Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho‐GTPase‐dependent actin cytoskeletal signaling in fetal lungs

Unachukwu, Uchenna; Trischler, Jordis; Goldklang, Monica; Xiao, Rui; DʼArmiento, Jeanine

doi:10.1096/fj.201601063r

Cited by 14 publications

(6 citation statements)

References 63 publications

(88 reference statements)

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“…Adverse effects on lung function (Drummond et al, 2017) and morphology (Noel et al, 2017) have been shown and synergistic effects between pre- and postnatal exposure have been identified. A recent study provided first insights into CS-related transcriptional alterations in the fetal lung (Unachukwu et al, 2017). Regarding ambient air pollution, however, we yet remain the first to provide evidence of an effect of prenatal and early-life postnatal exposure to particulate matter on lung development.…”

Section: Discussionmentioning

confidence: 99%

Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life

Lopes

Groth

Veras

et al. 2018

Environmental Pollution

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Gestational exposure to air pollution is associated with negative outcomes in newborns and children. In a previous study, we demonstrated a synergistic negative effect of pre- and postnatal exposure to PM on lung development in mice. However, the means by which air pollution affects development of the lung have not yet been identified. In this study, we exposed pregnant BALB/c mice and their offspring to concentrated urban PM (from São Paulo, Brazil; target dose 600 μg/m for 1 h daily). Exposure was started on embryonic day 5.5 (E5.5, time of placental implantation). Lung tissue of fetuses and offspring was submitted to stereological and transcriptomic analyses at E14.5 (pseudoglandular stage of lung development), E18.5 (saccular stage) and P40 (postnatal day 40, alveolarized lung). Additionally, lung function and cellularity of bronchoalveolar lavage (BAL) fluid were studied in offspring animals at P40. Compared to control animals that were exposed to filtered air throughout gestation and postnatal life, PM-exposed mice exhibited higher lung elastance and a lower alveolar number at P40 whilst the total lung volume and cellularity of BAL fluid were not affected. Glandular and saccular structures of fetal lungs were not altered upon gestational exposure; transcriptomic signatures, however, showed changes related to DNA damage and its regulation, inflammation and regulation of cell proliferation. A differential expression was validated at E14.5 for the candidates Sox8, Angptl4 and Gas1. Our data substantiate the in utero biomolecular effect of gestational exposure to air pollution and provide first-time stereological evidence that pre- and early life-postnatal exposure compromise lung development, leading to a reduced number of alveoli and an impairment of lung function in the adult mouse.

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Section: Discussionmentioning

confidence: 99%

Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life

Lopes

Groth

Veras

et al. 2018

Environmental Pollution

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“…The Wnt signaling is essential for lung organogenesis, as it is active throughout the development of the fetal lung. In the embryonic lung, it regulates cellular fate, proliferation and differentiation, stem cell maintenance, and lung branching morphogenesis (41,104). Numerous in vitro and in vivo studies using gene knockdown approaches as well as knockout and transgenic mouse models enabled isolation and identification of the roles and functions of specific Wnt-related genes in lung morphogenesis (41).…”

Section: L716mentioning

confidence: 99%

In utero exposures to electronic-cigarette aerosols impair the Wnt signaling during mouse lung development

Noël

Hansen

Zaman

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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Currently, more than 9 million American adults, including women of childbearing age, use electronic-cigarettes (e-cigs). Further, the prevalence of maternal vaping now approaching 10% is similar to that of maternal smoking. Little, however, is known about the effects of fetal exposures to nicotine-rich e-cig aerosols on lung development. In this study, we assessed whether in utero exposures to e-cig aerosols compromised lung development in mice. A third-generation e-cig device was used to expose pregnant BALB/c mice by inhalation to 36 mg/mL of nicotine cinnamon-flavored e-cig aerosols for 14–31 days. This included exposures for either 12 days before mating plus during gestation (preconception groups) or only during gestation (prenatal groups). Respective control mice were exposed to filtered air. Subgroups of offspring were euthanized at birth or at 4 wk of age. Compared with respective air-exposed controls, both preconception and prenatal exposures to e-cig aerosols significantly decreased the offspring birth weight and body length. In the preconception group, 7 inflammation-related genes were downregulated, including 4 genes common to both dams and fetuses, denoting an e-cig immunosuppressive effect. Lung morphometry assessments of preconception e-cig-exposed offspring showed a significantly increased tissue fraction at birth. This result was supported by the downregulation of 75 lung genes involved in the Wnt signaling, which is essential to lung organogenesis. Thus, our data indicate that maternal vaping impairs pregnancy outcomes, alters fetal lung structure, and dysregulates the Wnt signaling. This study provides experimental evidence for future regulations of e-cig products for pregnant women and developmentally vulnerable populations.

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“…GO-term analysis of downregulated protein-coding genes was enriched in the regulation of rho protein signal transduction ( SFig. 2 ), previously reported to be dysregulated by smoke exposure (34, 35). To determine whether CS exposure effects extend beyond changes at the level of transcription, we next measured cytokine and chemokine protein production changes secreted from CS-exposed BMDMs by ELISA, finding that Il9, Il16, Gcsf, and Vegf were all significantly downregulated by CS ( Fig.1F-I ).…”

Section: Resultsmentioning

confidence: 99%

LincRNA-Cox2 regulates smoke-induced inflammation in murine macrophages

Carpenter

Salih

Robinson

et al. 2022

Preprint

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Cigarette smoke (CS) exposure is a risk factor for many chronic diseases including chronic obstructive pulmonary disease (COPD), however the mechanism by which smoke exposure can alter homeostasis and bring about chronic inflammation is poorly understood. Here, we showcase a novel role for smoke in regulating long noncoding RNAs (lncRNAs), showing that it activates lincRNA-Cox2, which we previously characterized as functional in inflammatory regulation. Exposing lincRNA-Cox2 murine models to smoke in vivo confirmed lincRNA-Cox2 as a regulator of inflammatory gene expression in response to smoke both systemically and within the lung. We also report that lincRNA-Cox2 negatively regulates genes in smoked bone marrow derived macrophages exposed to LPS stimulation. In addition to the effects on lncRNAs, we also report dysregulated transcription and splicing of inflammatory protein-coding genes in the bone marrow niche following CS exposure in vivo. Collectively, this work provides insights into how innate immune signaling from gene expression to splicing is altered following in vivo exposure to CS and highlights an important new role for lincRNA-Cox2 in regulating immune genes following smoke exposure.

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Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho‐GTPase‐dependent actin cytoskeletal signaling in fetal lungs

Cited by 14 publications

References 63 publications

Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life

Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life

In utero exposures to electronic-cigarette aerosols impair the Wnt signaling during mouse lung development

LincRNA-Cox2 regulates smoke-induced inflammation in murine macrophages

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