Prenatal Secondhand Cigarette Smoke Promotes Th2 Polarization and Impairs Goblet Cell Differentiation and Airway Mucus Formation

Abstract

Parental, particularly maternal, smoking increases the risk of childhood allergic asthma and infection. Similarly, in a murine allergic asthma model, prenatal plus early postnatal exposure to secondhand cigarette smoke (SS) exacerbates airway hyperreactivity and Th2 responses in the lung. However, the mechanism and contribution of prenatal versus early postnatal SS exposure on allergic asthma remains unresolved. To identify the effects of prenatal and/or early postnatal SS on allergic asthma, BALB/c dams and their offspring were exposed gestationally and/or 8–10 weeks post-birth to filtered air or SS. Prenatal, but not postnatal SS strongly increased methacholine and allergen (Aspergillus)-induced airway resistance, Th2-cytokines levels and atopy, and activated the Th2 polarizing pathway GATA3/Lck/ERK1/2/STAT6. Either prenatal and/or early postnatal SS downregulated the Th1-specific transcription factor T-bet and, surprisingly, in spite of high levels of IL-4/IL-13, dramatically blocked the allergen-induced mucous cell metaplasia, airway mucus formation, and the expression of mucus-related genes/proteins: Muc5ac, GABAA-receptors, and SPDEF. Given that SS/nicotine exposure of normal adult mice promotes mucus formation, the results suggest that fetal and neonatal lung are highly sensitive to cigarette smoke. Thus, while the gestational SS promotes Th2 polarization/allergic asthma, it may also impair and/or delay the development of fetal and neonatal lung, affecting mucociliary clearance and Th1 responses. Together, this may explain the increased susceptibility of children from smoking parents to allergic asthma and childhood respiratory infections.

The association between environmental tobacco smoke exposure and childhood respiratory disease: a review

“…Further, there is evidence linking the effects of tobacco smoke exposure to impaired early-life immune function resulting in an imbalance in Th1 and Th2 responses increasing the susceptibility to allergic diseases and childhood respiratory infections [14,17]. …”

Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring

“…Recent studies suggest that exposure to specific environmental stimuli during critical early life periods influence the development of asthma later in life. For example, childhood exposure to microbial products 11 , cigarette smoke 12, 13 , or environmental pollutants 14 influences asthma development later in life. This critical developmental window appears to extend into the prenatal period as well, as in utero exposures to these factors also influence asthma risk 13, 15–18 , as do alterations in maternal diet 19, 20 .…”

“…For example, childhood exposure to microbial products 11 , cigarette smoke 12, 13 , or environmental pollutants 14 influences asthma development later in life. This critical developmental window appears to extend into the prenatal period as well, as in utero exposures to these factors also influence asthma risk 13, 15–18 , as do alterations in maternal diet 19, 20 . Similarly, infection with the helminthic parasite Schistosoma mansoni increases development of asthma in offspring if pregnancy was initiated during the “Th2 phase” of the anti-parasitic immune response 21 .…”

Alterations in DNA methylation and airway hyperreactivity in response toin uteroexposure to environmental tobacco smoke

“…A recent systematic review and meta-analysis of 13 studies examining the effects of prenatal smoking reported a 42–50% increased risk of asthma in infants and adolescents exposed to smoke prenatally (Burke et al, 2012). Several animal model studies have clearly demonstrated that i n utero exposure to maternal smoking is a primary cause of impaired lung function, AHR and onset of asthma (Singh et al, 2011; Yochum et al, 2014). While the impact of active maternal smoking on offspring development is well established, the impact of prenatal ETS exposure has been less studied despite the large number of women exposed to ETS during pregnancy.…”