Article Text

  1. L. Cerny1,
  2. Y. Wang1,
  3. J. Santos1,
  4. R. Sakurai1,
  5. J. S. Torday1,
  6. V. K. Rehan1
  1. 1Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.


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 E2 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 PGJ2 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 PGJ2 (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 PGJ2 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.

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