<i>In utero</i> exposure to second‐hand smoke activates pro‐asthmatic and oncogenic miRNAs in adult asthmatic mice

Xiao, Rui; Noël, Alexandra; Perveen, Zakia; Penn, Arthur

doi:10.1002/em.21998

Cited by 22 publications

(21 citation statements)

References 45 publications

(69 reference statements)

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“…As mentioned previously, it is well known that both types of alteration are associated with tumor formation, with hypomethylation status being associated with activation of oncogenes and hypermethylation with silencing of tumor suppressors [40]. Thus, in addition to our results, there is increasing evidence for epigenetic effects of in utero SHS exposure alone on lung development with persistence into adult life, and this may predispose to respiratory morbidity, including lung cancer [39]. …”

Section: Discussionsupporting

confidence: 76%

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Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

et al. 2017

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BackgroundAn increasing number of epidemiological and experimental studies have associated exposure to second-hand smoke (SHS) during pregnancy with adverse outcomes in newborns. As we have previously shown in mice, in utero exposure to SHS at critical stages of fetal development, results in altered lung responses and increased disease susceptibility upon re-exposure to irritants (SHS or ovalbumin) in adulthood. In this study, we asked whether the in utero SHS exposure alone is sufficient to alter lung structure and function in adult mice.MethodsPregnant BALB/c mice were exposed from days 6 to 19 of pregnancy to 10 mg/m3 of SHS or HEPA-filtered air. Male and female offspring (n = 13–15/group) were sacrificed at 15 weeks of age. We measured lung function with non-invasive and invasive methods, performed lung morphometric analysis on trichrome-stained lung tissue samples, and assessed lung gene expression via RNA sequencing and protein assays.Results In utero SHS exposure significantly increased mean linear intercept and decreased the surface area per unit volume of the lungs in both males and females, indicating perturbation in alveolar developmental processes. Tidal volume, minute volume and inspiratory capacity were significantly decreased compared with the controls only in male mice exposed in utero to SHS, suggesting that males are more sensitive than females to an SHS insult during lung development. This also suggests that in our model, lung structure changes may be necessary but are not sufficient to impair lung function. SERPINA1A, the mouse ortholog of human α1-antitrypsin, deficiency of which is a known genetic risk factor for emphysema, was down-regulated at the protein level in the in utero SHS-exposed mice. Additionally, DNMT3A protein expression was dysregulated, indicating that DNA methylation occurred in the lungs.ConclusionsOur results indicate that in utero SHS exposure alone alters both lung function and structure well into adulthood (15 weeks) in male mice. Furthermore, lung function alterations in this model are sex-specific, with males being more susceptible to in utero SHS effects. Overall, our data suggest that in utero SHS exposure alone can predispose to adult lung diseases.

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Section: Discussionsupporting

confidence: 76%

“…SHS is a major indoor air pollutant and increasing numbers of epidemiological and experimental studies have associated in utero exposure to SHS with adverse outcomes in newborns [2, 23, 25, 37–39]. Here we investigated whether in utero SHS exposure alone is sufficient to alter lung structure and function in adult mice.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

et al. 2017

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“…Although a number of studies have investigated the long-term effects of in utero SHS exposure (16)(17)(18)54), a limited number of studies have explored the short-term effects of neonatal SHS exposure. Given the highly sensitive stage of ongoing lung development, the superimposition of exposure to SHS or any other airborne environmental pollutant upon early postnatal life makes interpretation of these studies challenging.…”

Section: Discussionmentioning

confidence: 99%

Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease

Lewis

Sultana

Sharma

et al. 2017

The Journal of Immunology

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Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed transgenic (-Tg) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed -Tg (FA-Tg) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed -Tg (SHS-Tg) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg mice exhibited marked mucus obstruction and responses, SHS-Tg mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, responses, and delayed bacterial clearance in SHS-Tg mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg mice, the SHS-Tg mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.

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“…The regulation of miR-92a-3p modified the transcription of KAT2B and PARP1, which played an important role in the development of combined allergic rhinitis and asthma syndrome [26]. Xiao et al reported that miR-155 participated in immune regulation by setting a balance between Th1 and Th2 responses, and the expression level of miR-155-5p was highly related to protein expression of the pro-asthmatic Th2 cytokines in bronchoalveolar lavage fluid (BALF) samples [27]. A study of sputum showed miR-223-3p was significantly upregulated in sputum of patients with severe asthma, and was highest in neutrophilic asthma, the expression was also associated with airway obstruction (FEV1/ forced vital capacity) [28].…”

Section: Literature Validation Of Rnas In Key Lncrnas Related Cerna Smentioning

confidence: 99%

Construction of asthma related competing endogenous RNA network revealed novel long non-coding RNAs and potential new drugs

Liao

Wang

et al. 2020

Respir Res

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Background: Asthma is a heterogeneous disease characterized by chronic airway inflammation. Long non-coding RNA can act as competing endogenous RNA to mRNA, and play significant role in many diseases. However, there is little known about the profiles of long non-coding RNA and the long non-coding RNA related competing endogenous RNA network in asthma. In current study, we aimed to explore the long non-coding RNA-microRNA-mRNA competing endogenous RNA network in asthma and their potential implications for therapy and prognosis. Methods: Asthma-related gene expression profiles were downloaded from the Gene Expression Omnibus database, re-annotated with these genes and identified for asthma-associated differentially expressed mRNAs and long noncoding RNAs. The long non-coding RNA-miRNA interaction data and mRNA-miRNA interaction data were downloaded using the starBase database to construct a long non-coding RNA-miRNA-mRNA global competing endogenous RNA network and extract asthma-related differentially expressed competing endogenous RNA network. Finally, functional enrichment analysis and drug repositioning of asthma-associated differentially expressed competing endogenous RNA networks were performed to further identify key long non-coding RNAs and potential therapeutics associated with asthma. Results: This study constructed an asthma-associated competing endogenous RNA network, determined 5 key long non-coding RNAs (MALAT1, MIR17HG, CASC2, MAGI2-AS3, DAPK1-IT1) and identified 8 potential new drugs (Tamoxifen, Ruxolitinib, Tretinoin, Quercetin, Dasatinib, Levocarnitine, Niflumic Acid, Glyburide). Conclusions: The results suggested that long non-coding RNA played an important role in asthma, and these novel long non-coding RNAs could be potential therapeutic target and prognostic biomarkers. At the same time, potential new drugs for asthma treatment have been discovered through drug repositioning techniques, providing a new direction for the treatment of asthma.

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In utero exposure to second‐hand smoke activates pro‐asthmatic and oncogenic miRNAs in adult asthmatic mice

Cited by 22 publications

References 45 publications

Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease

Construction of asthma related competing endogenous RNA network revealed novel long non-coding RNAs and potential new drugs

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