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PPAR-γ agonist rosiglitazone reverses perinatal nicotine exposure-induced asthma in rat offspring
Jie Liu1, Reiko Sakurai1, Virender K Rehan2
1Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
Insights
Perinatal nicotine exposure causes asthma in offspring, but treatment with rosiglitazone (RGZ), a PPAR-γ agonist, starting after birth can reverse these effects. This offers a potential intervention for nicotine-induced lung damage.
Area of Science:
- Respiratory medicine
- Developmental toxicology
- Pharmacology
Background:
- Perinatal nicotine exposure is linked to offspring asthma due to reduced PPAR-γ signaling.
- The potential for reversing established nicotine-induced asthma has not been investigated.
Purpose of the Study:
- To determine if a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone (RGZ), can reverse asthma-like conditions induced by perinatal nicotine exposure in rats.
Main Methods:
- Pregnant rats received nicotine or placebo; offspring were treated with RGZ or placebo postnatally.
- Pulmonary function (airway resistance, compliance) and airway mesenchymal marker expression were assessed at postnatal day 21.
Main Results:
- Nicotine exposure increased airway resistance, decreased compliance, and elevated mesenchymal markers.
- Postnatal RGZ treatment reversed these functional and molecular changes, normalizing lung function.
Conclusions:
- PPAR-γ agonist RGZ can reverse nicotine-induced airway hyperresponsiveness and molecular changes.
- Intervention with RGZ postnatally is effective in reversing perinatal nicotine exposure-induced lung alterations.
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.
