Alterations of peroxisome proliferator-activated receptor γ and monocyte chemoattractant protein 1 gene expression in the nitrofen-induced hypoplastic lung.

Background/purpose: Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in normal lung development. Peroxisome proliferator-activated receptor γ messenger RNA (mRNA) is detectable at 18 days of gestation in fetal rat lungs, and levels peak just before birth. Peroxisome proliferator-activated receptor γ agonists are reported to stimulate lung development, whereas inhibition of PPARγ disrupts postnatal lung maturation. Monocyte chemoattractant protein 1 (MCP-1), which is inhibited by PPARγ, is reported to disrupt late lung morphogenesis. This study was designed to investigate the hypothesis that PPARγ expression is downregulated and that MCP-1 expression is upregulated during the late stages of lung development in nitrofen-induced hypoplastic lungs.

Methods: Pregnant rats were treated with nitrofen or vehicle on D9. RNA was extracted from fetal lungs (D18 and D21), and relative mRNA expression levels of PPARγ and MCP-1 were determined by reverse transcriptase-polymerase chain reaction. Immunohistochemistry was performed to evaluate protein expression/distribution of PPARγ and MCP-1.

Results: Relative mRNA expression levels of PPARγ were significantly downregulated in the nitrofen group compared with controls on D21, whereas MCP-1 levels were upregulated. Immunohistochemical study showed markedly decreased PPARγ and increased MCP-1 immunoreactivity in the nitrofen-induced hypoplastic lungs compared with controls on gestational day 21.

Conclusion: Altered pulmonary gene expression of PPARγ and MCP-1 during late gestation may impair lung development and maturation, contributing to pulmonary hypoplasia in the nitrofen-induced congenital diaphragmatic hernia model.