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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/L182    most recent 00319.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Rehan, V. K. Articles by Torday, J. S. Search for Related Content PubMed PubMed Citation Articles by Rehan, V. K. Articles by Torday, J. S.

A paradoxical temporal response of the PTHrP/PPAR signaling pathway to lipopolysaccharide in an in vitro model of the developing rat lung

Departments of ¹Pediatrics and ²Obstetrics and Gynecology, Harbor-University of California at Los Angeles Medical Center, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles, David Geffen School of Medicine at University of California at Los Angeles, Torrance, California

Submitted 18 August 2006 ; accepted in final form 10 April 2007

Chorioamnionitis alters lung development, resulting in a paradoxical 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 outcomes is not known. We hypothesized that specific alterations in alveolar epithelial-mesenchymal interactions might explain this apparent disparity in the pulmonary outcome following chorioamnionitis. We determined the effects of lipopolysaccharide (LPS) on parathyroid hormone-related protein (PTHrP)-driven epithelial-mesenchymal interactions that are essential for normal lung development and homeostasis. Lung explants from embryonic day 19.5 Sprague-Dawley rat fetuses were treated with LPS with or without a PTHrP pathway agonist, prostaglandin J₂ (PGJ₂). LPS treatment affected the production of proinflammatory cytokines and the expression of the key markers of the epithelial-mesenchymal paracrine interactions in a time-dependent manner. At 6 h, there was a significant increase in the expression of PTHrP and the other key markers of alveolar homeostasis without any significant effect on -smooth muscle actin (SMA). In contrast, at 72 h, there was a significant decrease in the expression of PTHrP and the other key markers of alveolar homeostasis accompanied by a significant increase in SMA expression. The cytokine and molecular changes at 72 h were completely prevented by the concomitant treatment with PGJ₂. We speculate that these data provide a likely mechanism for the acute stimulation of lung differentiation, accompanied paradoxically by BPD following chorioamnionitis, and suggest that by specifically targeting PTHrP signaling, the inflammation-induced molecular injury that is known to result in BPD can be prevented.

bronchopulmonary dysplasia; chorioamnionitis; chronic lung disease; parathyroid hormone-related protein

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