Spatiotemporal alterations in Sprouty-2 expression and tyrosine phosphorylation in nitrofen-induced pulmonary hypoplasia

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• 作者：Florian Friedmacher ; Jan-Hendrik Gosemann ; Naho Fujiwara ; Luis A.J. Alvarez ; Nicolae Corcionivoschi ; Prem Puri
• 关键词：Sprouty-2 ; Tyrosine phosphorylation ; Foetal lung development ; Nitrofen ; Pulmonary hypoplasia
• 刊名：Journal of Pediatric Surgery
• 出版年：November, 2013
• 年：2013
• 卷：48
• 期：11
• 页码：2219-2225
• 全文大小：1348 K

文摘

Background/Purpose

Pulmonary hypoplasia (PH) is a life-threatening condition of newborns presenting with congenital diaphragmatic hernia (CDH). Sprouty-2 functions as a key regulator of fibroblast growth factor receptor (FGFR) signalling in developing foetal lungs. It has been reported that FGFR-mediated alveolarization is disrupted in nitrofen-induced PH. Sprouty-2 knockouts show severe defects in lung morphogenesis similar to nitrofen-induced PH. Upon FGFR stimulation, Sprouty-2 is tyrosine-phosphorylated, which is essential for its physiological function during foetal lung development. We hypothesized that Sprouty-2 expression and tyrosine phosphorylation are altered in nitrofen-induced PH.

Methods

Time-pregnant rats received either nitrofen or vehicle on gestation day 9 (D9). Foetal lungs were dissected on D18 and D21. Pulmonary Sprouty-2 gene and protein expression levels were analyzed by qRT-PCR, Western blotting and immunohistochemical staining.

Results

Relative mRNA expression of Sprouty-2 was significantly decreased in hypoplastic lungs without CDH (0.1050 卤 0.01 vs. 0.3125 卤 0.01; P < .0001) and with CDH (0.1671 卤 0.01 vs. 0.3125 卤 0.01; P < .0001) compared to controls on D18. Protein levels of Sprouty-2 were markedly decreased in hypoplastic lungs on D18 with decreased tyrosine phosphorylation levels on D18 and D21 detected at the molecular weight of Sprouty-2 consistent with Sprouty-2 tyrosine phosphorylation. Sprouty-2 immunoreactivity was markedly decreased in hypoplastic lungs on D18 and D21.

Conclusion

Spatiotemporal alterations in pulmonary Sprouty-2 expression and tyrosine phosphorylation during the late stages of foetal lung development may interfere with FGFR-mediated alveolarization in nitrofen-induced PH.