Combining keratinocyte growth factor transfection into the airways and tracheal occlusion in a fetal sheep model of congenital diaphragmatic hernia

Abstract

Thus, BGTC/DOPE liposomes can mediate efficient KGF transfection into the airways in a fetal sheep model of CDH. Furthermore, combining KGF transfection and TO resulted not only (as did TO alone) in the correction of the CDH-associated lung hypoplasia and decreased RAC, but also in increased SPB synthesis, suggesting a better maturation of the re-growing lung (compared to TO alone). Additional studies are required to further explore the therapeutic potential of such a combined strategy; in particular, studies evaluating the lung function of in utero-treated CDH lamb newborns.

Excessive Reversal of Epidermal Growth Factor Receptor and Ephrin Signaling Following Tracheal Occlusion in Rabbit Model of congenital Diaphragmatic Hernia

“…In our study, DHTO lungs demonstrated decreased protein synthesis compared with DH and control lungs, although no specific protein group, such as surfactant proteins, were differentially regulated. This is consistent with human studies demonstrating no difference in surfactant quality or composition in CDH (13) but is inconsistent with animal studies showing the opposite (10,11). With regards to cell hyperplasia, using nitrofen model of CDH, Chapin, et al demonstrated that rat DH lungs contain less DNA than control and that lung Consistent with our gene expression findings (Figure 4), the pathways and processes downregulated by DH were excessively upregulated in DHTO and vice versa ( Figure 8A).…”

“…DNA content is increased by TO (10). Saada, et al observed epithelial hyperplasia in a sheep model of DHTO (11), and after TO in the rat nitrogen model, there is an increased ratio of alveolar type I to alveolar type II cells (10). Taken together, these findings suggest than one or more epithelial mitogens may be important in the adaptive and maladaptive responses in CDH treated with TO.…”

“…While TO for CDH may gain more widespread acceptance in the coming years, there remains an urgent need to understand the cellular responses to CDH and TO so that targeted therapies may be developed to improve fetal lung development and to limit any undesirable effects of TO. There have been reports of how CDH and TO impact lung matrix synthesis (6)(7)(8)(9), lung epithelial function and surfactant (10)(11)(12)(13) and microvascular development (14)(15)(16), and that tracheal occlusion reverses some of resulting in severe pulmonary hypoplasia (2). Despite optimal medical and surgical care, mortality remains high with survivors experiencing severe restrictive lung disease and significant pulmonary hypertension (1).…”

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

“…It adds to a small body of studies published in larger animal models (sheep or rabbit) in novel therapies for CDH. In sheep, only transplacental tadalafil has previously been investigated [17,45]. …”

Effect of keratinocyte growth factor on growth and transdifferentiationof primary alveolar epithelial type II cells

“…It also can activate transepithelial ion transport in alveoli and preserves expression of water channels to alleviate high-altitude pulmonary edema (3). An increasing number of studies suggest that KGF protects the lungs from a variety of damage via different mechanisms (4), as well as regulating the development of bronchi during maturation of the fetal lung (5). Nevertheless, the underlying protective mechanism of KGF remains elusive.…”