Background In utero exposure to maternal smoking is associated with adverse pulmonary effects, including reduced lung function and increased incidence of asthma, with both earlier onset and greater severity. However, the mechanisms underlying these adverse pulmonary effects are unknown, and there is no effective preventive or therapeutic intervention. Recently, we suggested that down-regulation of homeostatic mesenchymal peroxisome proliferator-activated receptor γ (PPAR-γ signaling following in utero nicotine (Nic) exposure might be a contributor to chronic lung diseases such as asthma. Furthermore, by up-regulating PPAR-γ, we might be able to prevent Nic-induced adverse pulmonary effects.
Objective To determine (1) the change in the compliance (C) and resistance (R) of the respiratory system and bronchial reactivity following in utero Nic exposure and (2) if administration of a PPAR-γ agonist blocks the effects of in utero Nic exposure on C and bronchial reactivity.
Methods Pregnant Sprague-Dawley rat dams received placebo (diluent), Nic (1 or 2 mg/kg), Nic + a PPAR-γ agonist rosiglitazone (RGZ) (3 mg/kg), or Nic (2 mg/kg) + RGZ (3 mg/kg) + a PPAR-γ antagonist GW9662 (0.25 mg/kg), IP in 100 μL volumes daily from e6 until term. Pups were delivered spontaneously and breast-fed ad libitum. At postnatal days 8 to 14, the pups were studied for C and R of the respiratory system, at baseline and following methacholine (MC) challenge (up to 2 mg/mL dose). Measurements were made on anesthetized ventilated (MiniVent, Harvard Apparatus, Holliston, MA) pups at 8 mL/kg tidal volume in a whole-body plethysmograph.
Results Compared with control, with perinatal Nic exposure, there was a significant decrease in C without any change in R under basal conditions. There was a significant decrease in C and a significant increase in R following MC challenge. Concomitant treatment with RGZ completely blocked the Nic-induced alterations in pulmonary C and R under both basal and MC-challenge conditions. Treatment with GW9662 partially blocked RGZ-mediated effects on R and C.
Conclusion Alterations in pulmonary function in a rodent model of perinatal Nic exposure are completely blocked by concomitant administration of RGZ. We speculate that perinatal Nic exposure significantly affects both alveolar and airway PPAR-γ signaling.
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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