Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high-output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left-sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

A fibroblast-dependent TGFß1/sFRP2 noncanonical Wnt signaling axis underlies epithelial metaplasia in idiopathic pulmonary fibrosis.

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate this, we administered the fibroblast-selective TGFß1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Unexposed biopsy samples showed higher fibroblast TGFß1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG significantly downregulated TGFß1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted Frizzle-like Receptor Protein 2 (sFRP2), an unrecognized TGFß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s). In human AEC2-fibroblast coculture organoids, sFRP2 was essential for AEC2 trans-differentiation to basal cells. Precision cut lung slices (PCLS) from normal donors demonstrated that TGFß1 promoted KRT17 expression and AEC2 morphological change, while sFRP2 was necessary for KRT5 expression in AEC2-derived basaloid cells. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin-related signaling in AEC2s were required for sFRP2-induced KRT5 expression. These findings highlight stage-specific TGFß1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify the TGFß1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.

Systemic capillary leak syndrome secondary to decompression sickness.

Systemic capillary leak syndrome is a rare derangement of endothelial function characterised by extravasation of plasma and proteins into the interstitial space. Primary capillary leak syndrome is a rare, episodic medical illness of unknown molecular pathology while secondary capillary leak syndrome may be precipitated by any number of inflammatory and infectious syndromes. Decompression sickness, a disorder of depressurisation, has been identified as a very rare trigger. We present a structured case report of systemic capillary leak syndrome secondary to decompression sickness following deep diving, informing physicians of this potential complication. No pharmacological therapy has substantial evidence in the treatment of acute systemic capillary leak syndrome. By review of current recommendations for acute management, we also emphasise an observed positive response to judicious fluid resuscitation and an oral cyclic AMP-elevating agent (ie, terbutaline).

PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease.

Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NFκB signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.

Comparative genomics between matched solid and lepidic portions of semi-solid lung adenocarcinomas.

BACKGROUND: Genetic changes that drive the transition from lepidic to invasive cancer development within a radiographic ground glass or semi-solid lung lesion (SSL) are not well understood. Biomarkers to predict the transition to solid, invasive cancer within SSL are needed. METHODS: Patients with surgically resected SSL were identified retrospectively from a surgical database. Clinical characteristics and survival were compared between stage I SSL (n = 65) and solid adenocarcinomas (n = 120) resected during the same time period. Areas of normal lung, in situ lepidic, and invasive solid tumor were microdissected from within the same SSL specimens and next generation sequencing (NGS) and Affymetrix microarray of gene expression were performed. RESULTS: There were more never smokers, Asian patients, and sub-lobar resections among SSL but no difference in 5-year survival between SSL and solid adenocarcinoma. Driver mutations found in both lepidic and solid invasive portion were EGFR (43%), KRAS (21%), and DNMT3A (5%). CEACAM5 was the most upregulated gene found in solid, invasive portions of SSL. Lepidic and invasive solid areas had many similarities in gene expression, however there were some significant differences with the gene SPP1 being a unique biomarker for the invasive component of a SSL. CONCLUSIONS: Common lung cancer driver mutations are present in in situ lepidic as well as invasive solid portions of a SSL, suggesting early development of driver mutations. CEACAM5 and SPP1 emerged as promising biomarkers of invasive potential in semi-solid lesions. Other studies have shown both genes to correlate with poor prognosis in lung cancer and their role in evolution of semi-solid lung lesions warrants further study.

Integrated Genomic and Clinicopathologic Approach Distinguishes Pancreatic Grade 3 Neuroendocrine Tumor From Neuroendocrine Carcinoma and Identifies a Subset With Molecular Overlap.

Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Although current recommendations suggest that immunohistochemistry for p53, Rb, ATRX, and DAXX can distinguish most cases, some cases remain difficult to classify using this approach. In this study, we reviewed 47 high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains, we performed capture-based sequencing of approximately 500 cancer genes and immunohistochemistry for p16 and trypsin or chymotrypsin. Using an integrated molecular and clinicopathologic approach, 42 (89%) of 47 cases had a clear final diagnosis of either G3 PanNET (n = 17), PanNEC (n = 17), or mixed acinar-NEC (n = 8). The 17 G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. The 17 PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was coaltered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. The 8 acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Five cases remained difficult to classify, 3 of which exhibited overlapping molecular features with alterations in MEN1 with or without ATRX, and RB1 with or without TP53, making it unclear whether to classify as PanNET or PanNEC. Our data demonstrate that molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC.

Consensus Statements on Deployment-Related Respiratory Disease, Inclusive of Constrictive Bronchiolitis: A Modified Delphi Study.

BACKGROUND: The diagnosis of constrictive bronchiolitis (CB) in previously deployed individuals, and evaluation of respiratory symptoms more broadly, presents considerable challenges, including using consistent histopathologic criteria and clinical assessments. RESEARCH QUESTION: What are the recommended diagnostic workup and associated terminology of respiratory symptoms in previously deployed individuals? STUDY DESIGN AND METHODS: Nineteen experts participated in a three-round modified Delphi study, ranking their level of agreement for each statement with an a priori definition of consensus. Additionally, rank-order voting on the recommended diagnostic approach and terminology was performed. RESULTS: Twenty-five of 28 statements reached consensus, including the definition of CB as a histologic pattern of lung injury that occurs in some previously deployed individuals while recognizing the importance of considering alternative diagnoses. Consensus statements also identified a diagnostic approach for the previously deployed individual with respiratory symptoms, distinguishing assessments best performed at a local or specialty referral center. Also, deployment-related respiratory disease (DRRD) was proposed as a broad term to subsume a wide range of potential syndromes and conditions identified through noninvasive evaluation or when surgical lung biopsy reveals evidence of multicompartmental lung injury that may include CB. INTERPRETATION: Using a modified Delphi technique, consensus statements provide a clinical approach to possible CB in previously deployed individuals. Use of DRRD provides a broad descriptor encompassing a range of postdeployment respiratory findings. Additional follow-up of individuals with DRRD is needed to assess disease progression and to define other features of its natural history, which could inform physicians better and lead to evolution in this nosology.

A review of cardio-pulmonary microvascular dysfunction in pulmonary hypertension.

Microvascular dysfunction progressing to pulmonary hypertension can be a primary cause of right ventricular failure or a secondary cause because of an underlying systemic illness. Little is known regarding the etiology and epidemiology of coronary microvascular dysfunction in pulmonary hypertension. Despite this limitation, its presence has been described in patients with pulmonary hypertension. This review focuses on the pathogenesis of cardiac and pulmonary microvascular dysfunction in pulmonary hypertension. Additionally, this review provides a contemporary assessment on the diagnosis and treatment of microvascular dysfunction in patients in pulmonary hypertension. This topic is important to raise awareness of microvascular dysfunction in the coronary and pulmonary circulation, so that future studies will investigate its impact on the pulmonary hypertension patient cohort.

Rare case of occupational pulmonary hemorrhage in a firefighter.

Alveolar hemorrhage associated with physical exertion, known as exercise-induced pulmonary hemorrhage (EIPH), is a rare condition linked to strenuous exertion. This can be an unusual form of respiratory and occupational illness. We present the case of a healthy firefighter who developed fatal pulmonary hemorrhage after participating in a strenuous physical training exercise regimen. This case represents a severe presentation of EIPH, which results from the disruption of the pulmonary blood-gas barrier as a result of strenuous exertion. Clinicians caring for those in vocations and recreation involving extremely vigorous exercise should be aware that such activities can cause EIPH.

Persistence of persistent pulmonary hypertension of the newborn: A case of de novo TBX4 variant.

We present a case of a late preterm infant placed on extracorporeal life support in the first day of life for persistent pulmonary hypertension of the newborn. Developmental arrest, pulmonary vascular hypertensive changes, and pulmonary interstitial glycogenosis were present on lung biopsy at 7 weeks of age. Pulmonary hypertension has persisted through childhood. Genetic testing at 8 years identified a novel mutation in TBX4.

Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast.

Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.

Aerosolized vitamin E acetate causes oxidative injury in mice and in alveolar macrophages.

Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity.

The hidden history of hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is a relatively new construct, first reported in the early 20th century, despite major aetiological factors (farming, bird husbandry) having been part of human activities for millennia. Initial confirmed HP reports included exposure to farming and forestry (1932) and bird exposure (1965), much more recently than is often assumed. Later changes in occupational and living practices have led to HP associated with isocyanates, machine coolants, indoor mould, hot tubs and other exposures. Evolution of our pathological understanding of interstitial lung disease in general, wider computed tomography utilisation and advances in immunology and genomics have shaped our modern conceptualisation of HP. Examining historical accounts of HP and its causative factors not only considers when the first cases were recognised, but also explores why the disease emerged at specific times and places, and may provide further insights relevant to the mechanisms underlying HP and disease prevention.

Molecular Risk Stratification is Independent of EGFR Mutation Status in Identifying Early-Stage Non-Squamous Non-Small Cell Lung Cancer Patients at Risk for Recurrence and Likely to Benefit From Adjuvant Chemotherapy.

BACKGROUND: A clinically-certified gene expression profile improved survival in a cohort of stage I-IIA NSCLC patients by identifying those likely to benefit from adjuvant intervention. EGFR mutation status has not provided this type of predictive risk discrimination in stage IA NSCLC, and overtreatment of low-risk stage IB patients may have limited the overall benefit seen recently in the adjuvant application of a third-generation TKI. We compared EGFR mutation data to molecular risk stratification in a prospective, early-stage cohort. MATERIALS AND METHODS: Two hundred fifty eligible stage I-IIA non-squamous NSCLC patients underwent prospective molecular risk stratification by the 14-gene prognostic assay. Platinum doublet adjuvant chemotherapy (AC) was recommended for molecular high-risk (MHR). Differences in freedom from recurrence (FFR) and disease-free survival (DFS) were evaluated. RESULTS: At 29 months, prospective molecular testing yielded an estimated FFR of 94.6% and 72.4% in low-risk and untreated MHR patients, respectively, and 97.0% among MHR patients receiving AC (P < .001). In contrast, there was no association between EGFR status and recurrence, while molecular risk predicted survival and response to AC within both the EGFR mutation(+) and mutation(-) populations. Sixty-seven percent of EGFR(+) and 49% of EGFR(-) patients were molecular low-risk. CONCLUSION: This prospective study demonstrates the utility of the 14-gene assay independent of EGFR mutation. Basing adjuvant intervention in early-stage NSCLC on EGFR status alone may undertreat up to 51% of EGFR(-) patients likely to benefit from adjuvant intervention, and overtreat as many as 67% of EGFR(+) patients more likely to be free of residual disease.

Resectability, Recurrence, and Risk Stratification of Giant Solitary Fibrous Tumors in the Thoracic Cavity.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors most commonly arising from the pleura in the thoracic cavity. The impact of tumor size on risk of recurrence in thoracic SFTs is not well understood. METHODS: A single institution review was performed on all resected thoracic SFTs (1992-2019) with giant SFT defined as ≥ 15 cm. Clinical information, pathologic characteristics, and long-term survival data were collected, and predictors of recurrence and survival were evaluated with regression and Kaplan-Meier analysis. RESULTS: There were 38 thoracic SFTs resected from patients, with the majority of tumors (n = 23, 60.5%) originating from visceral pleura. There were nine (23.7%) giant SFTs with a mean size 20.4 cm (range 17-30 cm). Mean follow-up time was 81.0 months (range 1-261 months), during which 4 of 38 (10.5%) patients experienced a recurrence within the thorax (range 51-178 months). The presence of tumor necrosis (p = 0.021) and ≥ 4 mitoses per high-powered field (p = 0.010) were associated with SFT recurrence on univariate regression. Overall 5-year, 10-year, and 20-year survival was 78.2%, 72.6%, and 42.4%, respectively, and SFT-related mortality occurred in three patients at 83, 180, and 208 months postoperatively. There were no recurrences or SFT-related mortality among patients with giant SFT. CONCLUSION: This study represents one of the largest contemporary single institution reviews of long-term outcomes of giant thoracic SFT. Our data suggest that size is not a risk factor for recurrence in thoracic SFTs and long-term survival is excellent for giant SFTs.

Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis.

AIMS: Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence. METHODS AND RESULTS: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs. CONCLUSIONS: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.

Exposure Assessment Tools for Hypersensitivity Pneumonitis. An Official American Thoracic Society Workshop Report.

This report is based on proceedings from the Exposure Assessment Tools for Hypersensitivity Pneumonitis (HP) Workshop, sponsored by the American Thoracic Society, that took place on May 18, 2019, in Dallas, Texas. The workshop was initiated by members from the Environmental, Occupational, and Population Health and Clinical Problems Assemblies of the American Thoracic Society. Participants included international experts from pulmonary medicine, occupational medicine, radiology, pathology, and exposure science. The meeting objectives were to 1) define currently available tools for exposure assessment in evaluation of HP, 2) describe the evidence base supporting the role for these exposure assessment tools in HP evaluation, 3) identify limitations and barriers to each tool's implementation in clinical practice, 4) determine which exposure assessment tools demonstrate the best performance characteristics and applicability, and 5) identify research needs for improving exposure assessment tools for HP. Specific discussion topics included history-taking and exposure questionnaires, antigen avoidance, environmental assessment, specific inhalational challenge, serum-specific IgG testing, skin testing, lymphocyte proliferation testing, and a multidisciplinary team approach. Priorities for research in this area were identified.

Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate.

Electronic-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.