Publications by authors named "Laura E Crotty Alexander"

62 Publications

Compositional Differences in the Oral Microbiome of E-cigarette Users.

Front Microbiol 2021 31;12:599664. Epub 2021 May 31.

Pulmonary Critical Care Section, VA San Diego Healthcare System, La Jolla, CA, United States.

Electronic (e)-cigarettes have been advocated as a safer alternative to conventional tobacco cigarettes. However, there is a paucity of data regarding the impact of e-cigarette aerosol deposition on the human oral microbiome, a key component in human health and disease. We aimed to fill this knowledge gap through a comparative analysis of the microbial community profiles from e-cigarette users and healthy controls [non-smokers/non-vapers (NSNV)]. Moreover, we sought to determine whether e-cigarette aerosol exposure from vaping induces persistent changes in the oral microbiome. To accomplish this, salivary and buccal mucosa samples were collected from e-cigarette users and NSNV controls, with additional oral samples collected from e-cigarette users after 2 weeks of decreased use. Total DNA was extracted from all samples and subjected to PCR amplification and sequencing of the V3-V4 hypervariable regions of the 16S rRNA gene. Our analysis revealed several prominent differences associated with vaping, specific to the sample type (i.e., saliva and buccal). In the saliva, e-cigarette users had a significantly higher alpha diversity, observed operational taxonomic units (OTUs) and Faith's phylogenetic diversity (PD) compared to NSNV controls, which declined with decreased vaping. The buccal mucosa swab samples were marked by a significant shift in beta diversity between e-cigarette users and NSNV controls. There were also significant differences in the relative abundance of several bacterial taxa, with a significant increase in and in e-cigarette users. In addition, nasal swabs demonstrated a trend toward higher colonization rates with in e-cigarette users relative to controls (19 vs. 7.1%; = n.s.). Overall, these data reveal several notable differences in the oral bacterial community composition and diversity in e-cigarette users as compared to NSNV controls.
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http://dx.doi.org/10.3389/fmicb.2021.599664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200533PMC
May 2021

AI-guided discovery of the invariant host response to viral pandemics.

EBioMedicine 2021 Jun 11;68:103390. Epub 2021 Jun 11.

Moores Cancer Center, University of California San Diego, USA; Department of Cellular and Molecular Medicine, University of California San Diego, USA; Medicine, University of California San Diego, USA. Electronic address:

Background: Coronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach.

Method: Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions.

Findings: The 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity.

Interpretation: The ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

Funding: This work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S.

C, Cchi: Cooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists.

One Sentence Summary: The host immune response in COVID-19.
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http://dx.doi.org/10.1016/j.ebiom.2021.103390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193764PMC
June 2021

Chronic E-Cigarette Aerosol Inhalation Alters the Immune State of the Lungs and Increases ACE2 Expression, Raising Concern for Altered Response and Susceptibility to SARS-CoV-2.

Front Physiol 2021 31;12:649604. Epub 2021 May 31.

Pulmonary Critical Care Section, VA San Diego Healthcare System, La Jolla, CA, United States.

Conventional smoking is known to both increase susceptibility to infection and drive inflammation within the lungs. Recently, smokers have been found to be at higher risk of developing severe forms of coronavirus disease 2019 (COVID-19). E-cigarette aerosol inhalation (vaping) has been associated with several inflammatory lung disorders, including the recent e-cigarette or vaping product use-associated lung injury (EVALI) epidemic, and recent studies have suggested that vaping alters host susceptibility to pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the impact of vaping on lung inflammatory pathways, including the angiotensin-converting enzyme 2 (ACE2) receptor known to be involved in SARS-CoV-2 infection, mice were exposed to e-cigarette aerosols for 60 min daily for 1-6 months and underwent gene expression analysis. Hierarchical clustering revealed extensive gene expression changes occurred in the lungs of both inbred C57BL/6 mice and outbred CD1 mice, with 2,933 gene expression changes in C57BL/6 mice, and 2,818 gene expression changes in CD1 mice (>abs 1.25-fold change). Particularly, large reductions in IgA and CD4 were identified, indicating impairment of host responses to pathogens reductions in immunoglobulins and CD4 T cells. CD177, facmr, tlr9, fcgr1, and ccr2 were also reduced, consistent with diminished host defenses decreased neutrophils and/or monocytes in the lungs. Gene set enrichment (GSE) plots demonstrated upregulation of gene expression related to cell activation specifically in neutrophils. As neutrophils are a potential driver of acute lung injury in COVID-19, increased neutrophil activation in the lungs suggests that vapers are at higher risk of developing more severe forms of COVID-19. The receptor through which SARS-CoV-2 infects host cells, ACE2, was found to have moderate upregulation in mice exposed to unflavored vape pens, and further upregulation (six-fold) with JUUL mint aerosol exposure. No changes were found in mice exposed to unflavored Mod device-generated aerosols. These findings suggest that specific vaping devices and components of e-liquids have an effect on ACE2 expression, thus potentially increasing susceptibility to SARS-CoV-2. In addition, exposure to e-cigarette aerosols both with and without nicotine led to alterations in eicosanoid lipid profiles within the BAL. These data demonstrate that chronic, daily inhalation of e-cigarette aerosols fundamentally alters the inflammatory and immune state of the lungs. Thus, e-cigarette vapers may be at higher risk of developing infections and inflammatory disorders of the lungs.
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http://dx.doi.org/10.3389/fphys.2021.649604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194307PMC
May 2021

Assessing the potential impact of age and inhalant use on sleep in adolescents.

J Clin Sleep Med 2021 May 24. Epub 2021 May 24.

Pulmonary Critical Care Section, Veterans Affairs (VA) San Diego Healthcare System, La Jolla, CA 92161.

Study Objectives: Targeted marketing has caused a recent surge in teen e-cigarette usage. In all-age surveys, we isolated adolescent data (13-20 years) to assess age alongside e-cigarettes, traditional tobacco, and dual usage of both with sleep quality and cough. Based on existing adult literature, we hypothesized an association between dual usage and increased sleep latency.

Methods: Participants were recruited to complete surveys via social media sites. We performed three surveys: Survey 1 (n=47) in 2018, Survey 2 (n=1198) in 2019, Survey 3 (n=564) in 2020. Surveys 1 and 2 had three sections: past and current inhalant use, Pittsburgh Sleep Quality Index (PSQI), and Leicester Cough Questionnaire (LCQ). Survey 3 did not include the LCQ, instead the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ9). The adolescent data were isolated (n=609).

Results: Adolescents reported longer sleep duration with increasing age by one-way ANOVA. By Tukey's multiple comparisons test, females slept more at ages 19 and 20 than at age 14 (p<0.01). Female dual users slept more than nonsmokers, (p=0.01; mean difference 43.8 minutes; CI=0.11 to 1.36). We observed an association between dual use and sleep latency versus nonsmokers (p=0.0008; mean difference 6.27 minutes; CI=1.40 to 11.13). We saw no correlation between inhalant use and cough.

Conclusions: In females, we observed a peak in sleep hours at age 19. College-aged females may wake later than younger adolescent females. The data also raised concern for sleep disruption and nicotine-induced wakefulness. Further data are required in order to define public health strategies.
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http://dx.doi.org/10.5664/jcsm.9414DOI Listing
May 2021

Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

Clin Infect Dis 2021 May 14. Epub 2021 May 14.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.

Background: Increased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.

Methods: Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.

Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.

Conclusions: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.
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http://dx.doi.org/10.1093/cid/ciab437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241438PMC
May 2021

Development of a National Academic Boot Camp to Improve Fellowship Readiness.

ATS Sch 2020 Dec 22;2(1):49-65. Epub 2020 Dec 22.

Pulmonary Critical Care Section, Veterans Affairs San Diego Healthcare System, San Diego, California; and.

Pulmonary and critical care medicine (PCCM) fellowship requires a high degree of medical knowledge and procedural competency. Gaps in fellowship readiness can result in significant trainee anxiety related to starting fellowship training.

To improve fellowship readiness and alleviate anxiety for PCCM-bound trainees by improving confidence in procedural skills and cognitive domains.

Medical educators within the American Thoracic Society developed a national resident boot camp (RBC) to provide an immersive, experiential training program for physicians entering PCCM fellowships. The RBC curriculum is a 2-day course designed to build procedural skills, medical knowledge, and clinical confidence through high-fidelity simulation and active learning methodology. Separate programs for adult and pediatric providers run concurrently to provide unique training objectives targeted to their learners' needs. Trainee assessments include multiple-choice pre- and post-RBC knowledge tests and confidence assessments, which are scored on a four-point Likert scale, for specific PCCM-related procedural and cognitive skills. Learners also evaluate course material and educator effectiveness, which guide modifications of future RBC programs and provide feedback for individual educators, respectively.

The American Thoracic Society RBC was implemented in 2014 and has grown annually to include 132 trainees and more than 100 faculty members. Mean knowledge test scores for participants in the 2019 RBC adult program increased from 55% (±14% SD) on the pretest to 72% (±11% SD;  < 0.001) after RBC completion. Similarly, mean pretest scores for pediatric course attendees increased from 54% (±13% SD) to 62% (±19% SD;  = 0.17). Specific content domains that improved by 10% or more between pre- and posttests included airway management, bronchoscopy, pulmonary function testing, and code management for adult course participants, and airway management, pulmonary function testing, and extracorporeal membrane oxygenation for pediatric course participants. Trainee confidence also significantly improved across all procedural and cognitive domains for adult trainees and in 10 of 11 domains for pediatric course attendees. Course content for the 2019 RBC was overwhelmingly rated as "on target" for the level of learner, with <4% of respondents indicating any specific session was "much too basic" or "much too advanced."

RBC participation improved PCCM-bound trainee knowledge, procedural familiarity, and confidence. Refinement of the RBC curriculum over the past 7 years has been guided by educator and course evaluations, with the ongoing goal of meeting the evolving educational needs of rising PCCM trainees.
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http://dx.doi.org/10.34197/ats-scholar.2020-0091OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043273PMC
December 2020

Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury.

Am J Physiol Lung Cell Mol Physiol 2021 05 10;320(5):L821-L831. Epub 2021 Feb 10.

VA San Diego Healthcare System, San Diego, California.

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury because of AKI.
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http://dx.doi.org/10.1152/ajplung.00578.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174821PMC
May 2021

E-cigarettes compromise the gut barrier and trigger inflammation.

iScience 2021 Feb 6;24(2):102035. Epub 2021 Jan 6.

Department of Pathology, University of California, San Diego, CA 92093, USA.

E-cigarette usage continues to rise, yet the safety of e-cigarette aerosols is questioned. Using murine models of acute and chronic e-cigarette aerosol inhalation, murine colon transcriptomics, and murine and human gut-derived organoids in co-culture models, we assessed the effects of e-cigarette use on the gut barrier. Histologic and transcriptome analyses revealed that chronic, but not acute, nicotine-free e-cigarette use increased inflammation and reduced expression of tight junction (TJ) markers. Exposure of murine and human enteroid-derived monolayers (EDMs) to nicotine-free e-cigarette aerosols alone or in co-culture with bacteria also causes barrier disruption, downregulation of TJ protein, and enhanced inflammation in response to infection. These data highlight the harmful effects of "non-nicotine" component of e-cigarettes on the gut barrier. Considering the importance of an intact gut barrier for host fitness and the impact of gut mucosal inflammation on a multitude of chronic diseases, these findings are broadly relevant to both medicine and public health.
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http://dx.doi.org/10.1016/j.isci.2021.102035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841355PMC
February 2021

E-cigarette aerosols containing nicotine modulate nicotinic acetylcholine receptors and astroglial glutamate transporters in mesocorticolimbic brain regions of chronically exposed mice.

Chem Biol Interact 2021 Jan 23;333:109308. Epub 2020 Nov 23.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH, 43614, USA. Electronic address:

Nicotine exposure increases the release of glutamate in part through stimulatory effects on pre-synaptic nicotinic acetylcholine receptors (nAChRs). To assess the impact of chronic electronic (e)-cigarette use on these drug dependence pathways, we exposed C57BL/6 mice to three types of inhalant exposures for 3 months; 1) e-cigarette aerosol generated from liquids containing nicotine (ECN), 2) e-cigarette aerosol generated from liquids containing vehicle chemicals without nicotine (Veh), and 3) air only (AC). We investigated the effects of daily e-cigarette exposure on protein levels of α7 nAChR and α4/β2 nAChR, gene expression and protein levels of astroglial glutamate transporters, including glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT), in the frontal cortex (FC), striatum (STR) and hippocampus (HIP). We found that chronic inhalation of ECN increased α4/β2 nAChR in all brain regions, and increased α7 nAChR expression in the FC and STR. The total GLT-1 relative mRNA and protein expression were decreased in the STR. Moreover, GLT-1 isoforms (GLT-1a and GLT-1b) were downregulated in the STR in ECN group. However, inhalation of e-cigarette aerosol downregulated xCT expression in STR and HIP compared to AC and Veh groups. ECN group had increased brain-derived neurotrophic factor in the STR compared to control groups. Finally, mass spectrometry detected high concentrations of the nicotine metabolite, cotinine, in the FC and STR in ECN group. This work demonstrates that chronic inhalation of nicotine within e-cigarette aerosols significantly alters the expression of nAChRs and astroglial glutamate transporters in specific mesocorticolimbic brain regions.
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http://dx.doi.org/10.1016/j.cbi.2020.109308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752837PMC
January 2021

Bleomycin-induced lung injury treated with venovenous extracorporeal membrane oxygenation (ECMO) and ultra-protective ventilator settings.

BMJ Case Rep 2020 Nov 23;13(11). Epub 2020 Nov 23.

Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, La Jolla, California, USA.

Bleomycin treats malignancies, such as germ cell tumours and Hodgkin lymphoma. While efficacious, it can cause severe drug-induced lung injury. We present a 42-year-old patient with stage IIB seminoma treated with radical orchiectomy followed by adjuvant chemotherapy with bleomycin, etoposide and cisplatin. His postbleomycin course was complicated by the rapid onset of hypoxic respiratory failure, progressing to acute respiratory distress syndrome and requiring venovenous extracorporeal membrane oxygenation (VV-ECMO) support. Although the patient was treated with high dose systemic steroids and ultra-protective ventilator strategies to minimise ventilator-induced lung injury while on VV-ECMO, his lung injury failed to improve. Care was withdrawn 29 days later. Lung autopsy revealed diffuse organising pneumonia. We found six case reports (including this one) of bleomycin-induced lung injury requiring VV-ECMO with a cumulative survival of 33% (2/6). While VV-ECMO may be used to bridge patients to recovery or lung transplant, the mortality is high.
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http://dx.doi.org/10.1136/bcr-2020-236474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684647PMC
November 2020

Vaping and e-cigarette use. Mysterious lung manifestations and an epidemic.

Curr Opin Immunol 2020 10 10;66:143-150. Epub 2020 Nov 10.

Pulmonary Critical Care Section, VA San Diego Healthcare System, La Jolla, CA 92161, United States; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, United States. Electronic address:

Electronic (e)-cigarette use and the practice of vaping has rapidly expanded both in adult smokers and previously nicotine naïve youths. Research has focused on harm reduction in adults using e-cigarettes to stop or reduce traditional cigarette use, but the short and long-term safety of these products has not been established. Vaping has more recently been associated with a growing list of pulmonary complications with the most urgent being the e-cigarette or vaping product use-associated lung injury (EVALI) epidemic. This review details the inhalant toxicology of vaping products, the described lung diseases associated with vaping with a focus on EVALI, and the predicted long-term consequences of e-cigarette use, including increased asthma severity.
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http://dx.doi.org/10.1016/j.coi.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755270PMC
October 2020

Vaping disrupts ventilation-perfusion matching in asymptomatic users.

J Appl Physiol (1985) 2021 02 12;130(2):308-317. Epub 2020 Nov 12.

Pulmonary Imaging Laboratory, Department of Radiology, UC San Diego Health Sciences, San Diego, California.

Inhalation of e-cigarette's aerosols (vaping) has the potential to disrupt pulmonary gas exchange, but the effects in asymptomatic users are unknown. We assessed ventilation-perfusion (V̇/Q̇) mismatch in asymptomatic e-cigarette users, using magnetic resonance imaging (MRI). We hypothesized that vaping induces V̇/Q̇ mismatch through alterations in both ventilation and perfusion distributions. Nine young, asymptomatic "Vapers" with >1-yr vaping history, and no history of cardiopulmonary disease, were imaged supine using proton MRI, to assess the right lung at baseline and immediately after vaping. Seven young "Controls" were imaged at baseline only. Relative dispersion (SD/means) was used to quantify the heterogeneity of the individual ventilation and perfusion distributions. V̇/Q̇ mismatch was quantified using the second moments of the ventilation and perfusion versus V̇/Q̇ ratio distributions, log scale, LogSDV̇, and LogSDQ̇, respectively, analogous to the multiple inert gas elimination technique. Spirometry was normal in both groups. Ventilation heterogeneity was similar between groups at baseline (Vapers, 0.43 ± 0.13; Controls, 0.51 ± 0.11; = 0.13) but increased after vaping (to 0.57 ± 0.17; = 0.03). Perfusion heterogeneity was greater ( = 0.04) in Vapers at baseline (0.53 ± 0.06) compared with Controls (0.44 ± 0.10) but decreased after vaping (to 0.42 ± 0.07; = 0.005). Vapers had greater ( = 0.01) V̇/Q̇ mismatch at baseline compared with Controls (LogSDQ̇ = 0.61 ± 0.12 vs. 0.43 ± 0.12), which was increased after vaping (LogSDQ̇ = 0.73 ± 0.16; = 0.03). V̇/Q̇ mismatch is greater in Vapers and worsens after vaping. This suggests subclinical alterations in lung function not detected by spirometry. This research provides evidence of vaping-induced disruptions in ventilation-perfusion matching in young, healthy, asymptomatic adults with normal spirometry who habitually vape. The changes in ventilation and perfusion distributions, both at baseline and acutely after vaping, and the potential implications on hypoxic vasoconstriction are particularly relevant in understanding the pathogenesis of vaping-induced dysfunction. Our imaging-based approach provides evidence of potential subclinical alterations in lung function below thresholds of detection using spirometry.
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http://dx.doi.org/10.1152/japplphysiol.00709.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948111PMC
February 2021

Effects of 3-Month Exposure to E-Cigarette Aerosols on Glutamatergic Receptors and Transporters in Mesolimbic Brain Regions of Female C57BL/6 Mice.

Toxics 2020 Oct 29;8(4). Epub 2020 Oct 29.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, the University of Toledo, Toledo, OH 43614, USA.

Electronic cigarettes (e-cigs) use has been dramatically increased recently, especially among youths. Previous studies from our laboratory showed that chronic exposure to e-cigs, containing 24 mg/mL nicotine, was associated with dysregulation of glutamate transporters and neurotransmitter levels in the brain of a mouse model. In this study, we evaluated the effect of three months' continuous exposure to e-cig vapor (JUUL pods), containing a high nicotine concentration, on the expression of glutamate receptors and transporters in drug reward brain regions such as the nucleus accumbens (NAc) core (NAc-core), NAc shell (NAc-shell) and hippocampus (HIP) in female C57BL/6 mice. Three months' exposure to mint- or mango-flavored JUUL (containing 5% nicotine, 59 mg/mL) induced upregulation of metabotropic glutamate receptor 1 (mGluR1) and postsynaptic density protein 95 (phosphorylated and total PSD95) expression, and downregulation of mGluR5 and glutamate transporter 1 (GLT-1) in the NAc-shell. In addition, three months' exposure to JUUL was associated with upregulation of mGluR5 and GLT-1 expression in the HIP. These findings demonstrated that three-month exposure to e-cig vapor containing high nicotine concentrations induced differential effects on the glutamatergic system in the NAc and HIP, suggesting dysregulation of glutamatergic system activity in mesolimbic brain regions.
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http://dx.doi.org/10.3390/toxics8040095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712012PMC
October 2020

Vaping-related lung injury.

Virchows Arch 2021 Jan 27;478(1):81-88. Epub 2020 Oct 27.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The use of electronic nicotine delivery systems has increased in popularity dramatically over the past decade. Although lung diseases caused by vaping have been reported since the modern invention of the electronic cigarette, in the summer of 2019, patients began to present to health care centers at epidemic levels with an acute respiratory illness relating to vaping, which the Center for Disease Control termed E-cigarette or vaping product use-associated lung injury (EVALI). This review discusses electronic nicotine delivery systems as well as the etiology, clinical presentation, imaging findings, pathologic features, treatment, and long-term consequences of EVALI. We conclude with the practical impact EVALI has had on the practice of pathology.
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http://dx.doi.org/10.1007/s00428-020-02943-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590536PMC
January 2021

Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19.

bioRxiv 2020 Oct 18. Epub 2020 Oct 18.

SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines.

Graphic Abstract:

Highlights: Human lung organoids with mixed proximodistal epithelia are createdProximal airway cells are critical for viral infectivityDistal alveolar cells are important for emulating host responseBoth are required for the overzealous response in severe COVID-19.

In Brief: An integrated stem cell-based disease modeling and computational approach demonstrate how both proximal airway epithelium is critical for SARS-CoV-2 infectivity, but distal differentiation of alveolar pneumocytes is critical for simulating the overzealous host response in fatal COVID-19.
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http://dx.doi.org/10.1101/2020.10.17.344002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587781PMC
October 2020

Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome.

Am J Respir Cell Mol Biol 2021 01;64(1):89-99

Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois.

A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31 CD45cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistant or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistant or LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.
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http://dx.doi.org/10.1165/rcmb.2020-0145OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780991PMC
January 2021

AI-guided discovery of the invariant host response to viral pandemics.

bioRxiv 2020 Sep 22. Epub 2020 Sep 22.

We sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. Surprisingly, this 166-gene signature was conserved in all ral andemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures and signatures, respectively. The signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, the signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

One Sentence Summary: The host immune response in COVID-19.
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http://dx.doi.org/10.1101/2020.09.21.305698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523116PMC
September 2020

Effects of e-cigarettes and vaping devices on cardiac and pulmonary physiology.

J Physiol 2020 11 12;598(22):5039-5062. Epub 2020 Oct 12.

Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, CA, USA.

E-cigarette aerosols are exceedingly different from conventional tobacco smoke, containing dozens of chemicals not found in cigarette smoke. It is highly likely that chronic use of e-cigarettes will induce pathological changes in both the heart and lungs. Here we review human and animal studies published to date and summarize the cardiopulmonary physiological changes caused by vaping. In terms of cardiac physiology, acute exposure to e-cigarette aerosols in human subjects led to increased blood pressure and heart rate, similar to traditional cigarettes. Chronic exposure to e-cigarette aerosols using animal models caused increased arterial stiffness, vascular endothelial changes, increased angiogenesis, cardiorenal fibrosis and increased atherosclerotic plaque formation. Pulmonary physiology is also affected by e-cigarette aerosol inhalation, with increased airway reactivity, airway obstruction, inflammation and emphysema. Research thus far demonstrates that the heart and lung undergo numerous changes in response to e-cigarette use, and disease development will depend on how those changes combine with both environmental and genetic factors. E-cigarettes have been advertised as a healthy alternative to cigarette smoking, and users are under the impression that vaping of e-cigarettes is harmless, but these claims that e-cigarettes are safer and healthier are not based on evidence. Data from both humans and animal models are consistent in demonstrating that vaping of e-cigarettes causes health effects both similar to and disparate from those of cigarette smoking. Further work is needed to define the long-term cardiopulmonary effects of e-cigarette use in humans.
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http://dx.doi.org/10.1113/JP279754DOI Listing
November 2020

Cigarette Smoke Exposure Promotes Virulence of Pseudomonas aeruginosa and Induces Resistance to Neutrophil Killing.

Infect Immun 2020 10 19;88(11). Epub 2020 Oct 19.

Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, California, USA

It is widely known that cigarette smoke damages host defenses and increases susceptibility to bacterial infections. , a Gram-negative bacterium that commonly colonizes the airways of smokers and patients with chronic lung disease, can cause pneumonia and sepsis and can trigger exacerbations of lung diseases. colonizing airways is consistently exposed to inhaled cigarette smoke. Here, we investigated whether cigarette smoke alters the ability of this clinically significant microbe to bypass host defenses and cause invasive disease. We found that cigarette smoke extract (CSE) exposure enhances resistance to human neutrophil killing, but this increase in pathogenicity was not due to resistance to neutrophil extracellular traps. Instead, exposed to CSE (CSE-PSA) had increased resistance to oxidative stress, which correlated with increased expression of , a gene essential for defense against oxidative stress. In addition, exposure to CSE induced enhanced biofilm formation and resistance to the antibiotic levofloxacin. Finally, CSE-PSA had increased virulence in a model of pneumonia, with 0% of mice infected with CSE-PSA alive at day 6, while 28% of controls survived. Altogether, these data show that cigarette smoke alters the phenotype of , increasing virulence and making it less susceptible to killing by neutrophils and more capable of causing invasive disease. These findings provide further explanation of the refractory nature of respiratory illnesses in smokers and highlight cigarette smoking as a potential driver of virulence in this important airway pathogen.
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http://dx.doi.org/10.1128/IAI.00527-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573448PMC
October 2020

Response.

Chest 2020 08;158(2):836-837

Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2020.04.018DOI Listing
August 2020

Is Increased Sleep Responsible for Reductions in Myocardial Infarction During the COVID-19 Pandemic?

Am J Cardiol 2020 09 20;131:128-130. Epub 2020 Jun 20.

Pulmonary Critical Care Section, Veterans Affairs (VA) San Diego Healthcare System, La Jolla, California; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, California. Electronic address:

The COVID-19 pandemic caused by the highly contagious SARS-CoV-2 virus has had devastating consequences across the globe. However, multiple clinics and hospitals have experienced a decrease in rates of acute myocardial infarction and corresponding cardiac catheterization lab activations, raising the question: Has the risk of myocardial infarction decreased during COVID? Sleep deprivation is known to be an independent risk factor for myocardial infarction, and sleep has been importantly impacted during the pandemic, possibly due to the changes in work-home life leading to a lack of structure. We conducted a social media-based survey to assess potential mechanisms underlying the observed improvement in risk of myocardial infarction. We used validated questionnaires to assess sleep patterns, tobacco consumption and other important health outcomes to test the hypothesis that increases in sleep duration may be occurring which have a beneficial impact on health. We found that the COVID-19 pandemic led to shifts in day/night rhythm, with subjects waking up 105 minutes later during the pandemic (p <0.0001). Subjects also reported going to sleep 41 minutes later during the pandemic (p <0.0001). These shifts led to longer duration of sleep during the COVID-19 pandemic. Before the pandemic, subjects reported sleeping 6.8 hours per night, which rose to 7.5 hours during the pandemic, a 44 minute or 11% increase (p <0.0001). We acknowledge the major negative health impact of the global pandemic but would advocate for using this crisis to improve the work and sleep habits of the general population, which may lead to overall health benefits for our society.
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http://dx.doi.org/10.1016/j.amjcard.2020.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305870PMC
September 2020

What are the mechanisms underlying vaping-induced lung injury?

J Clin Invest 2020 06;130(6):2754-2756

Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1172/JCI138644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260008PMC
June 2020

E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

Am J Respir Crit Care Med 2020 09;202(6):795-802

Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.
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http://dx.doi.org/10.1164/rccm.201912-2332WSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491408PMC
September 2020

Reply to Letter to the Editor: "Comment on 'E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation'".

Am J Physiol Cell Physiol 2020 03;318(3):C706

Department of Anesthesiology, Division of Critical Care, University of California, San Diego, La Jolla, California.

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http://dx.doi.org/10.1152/ajpcell.00037.2020DOI Listing
March 2020

The Evolving Landscape of e-Cigarettes: A Systematic Review of Recent Evidence.

Chest 2020 05 30;157(5):1362-1390. Epub 2020 Jan 30.

School of Medicine, University of Adelaide, Adelaide, SA, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia. Electronic address:

Smoking continues to be a burden to economies and health-care systems across the world. One proposed solution to the problem has been e-cigarettes; however, because they are a relatively new product in the market, little is known about their potential health impacts. Furthermore, e-cigarettes continue to evolve at a rapid rate, making it necessary to regularly review and summarize available studies. Although e-cigarettes are marketed as a smoking cessation tool by some manufacturers, the reality is that many nonsmokers, including youth, are using them. This review focuses on two major demographic groups (smokers and nonsmokers) and evaluates the most recent data (early 2017 to mid 2019) regarding the potential health effects of e-cigarettes. We assessed peer-reviewed studies on the health impacts of e-cigarettes, with a particular focus on common questions asked by policy makers, clinicians, and scientists: (1) What are the effects of e-cigarettes compared with air/not smoking?; (2) Is there any direct evidence of harm or benefit to humans?; (3) Is there a risk from secondhand exposure?; (4) What are the risks and/or benefits of e-cigarettes compared with tobacco cigarette use?; (5) Are there risks or benefits to specific populations (eg, people with COPD or asthma, pregnant women [and their offspring])?; (6) What are the effects of flavoring chemicals?; (7) What are the effects of including nicotine in e-liquids?; (8) How often is nicotine concentration labeling incorrect?; and (9) What are the risks when e-cigarettes explode?
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http://dx.doi.org/10.1016/j.chest.2019.12.042DOI Listing
May 2020

Why Is Vaping Going Up in Flames?

Ann Am Thorac Soc 2020 05;17(5):545-549

Department of Medicine, University of California at San Diego, San Diego, California; and.

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http://dx.doi.org/10.1513/AnnalsATS.201910-802PSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263393PMC
May 2020

Identifying, tracking, and treating lung injury associated with e-cigarettes or vaping.

Lancet 2019 12 8;394(10214):2041-2043. Epub 2019 Nov 8.

University of Connecticut, Mansfield, CT, USA.

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http://dx.doi.org/10.1016/S0140-6736(19)32730-8DOI Listing
December 2019
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