We found that nitrofen treatment impaired lung structure, as evidenced by decreased branching at day 0, but lung structure was not different from controls after 3 days in culture. Nitrofen reduced lung VEGF but not endothelial NO synthase protein level. Treatment with NO enhanced lung growth in control and nitrofen-exposed lungs; however, the response to NO in the nitrofen-treated lungs was reduced when compared with controls. VEGF treatment did not cause a further increase in lung complexity after nitrofen exposure. SU-5416 treatment altered lung structure, which improved with NO but not VEGF treatment. Both nitrofen and SU-5416 treatment increased apoptosis in the mesenchyme of fetal lung explants. We conclude that nitrofen exposure increased apoptosis, decreased lung growth and reduced VEGF expression, and that exogenous NO but not VEGF treatment enhances lung growth. Disruption of lung architecture after VEGF receptor blockade was similar to nitrofen-induced changes but was more responsive to NO.
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PMID:Impaired VEGF and nitric oxide signaling after nitrofen exposure in rat fetal lung explants. 1799 83

Fetal lung hypoplasia is a common finding in several fetal conditions such as congenital diaphragmatic hernia (CDH). Interestingly, previous studies have demonstrated that hypoplastic lungs have the ability to recover to normal size, when relieved from mechanical factors. However, the underlying mechanisms remain largely unknown. Recently, interleukin-6 (IL-6) has been involved in catch-up growth phenomenon in children. Thus, we hypothesized that IL-6 could mediate fetal growth recover from hypoplastic lungs. Control and nitrofen-induced hypoplastic lung explants were cultured either in normal conditions or with IL-6 neutralizing antibodies. The total number of peripheral airway buds, epithelial perimeter, and total explant area were analyzed and daily branching rates were calculated. Additionally, IL-6 mRNA and protein expression was assessed both in qualitative (by in situ hybridization and immunohistochemistry) and in quantitative (by real-time PCR and Western blot) approaches, in control and hypoplastic lungs (nitrofen and CDH groups). Nitrofen-induced hypoplastic lungs showed in vitro, out of systemic environment, the ability to recover from hypoplasia and presented daily branching rates significantly higher than controls. Blocking IL-6 activity significantly diminished the intrinsic capacity of hypoplastic fetal lungs to recover from hypoplasia and attenuated their daily branching rates. Although more exacerbated in CDH, both nitrofen-exposed lungs presented significant IL-6 mRNA and protein over-expression throughout all studied gestational ages. The present study suggests, for the first time, that fetal lung is able to recover from growth retardation through a way that resembles the catch-up growth phenomenon, and it seems to be, at least partially, orchestrated by intrinsic mechanisms implicating IL-6.
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PMID:Intrinsic catch-up growth of hypoplastic fetal lungs is mediated by interleukin-6. 1850 Jul 30

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH.
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PMID:Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH. 2593 71

The aim of this study was to investigate the therapeutic effects and underlying mechanism of tetramethylpyrazine (TMP) on lung development using a rat model of congenital diaphragmatic hernia (CDH). Nitrofen was used to induce CDH. Pregnant rats were divided into three groups: control, CDH, and CDH+TMP. 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 markedly abnormal structure was observed, as evidenced by pulmonary hypoplasia and vascular remodeling, in the CHD. These abnormalities were improved in the CDH+TMP. There were significant differences between the CHD and CHD+TMP in percentage of medial wall thickness, arteriole muscularization, radial alveolar counts, AA%, and alveolar septal thickness. YAP expression was markedly increased in the CHD compared to the controls, 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 CHD, potentially through increasing expression of LATS1 and phosphorylation of YAP.
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PMID:Effect of antenatal tetramethylpyrazine on lung development and YAP expression in rat model of experimental congenital diaphragmatic hernia. 3205 76


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