A paradoxical temporal response of the PTHrP/PPARgamma signaling pathway to lipopolysaccharide in an in vitro model of the developing rat lung.
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 J(2) (PGJ(2)). 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 alpha-smooth muscle actin (alphaSMA). 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 alphaSMA expression. The cytokine and molecular changes at 72 h were completely prevented by the concomitant treatment with PGJ(2). 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.
Rehan
Virender K
VK
Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles, David Geffen School of Medicine at UCLA, Torrance, California 90502, USA. vrehan@labiomed.org
Dargan-Batra
Soina K
SK
Wang
Ying
Y
Cerny
Laura
L
Sakurai
Reiko
R
Santos
Jamie
J
Beloosesky
Ron
R
Gayle
Dave
D
Torday
John S
JS
D000818:Animals; D000831:Animals, Newborn; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000254:growth & development*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; D014280:Triglycerides; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2