Background Intrauterine lung inflammation alters lung development, resulting in a decrease in the incidence of respiratory distress syndrome, but an increase in the incidence of bronchopulmonary dysplasia (BPD). The mechanism(s) underlying this disparity in the pulmonary outcome is not known. Since the spatio-temporal sequence of epithelial-mesenchymal interactions plays a key role in normal lung development and homeostasis, we hypothesize that specific alterations in these cell-cell interactions may explain this apparent disparity in the pulmonary outcome in response to prenatal lung inflammation.
Objective To determine the effects of Lipopolysaccharide (LPS) on Parathyroid Hormone-related Protein (PTHrP)-driven epithelial-mesenchymal interactions that have been previously shown by us to be essential in the maintenance of lung homeostasis.
Design/Methods Lung explants from embryonic (e) 19.5 (term = e22) Sprague Dawley rat pups were treated with LPS (0-50 ng/ml) with or without a PTHrP pathway agonist, Prostaglandin J2 (PGJ2) for up to 72h. The explants were maintained in Waymouth's medium at 370C/5% CO2. At specific time points (6, 12, 24, 48, and 72h), mRNA and proteins were extracted and analyzed for the expression of the specific intermediates of PTHrP-driven epithelial-mesenchymal interactions, which included Peroxisome Proliferator Activated Receptorγ (PPARγ), Adipocyte Differentiation Related Protein (ADRP), leptin, leptin receptor, Surfactant Protein-B (SP-B), α smooth muscle actin (SMA) and elastin, in addition to PTHrP and PTHrP receptor by both RT-PCR and Western hybridization.
Results LPS treatment affected the expression of the key markers of the epithelial-mesenchymal paracrine loop in a dose- and time-dependent manner. There were initially (6-24h) significant increases in the expressions of PTHrP, PPARγ, ADRP, leptin, and SP-B (p ≤0.05), without any significant effect on the expressions of αSMA and elastin. This was followed by later (48-72h) significant decreases in the expressions of PTHrP, PPARγ, leptin, and leptin receptor, which were accompanied by significant increases in the expression of αSMA and elastin (p ≤0.05), the key markers of BPD. These changes were completely prevented by the concomitant treatment with PGJ2.
Conclusions These data provide an integrative mechanism for the acute stimulation of lung differentiation accompanied paradoxically by BPD following intrauterine inflammation. Further, treatment with specific agonists of epithelial-mesenchymal interactions can prevent inflammation-induced molecular lung injury that is known to result in BPD.
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