Exposure to cigarette smoke during pregnancy impairs lung embryonic development, which may increase the baby’s later-in-life risk for disorders like chronic obstructive pulmonary disease (COPD), a mouse study suggests.
Smoke was found to increase the levels of the amphiregulin (AREG) protein, which may impair the formation of certain lung cells.
The study, “Prenatal smoke exposure dysregulates lung epithelial cell differentiation in mouse offspring: role for AREG-induced EGFR signaling,” was published in the American Journal of Physiology – Lung Cellular and Molecular Physiology.
Smoke exposure before birth is associated with a higher risk for respiratory diseases for the offspring later in life, including asthma in children and adolescents, and COPD in adulthood.
Previous research had suggested that exposure to smoke during pregnancy alters the normal development of the baby’s lungs, and that this is a potential trigger for the later development of COPD and other lung diseases.
Now, a team led by researchers at the University of Groningen, in the Netherlands, investigated further how smoke exposure impairs lung development.
Female pregnant mice and one-day-old offspring were used in the study. The animals were exposed to cigarette smoke or fresh air (control group) during two sessions of 50 minutes per day, with a three-hour gap in between. The exposure began seven days prior to mating and continued until the day after the offspring were born.
The amount of smoke exposure increased as the sessions went along: the animals were first exposed to the smoke of three cigarettes, which was augmented up to a maximum of 10 cigarettes.
The researchers analyzed how smoke affected lung development by looking at the number of ciliated cells and club cells. Ciliated cells — cilia are hair-like projections on most tissue cells — are important for the flow and removal of microbes and debris up and out of the airways. Club cells are the progenitor cells of ciliated cells.
Results showed that the newborn mice (neonates) that had been exposed to smoke during pregnancy had significantly lower numbers of ciliated cells, compared with control animals not exposed to smoke. Moreover, this decrease in ciliated cells was accompanied by lower levels of the Foxj1 gene, known to be involved in cilia formation.
No differences were seen for the number of club cells, although an increase in the levels of two genes, Foxm1 and Spdef, was seen in the smoke-exposed group. These genes are mostly involved in the formation of lung secretory cells (club and goblet cells).
The team also evaluated how smoke exposure impacted the number of cells that form the alveoli, the small air sacs that exchange gases in the lung, called alveolar epithelial type I and II cells (AECI and AECII cells).
Newborns exposed to smoke had a higher number of AECII cells, as shown by the increased levels of two of these cells’ markers, pro-SPC and NKX2.1.
The number of AECI cells showed no differences between smoke-exposed and control animals. However, the levels of the Pdpn and Gramd2 genes were significantly reduced when compared with the controls. Pdpn and Gramd2 genes are involved in AECI maturation; their reduced levels indicate a delay in alveolar development.
Next, the researchers investigated what molecular factor(s) could play a role in the impact of smoke in lung development.
They focused on the epidermal growth factor receptor (EGFR) signaling pathway as it is key for the development of the lungs, including the branching of the airways and alveolarization.
EGFR signaling is primarily regulated by two ligands, AREG and the epidermal growth factor (EGF). Yet, AREG and EGF are involved in different biological roles. While AREG promotes programmed cell death (apoptosis) and cell proliferation, EGF is involved in the maturation of epithelial cells.
AREG-induced EGFR signaling also has been described to suppress the maturation of ciliated cells in the lung.
The investigators found a higher number of AREG-positive cells in smoke-exposed newborns as compared with the controls. This effect was most pronounced in females. Moreover, the levels of the Areg gene were higher in smoke-exposed neonates compared with controls.
To validate the finding that AREG was responsible for the observed changes in the lungs, the researchers used mouse lung organoids, a mini lung-model grown in the lab. They treated lung organoids with AREG and compared how cells changed in comparison with untreated organoids.
The results showed that AREG-treated organoids had fewer ciliated cells, as seen in the newborn mice exposed to smoke. Also, AREG-treated organoids had more pro-SPC positive cells compared with untreated organoids.
Overall, the results suggested that smoke exposure before pregnancy impacts lung development by increasing AREG levels and impairing the normal formation of the lungs’ specialized cells.
Treatments that modulate AREG action could be potential therapies to help prevent respiratory diseases in children exposed to smoke before birth, the team suggested.
“We provide evidence that prenatal smoke exposure impairs lung development in the offspring, in which increased AREG/EGFR signaling may have a role,” the researchers wrote.
“AREG regulation during lung development may provide a novel intervention for aberrant lung development in children from smoking mothers,” they concluded.
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