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PPARγ agonist rosiglitazone prevents perinatal nicotine exposure-induced asthma in rat offspring
Jie Liu1, Reiko Sakurai, E M O'Roark
1Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Insights
Maternal smoke exposure during pregnancy harms offspring lung development, increasing asthma risk. A PPARγ agonist, rosiglitazone, effectively prevented these adverse effects in a rat model.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Developmental Biology
Background:
- Perinatal smoke exposure is linked to reduced lung function and increased asthma incidence in offspring.
- The underlying mechanisms remain unclear, and effective interventions are lacking.
- Downregulation of peroxisome proliferator-activated receptor-γ (PPARγ) signaling by in utero nicotine exposure is a potential contributor to chronic lung diseases.
Purpose of the Study:
- To investigate the effects of perinatal nicotine exposure on offspring pulmonary function and airway contractility.
- To determine if a PPARγ agonist, rosiglitazone (RGZ), can counteract the detrimental effects of perinatal nicotine exposure.
Main Methods:
- An in vivo rat model was used, exposing pregnant dams to placebo, nicotine, or nicotine + RGZ from embryonic day 6 to postnatal day 21.
- Offspring pulmonary function (resistance, compliance), tracheal contractility, and expression of mesenchymal markers were assessed.
- The impact of RGZ treatment on nicotine-induced pulmonary and molecular changes was evaluated.
Main Results:
- Perinatal nicotine exposure significantly increased respiratory system resistance and decreased compliance.
- Increased tracheal constriction response and mesenchymal markers of airway contractility were observed in nicotine-exposed offspring.
- Concomitant RGZ treatment completely prevented nicotine-induced alterations in pulmonary function and airway contractility.
Conclusions:
- Perinatal nicotine exposure adversely affects offspring lung development and function, potentially contributing to asthma.
- PPARγ signaling plays a crucial role in mediating these effects.
- PPARγ agonists, such as rosiglitazone, demonstrate potential as a preventive therapy for perinatal smoke exposure-induced lung diseases.
Abstract:
Perinatal exposure to maternal smoke is associated with adverse pulmonary effects, including reduced lung function and increased incidence of asthma. However, the mechanisms underlying these effects are unknown, and there is no effective preventive and/or therapeutic intervention. Recently, we suggested that downregulation of homeostatic mesenchymal peroxisome proliferator-activated receptor-γ (PPARγ) signaling following in utero nicotine exposure might contribute to chronic lung diseases such as asthma. We used an in vivo rat model to determine the effect of perinatal nicotine exposure on 1) offspring pulmonary function, 2) mesenchymal markers of airway contractility in trachea and lung tissue, and 3) whether administration of a PPARγ agonist, rosiglitazone (RGZ), blocks the molecular and functional effects of perinatal nicotine exposure on offspring lung. Pregnant Sprague-Dawley rat dams received placebo, nicotine, or nicotine + RGZ daily from embryonic day 6 until postnatal day 21, when respiratory system resistance, compliance, tracheal contractility, and the expression of markers of pulmonary contractility were determined. A significant increase in resistance and a decrease in compliance under basal conditions, with more pronounced changes following methacholine challenge, were observed with perinatal nicotine exposure compared with control. Tracheal constriction response and expression of mesenchymal markers of airway contractility were also significantly increased following perinatal nicotine exposure. Concomitant treatment with RGZ completely blocked the nicotine-induced alterations in pulmonary function, as well as the markers of airway contractility, at proximal and distal airway levels. These data suggest that perinatal smoke exposure-induced asthma can be effectively blocked by PPARγ agonists.
