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340 PREVENTION OF IN UTERO NICOTINE-INDUCED LUNG INJURY BY MODULATING THE WINGLESS/INT AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ SIGNALING PATHWAYS.
  1. K. Huynh1,
  2. Y. Wang1,
  3. R. Sakurai1,
  4. J. Santos1,
  5. J. S. Torday1,
  6. V. K. Rehan1
  1. 1Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

Abstract

Background In utero nicotine exposure disrupts the critical homeostatic pulmonary epithelial-mesenchymal paracrine signaling pathway, resulting in the transdifferentiation of alveolar intersitial fibroblasts (AIFs) to myofibroblasts (MYFs). AIF-to-MYF transdifferentiation is characterized by down-regulation of the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling pathway and up-regulation of the Wingless/Int (Wnt) signaling pathway. Although effects of in utero nicotine exposure on PPAR-γ signaling are known, there is no information regarding its effect on Wnt signaling. We hypothesize that in utero nicotine exposure up-regulates AIF Wnt signaling, and in utero nicotine-induced lung injury can be prevented by specific molecular targeting to down-regulate Wnt signaling and/or up-regulate PPAR-γ signaling.

Objectives To determine (1) how in utero nicotine exposure affects AIF Wnt signaling and (2) if Wnt signaling antagonists and/or PPAR-γ agonists can prevent in utero nicotine-induced AIF-to-MYF transdifferentiation.

Methods WI38 cells, a human embryonic pulmonary fibroblast cell line, were cultured using standard methods. At near-confluence, the cells were treated twith nicotine (10−9 M) with or without a Wnt pathway antagonist (Wnt inhibitory factor [WIF-1]), or a PPAR-γ agonist (rosiglitazone [RGZ] 10−5M) for 24 hours to 7 days. Then the expression of various intermediates in Wnt and PPAR-γ signaling was determined at the mRNA (RT-PCR) and protein (Western blot) levels.

Results Nicotine treatment up-regulated Wnt pathway signaling intermediates such as LEF-1, β-catenin, its downstream target α-smooth muscle actin (α-SMA), and down-regulated PPAR-γ pathway signaling intermediates such as PPAR-γ and adipocyte differentiation-related protein. Concomitant treatment with WIF-1 or RGZ completely inhibited the nicotine-induced up-regulation of the expression of LEF-1 and its downstream target α-SMA.

Conclusions By either down-regulating AIF Wnt signaling and/or by up- regulating AIF PPAR-γ signaling, prohomeostatic AIFs can be maintained, preventing MYF transdifferentiation, thereby potentially preventing in utero nicotine-induced lung injury.

Supported by grants from TRDRP ((14RT-0073 and 15IT-0250), Philip Morris USA Inc. and Philip Morris International, and NIH (HL55268 and HL075405).

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