Abstract
Background Prenatal inflammation results in a paradoxical decrease in respiratory distress syndrome but an increase in bronchopulmonary dysplasia. We have implicated epithelial-mesenchymal signaling in mediating this response. Cyclooxygenase 2 (COX-2) and its metabolites are known mediators of lung inflammation, yet their role in parathyroid hormone-related protein (PTHrP)-mediated epithelial-mesenchymal paracrine signaling is not known. We hypothesize that COX-2 plays an integral role in inflammation-induced lung injury via PTHrP-driven signaling. Objectives (1) Determine the dose response and time course of COX-2 expression and prostaglandin E 2 synthesis in lipopolysaccharide (LPS)-induced lung injury; (2) determine the specificity of COX-2 in mediating inflammation-induced effects on PTHrP signaling by examining (a) the effect of the nonselective COX inhibitor indomethacin on the expression of PTHrP signaling pathway-related markers and (b) the effect of the PTHrP signaling pathway agonist PGJ 2 on COX-2 expression. Design/Methods Fetal rat lung explants (FRLE), alveolar type II cells (ATII), and lipofibroblasts (LF) from embryonic day 19.5 Sprague-Dawley rat fetuses were treated with LPS (0-50 μg/mL) with or without I (1 or 10 μM) and PGJ 2 (5-50 μM) for up to 72 hours. FRLE, LF, and ATII cells were maintained in standard culture media. Using RT-PCR and Western hybridization, the expression of COX-2 and markers of the PTHrP pathway were analyzed, including PTHrP, PTHrP receptor, peroxisome proliferator-activated receptor γ, adipocyte differentiation-related protein, surfactant protein B, and cholinephosphate cytidyltransferase α. Results LPS treatment of FRLE, ATII, and LF increased COX-2 expression in a time- and dose-dependent manner. Increased expression of COX-2 and markers of the PTHrP signaling pathway were blocked by pretreatment with indomethacin. Treatment with PGJ 2 blocked the effect of LPS on PTHrP signaling pathway markers but did not block the increase in COX-2 expression. Conclusion COX-2 may play an integral role in LPS-induced prenatal lung inflammation and its modulation may attenuate the consequent lung injury. COX-2 does not seem to be centrally involved in LPS-induced effects on PTHrP-driven epithelial-mesenchymal paracrine signaling. We speculate that in combination, COX-2 inhibitors and PTHrP pathway agonists might have an additive effect on blocking LPS-induced lung injury. NIH grants HL55268 and HL075405.
Published Version
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