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1. Menthol in electronic cigarettes causes biophysical inhibition of pulmonary surfactant

   https://doi.org/10.1152/ajplung.00015.2022  

   Xu, Lu; Yang, Yi; Simien, Jennifer Michelle; Kang, Christopher; Li, Guangle; Xu, Xiaojie; Haglund, Ellinor; Sun, Rui; Zuo, Yi Y. (August 2022, American Journal of Physiology-Lung Cellular and Molecular Physiology)

   With an increasing prevalence of electronic cigarette (e-cigarette) use, especially among youth, there is an urgent need to better understand the biological risks and pathophysiology of health conditions related to e-cigarettes. A majority of e-cigarette aerosols are in the submicron size and would deposit in the alveolar region of the lung, where they must first interact with the endogenous pulmonary surfactant. To date, little is known whether e-cigarette aerosols have an adverse impact on the pulmonary surfactant. We have systematically studied the effect of individual e-cigarette ingredients on an animal-derived clinical surfactant preparation, bovine lipid extract surfactant, using a combination of biophysical and analytical techniques, including in vitro biophysical simulations using constrained drop surfactometry, molecular imaging with atomic force microscopy, chemical assays using carbon nuclear magnetic resonance and circular dichroism, and in silico molecular dynamics simulations. All data collectively suggest that flavorings used in e-cigarettes, especially menthol, play a predominant role in inhibiting the biophysical function of the surfactant. The mechanism of biophysical inhibition appears to involve menthol interactions with both phospholipids and hydrophobic proteins of the natural surfactant. These results provide novel insights into the understanding of the health impact of e-cigarettes and may contribute to better regulation of e-cigarette products. 

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2. E-Cigarette Use: Device Market, Study Design, and Emerging Evidence of Biological Consequences

   https://doi.org/10.3390/ijms222212452  

   Snoderly, Hunter T.; Nurkiewicz, Timothy R.; Bowdridge, Elizabeth C.; Bennewitz, Margaret F. (November 2021, International Journal of Molecular Sciences)

   Electronic cigarettes are frequently viewed as a safer alternative to conventional cigarettes; however, evidence to support this perspective has not materialized. Indeed, the current literature reports that electronic cigarette use is associated with both acute lung injury and subclinical dysfunction to the lung and vasculature that may result in pathology following chronic use. E-cigarettes can alter vascular dynamics, polarize innate immune populations towards a proinflammatory state, compromise barrier function in the pulmonary endothelium and epithelium, and promote pre-oncogenic phenomena. This review will summarize the variety of e-cigarette products available to users, discuss current challenges in e-cigarette study design, outline the range of pathologies occurring in cases of e-cigarette associated acute lung injury, highlight disease supporting tissue- and cellular-level changes resulting from e-cigarette exposure, and briefly examine how these changes may promote tumorigenesis. Continued research of the mechanisms by which e-cigarettes induce pathology benefit users and clinicians by resulting in increased regulation of vaping devices, informing treatments for emerging diseases e-cigarettes produce, and increasing public awareness to reduce e-cigarette use and the onset of preventable disease. 

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3. In utero exposure to electronic-cigarette aerosols decreases lung fibrillar collagen content, increases Newtonian resistance and induces sex-specific molecular signatures in neonatal mice

   https://doi.org/10.1007/s43188-021-00103-3  

   Cahill, Kerin M.; Gartia, Manas R.; Sahu, Sushant; Bergeron, Sarah R.; Heffernan, Linda M.; Paulsen, Daniel B.; Penn, Arthur L.; Noël, Alexandra (April 2022, Toxicological Research)

   Abstract Approximately 7% of pregnant women in the United States use electronic-cigarette (e-cig) devices during pregnancy. There is, however, no scientific evidence to support e-cig use as being ‘safe’ during pregnancy. Little is known about the effects of fetal exposures to e-cig aerosols on lung alveologenesis. In the present study, we tested the hypothesis that in utero exposure to e-cig aerosol impairs lung alveologenesis and pulmonary function in neonates. Pregnant BALB/c mice were exposed 2 h a day for 20 consecutive days during gestation to either filtered air or cinnamon-flavored e-cig aerosol (36 mg/mL of nicotine). Lung tissue was collected in offspring during lung alveologenesis on postnatal day (PND) 5 and PND11. Lung function was measured at PND11. Exposure to e-cig aerosol in utero led to a significant decrease in body weights at birth which was sustained through PND5. At PND5, in utero e-cig exposures dysregulated genes related to Wnt signaling and epigenetic modifications in both females (~ 120 genes) and males (40 genes). These alterations were accompanied by reduced lung fibrillar collagen content at PND5—a time point when collagen content is close to its peak to support alveoli formation. In utero exposure to e-cig aerosol also increased the Newtonian resistance of offspring at PND11, suggesting a narrowing of the conducting airways. At PND11, in females, transcriptomic dysregulation associated with epigenetic alterations was sustained (17 genes), while WNT signaling dysregulation was largely resolved (10 genes). In males, at PND11, the expression of only 4 genes associated with epigenetics was dysregulated, while 16 Wnt related-genes were altered. These data demonstrate that in utero exposures to cinnamon-flavored e-cig aerosols alter lung structure and function and induce sex-specific molecular signatures during lung alveologenesis in neonatal mice. This may reflect epigenetic programming affecting lung disease development later in life. 

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4. Microscale distribution and dynamic surface tension of pulmonary surfactant normalize the recruitment of asymmetric bifurcating airways

   https://doi.org/10.1152/japplphysiol.00543.2016  

   Yamaguchi, Eiichiro; Nolan, Liam P.; Gaver, Donald P. (May 2017, Journal of Applied Physiology)

   We investigate the influence of bifurcation geometry, asymmetry of daughter airways, surfactant distribution, and physicochemical properties on the uniformity of airway recruitment of asymmetric bifurcating airways. To do so, we developed microfluidic idealized in vitro models of bifurcating airways, through which we can independently evaluate the impact of carina location and daughter airway width and length. We explore the uniformity of recruitment and its relationship to the dynamic surface tension of the lining fluid and relate this behavior to the hydraulic (P Hyd ) and capillary (P Cap ) pressure drops. These studies demonstrate the extraordinary importance of P Cap in stabilizing reopening, even in highly asymmetric systems. The dynamic surface tension of pulmonary surfactant is integral to this stability because it modulates P Cap in a velocity-dependent manner. Furthermore, the surfactant distribution at the propagating interface can have a very large influence on recruitment stability by focusing surfactant preferentially to specific daughter airways. This implies that modification of the surfactant distribution through novel modes of ventilation could be useful in inducing uniformly recruited lungs, aiding in gas exchange, and reducing ventilator-induced lung injury. NEW & NOTEWORTHY The dynamic surface tension of pulmonary surfactant is integral to the uniformity of asymmetric bifurcation airway recruitments because it modulates capillary pressure drop in a velocity-dependent manner. Also, the surfactant distribution at the propagating interface can have a very large influence on recruitment stability by focusing surfactant preferentially to specific daughter airways. This implies that modification of the surfactant distribution through novel modes of ventilation could be useful in inducing uniformly recruited lungs, reducing ventilator-induced lung injury. 

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5. Intrauterine exposure to nicotine through maternal vaping disrupts embryonic lung and skeletal development via the Kcnj2 potassium channel

   https://doi.org/10.1016/j.ydbio.2023.06.002  

   Ozekin, Yunus H.; Saal, Maxwell L.; Pineda, Ricardo H.; Moehn, Kayla; Ordonez-Erives, Madison A.; Delgado Figueroa, Maria F.; Frazier, Caleb; Korth, Kamryn M.; Königshoff, Melanie; Bates, Emily A.; et al (September 2023, Developmental Biology)

   Smoking cigarettes during pregnancy is associated with adverse effects on infants including low birth weight, defective lung development, and skeletal abnormalities. Pregnant women are increasingly turning to vaping [use of electronic (e)-cigarettes] as a perceived safer alternative to cigarettes. However, nicotine disrupts fetal development, suggesting that like cigarette smoking, nicotine vaping may be detrimental to the fetus. To test the impact of maternal vaping on fetal lung and skeletal development in mice, pregnant dams were exposed to e-cigarette vapor throughout gestation. At embryonic day (E)18.5, vape exposed litter sizes were reduced and some embryos exhibited growth restriction compared to air exposed controls. Fetal lungs were collected for histology and whole transcriptome sequencing. Maternally nicotine vaped embryos exhibited histological and transcriptional changes consistent with impaired distal lung development. Embryonic lung gene expression changes mimicked transcriptional changes observed in adult mouse lungs exposed to cigarette smoke, suggesting that the developmental defects may be due to direct nicotine exposure. Fetal skeletons were analyzed for craniofacial and long bone lengths. Nicotine directly binds and inhibits the Kcnj2 potassium channel which is important for bone development. The length of the maxilla, palatal shelves, humerus, and femur were reduced in vaped embryos, which was further exacerbated by loss of one copy of the Kcnj2 gene. Nicotine vapor exposed Kcnj2KO/+ embryos also had significantly lower birth weights than unexposed animals of either genotype. Kcnj2 mutants had severely defective lungs with and without vape exposure, suggesting that potassium channels may be broadly involved in mediating the detrimental developmental effects of nicotine vaping. These data indicate that intrauterine nicotine exposure disrupts fetal lung and skeletal development likely through inhibition of Kcnj2. 

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