PPAR-γ agonist rosiglitazone reverses perinatal nicotine exposure-induced asthma in rat offspring

Am J Physiol Lung Cell Mol Physiol. 2015 Apr 15;308(8):L788-96. doi: 10.1152/ajplung.00234.2014. Epub 2015 Feb 6.

Abstract

In a rat model, downregulation of homeostatic mesenchymal peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling following perinatal nicotine exposure contributes to offspring asthma, which can be effectively prevented by concomitant administration of PPAR-γ agonist rosiglitazone (RGZ). However, whether perinatal nicotine exposure-induced asthma can be reversed is not known. We hypothesized that perinatal nicotine exposure-induced asthma would be reversed by PPAR-γ agonist RGZ. Pregnant rat dams received either placebo or nicotine from embryonic day 6 until term. Following spontaneous delivery at term, dams were continued on the assigned treatments, up to postnatal day 21 (PND21). However, at delivery, pups were divided into two groups; one group received placebo, and the other group received RGZ from PND1 to PND21. At PND21, pulmonary function and the expression of mesenchymal markers of airway contractility (α-smooth muscle actin, calponin, fibronectin, collagen I, and collagen III) were determined by immunoblotting and immunostaining for the evidence of reversibility of perinatal nicotine exposure-induced lung effects. Compared with controls, perinatal nicotine exposure caused 1) a significant increase in airway resistance and a decrease in airway compliance following methacholine challenge, 2) a significant increase in acetylcholine-induced tracheal constriction, and 3) increased pulmonary and tracheal expression of the mesenchymal markers of contractility. Treatment with RGZ, starting on PND1, reversed all of the nicotine-induced molecular and functional pulmonary effects, virtually normalizing the pulmonary phenotype of the treated animals. We conclude that perinatal nicotine exposure-induced functional and molecular alterations in upper and lower airways can be reversed by PPAR-γ agonist RGZ, allowing an effective intervention even when started postnatally.

Keywords: asthma; nicotine; peroxisome proliferator-activated receptor; pregnancy; smoking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / prevention & control*
  • Cells, Cultured
  • Female
  • Lung / metabolism
  • Lung / physiopathology
  • Muscle Contraction
  • Nicotine / toxicity*
  • PPAR gamma / agonists*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / prevention & control*
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / metabolism
  • Rosiglitazone
  • Thiazolidinediones / pharmacology*
  • Thiazolidinediones / therapeutic use

Substances

  • PPAR gamma
  • Receptors, Nicotinic
  • Thiazolidinediones
  • Rosiglitazone
  • Nicotine