14 results on '"Sauler, Maor"'
Search Results
2. Stem cell migration drives lung repair in living mice
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Chioccioli, Maurizio, primary, Liu, Shuyu, additional, Magruder, Sumner, additional, Tata, Aleksandra, additional, Borriello, Lucia, additional, McDonough, John E., additional, Konkimalla, Arvind, additional, Kim, Sang-Hun, additional, Nouws, Jessica, additional, Gonzalez, David G., additional, Traub, Brian, additional, Ye, Xianjun, additional, Yang, Tao, additional, Entenberg, David R., additional, Krishnaswamy, Smita, additional, Hendry, Caroline E., additional, Kaminski, Naftali, additional, Tata, Purushothama Rao, additional, and Sauler, Maor, additional
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- 2024
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3. Molecular Characterization of the Distal Lung: Novel Insights from Chronic Obstructive Pulmonary Disease Omics.
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Castaldi, Peter J. and Sauler, Maor
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CHRONIC obstructive pulmonary disease ,LUNGS ,PULMONARY fibrosis ,GENE expression ,INTERSTITIAL lung diseases - Abstract
The article focuses on how advanced omics technologies, particularly GWASs and scRNA-seq, are reshaping our understanding of Chronic Obstructive Pulmonary Disease (COPD). It explores the complex ecosystem of the distal lung, emphasizing genetic risk factors and the heterogeneity of cell types involved in COPD pathogenesis. Integration of these technologies reveals insights into the biological processes driving COPD initiation and progression.
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- 2024
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4. INTERACTIONS BETWEEN MITOCHONDRIAL DNA AND TOLL-LIKE RECEPTOR 9 MEDIATES PULMONARY FIBROSIS
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LEE, CHRIS, TRUJILLO, GLENDA, REGUEIRO-REN, ALICIA, LIU, CHUNJIAN, HU, BUQU, SUN, YING, KHOURY, JOHAD, KHOURY, JOHAD, AHANGARI, FARIDA, ISHIKAWA, GENTA, WALIA, ANJALI, PIVARNIK, TAYLOR, YU, SHEELINE, WOO, SAMUEL, FIORINI, VITORIA, MCGOVERN, JOHN, AL JUMAILY, KARAM, SUN, HUANXING, PENG, XUE YAN, ANTIN-OZERKIS, DANIELLE E, SAULER, MAOR, KAMINSKI, NAFTALI, and HERZOG, ERICA
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- 2024
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5. Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in Chronic Obstructive Pulmonary Disease.
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Rojas-Quintero, Joselyn, Ochsner, Scott A., New, Felicia, Divakar, Prajan, Chen Xi Yang, Wu, Tianshi David, Robinson, Jerid, Chandrashekar, Darshan Shimoga, Banovich, Nicholas E., Rosas, Ivan O., Sauler, Maor, Kheradmand, Farrah, Gaggar, Amit, Margaroli, Camilla, Estepar, Raul San Jose, McKenna, Neil J., and Polverino, Francesca
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CHRONIC obstructive pulmonary disease ,B cells ,TRANSCRIPTOMES ,GENE regulatory networks ,GENE expression - Abstract
Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: Lung sections from 40 patients with COPD and eversmokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Measurements and Main Results: Overall, 115 LFs from eversmokers andGlobal Initiative for ChronicObstructive LungDisease (GOLD) 1-2 andGOLD3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cellmarker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs (q-value= 2.56E-111). LFs frompatients withGOLD 1-2 COPDwith emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs frompatients with GOLD1-2COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cellmaturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2024
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6. ANTAGONISM OF CGAS ABROGATES INFLAMMATORY FIBROTIC RESPONSES IN TRANSLATIONAL MODELS OF SCLERODERMA-ASSOCIATED INTERSTITIAL LUNG DISEASE.
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YU, SHEELINE, LEE, CHRIS, HU, BUQU, SUN, YING, SHAO, SHUAI, SUN, HUANXING, GHINCEA, ALEXANDER, WOO, SAMUEL, MCGOVERN, JOHN, SABER, TINA, GUNES, BARAN L, KUJAWSKI, SOPHIA E, PEREZ, STEPHANIE, ODELL, WILLIAM, HINCHCLIFF, MONIQUE, VARGA, JOHN, SAULER, MAOR, GOMEZ, JOSE L, RYU, CHANGWAN, and HERZOG, ERICA
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- 2024
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7. Identification of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease Subgroups by Machine Learning Implementation in Electronic Health Records.
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Li H, Huston J, Zielonka J, Kay S, Sauler M, and Gomez J
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Rationale: Acute exacerbations of COPD (AECOPD) are heterogeneous. Machine learning (ML) has previously been used to dissect some of the heterogeneity in COPD. The widespread adoption of electronic health records (EHRs) has led to the rapid accumulation of large amounts of patient data as part of routine clinical care. However, it is unclear whether the implementation of ML in EHR-derived data has the potential to identify subgroups of AECOPD., Objectives: Determine whether ML implementation using EHR data from severe AECOPD requiring hospitalization identifies relevant subgroups., Methods: This study used two retrospective cohorts of patients with AECOPD (non-COVID-19 and COVID-19) treated at Yale-New Haven Hospital (YNHHS). K -means clustering was used to identify patient subgroups., Measurements and Main Results: We identified three subgroups in the non-COVID cohort (n=1,736). Each subgroup had distinct clinical characteristics. The reference subgroup was the largest (n=904), followed by cardio-renal (n = 548) and eosinophilic (n=284). The eosinophilic subgroup had milder severity of AECOPD, including a shorter hospital stay (p<0.01). The cardio-renal subgroup had the highest mortality during (5%) and in the year after hospitalization (30%). Validation of the severe AECOPD classifier in the COVID-19 cohort recapitulated the characteristics seen in the non-COVID cohort. AECOPD subgroups in the COVID-19 cohort had different IL-1 beta, IL-2R, and IL-8 levels (FDR ≤ 0.05. These specific leukocyte and cytokine profiles resulted in inflammatory differences between the AECOPD subgroups based on C-reactive protein levels., Conclusions: Incorporating ML with EHR-data allows the identification of specific clinical and biological subgroups for severe AECOPD., (JCOPDF © 2024.)
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- 2024
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8. B cell immune repertoire sequencing in tobacco cigarette smoking, vaping, and chronic obstructive pulmonary disease in the COPDGene cohort.
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Moll M, Xu Z, Boueiz A, Ryu MH, Silverman EK, Cho MH, Hersh CP, Sauler M, Polverino F, Kinney GL, Curtis JL, Crotty-Alexander LE, Vollmers C, and Castaldi PJ
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Rationale: Cigarette smoking (CS) impairs B cell function and antibody production, increasing infection risk. The impact of e-cigarette use ('vaping') and combined CS and vaping ('dual-use') on B cell activity is unclear., Objective: To examine B cell receptor sequencing (BCR-seq) profiles associated with CS, vaping, dual-use, COPD-related outcomes, and demographic factors., Methods: BCR-seq was performed on blood RNA samples from 234 participants in the COPDGene study. We assessed multivariable associations of B cell function measures (immunoglobulin heavy chain (IGH) subclass expression and usage, class-switching, V-segment usage, and clonal expansion) with CS, vaping, dual-use, COPD severity, age, sex, and race. We adjusted for multiple comparisons using the Benjamini-Hochberg method, identifying significant associations at 5% FDR and suggestive associations at 10% FDR., Results: Among 234 non-Hispanic white (NHW) and African American (AA) participants, CS and dual-use were significantly positively associated with increased secretory IgA production, with dual-use showing the strongest associations. Dual-use was positively associated with class switching and B cell clonal expansion, indicating increased B cell activation, with similar trends in those only smoking or only vaping. We observed significant associations between race and IgG antibody usage. AA participants had higher IgG subclass proportions and lower IgM usage compared to NHW participants., Conclusions: CS and vaping additively enhance B cell activation, most notably in dual-users. Self-reported race was strongly associated with IgG isotype usage. These findings highlight associations between B cell activation and antibody transcription, suggesting potential differences in immune and vaccine responses linked to CS, vaping, and race.
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- 2024
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9. COPD-iNET: a call to the lung community for action to combat the global epidemic of COPD.
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Yildirim AÖ, Conlon TM, Adcock IM, Gosens R, Lehmann M, Kapellos TS, Tesfaigzi Y, Polverino F, Sauler M, Wasnick R, and Neptune ER
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- Humans, Epidemics, Pulmonary Disease, Chronic Obstructive epidemiology, Global Health
- Abstract
Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose.
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- 2024
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10. A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis.
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Ishikawa G, Peng X, McGovern J, Ghincea A, Woo S, Okuno D, Yu S, Lee CJ, Liu A, Saber T, Hu B, Sun Y, Sun H, Jumaily KA, Feghali-Bostwick C, Sumida TS, Sauler M, Ryu C, and Herzog EL
- Abstract
Tissue fibrosis contributes to pathology in vital organs including the lung. Curative therapies are scant. Myofibroblasts, pivotal effector cells in tissue fibrosis, accumulate via incompletely understood interactions with their microenvironment. In an investigative platform grounded in experimental lung biology, we find that sympathetic innervation stimulates fibrotic remodeling via noradrenergic α1-adrenergic receptor engagement in myofibroblasts. We demonstrate the anti-fibrotic potential of targeted sympathetic denervation and pharmacological disruption of noradrenergic neurotransmitter functions mediated by α1-adrenoreceptors (α1-ARs). Using the α1-adrenoreceptor subtype D as a representative α1-AR, we discover direct noradrenergic input from sympathetic nerves to lung myofibroblasts utilizing established mouse models, genetic denervation, pharmacologic interventions, a newly invented transgenic mouse line, advanced tissue mimetics, and samples from patients with diverse forms of pulmonary fibrosis. The discovery of this previously unappreciated nerve-fibroblast axis in the lung demonstrates the crucial contribution of nerves to tissue repair and heralds a novel paradigm in fibrosis research., Competing Interests: COMPETING INTERESTS The authors declare that there is no conflict of interest.
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- 2024
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11. Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.
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Trujillo G, Regueiro-Ren A, Liu C, Hu B, Sun Y, Ahangari F, Fiorini V, Ishikawa G, Al Jumaily K, Khoury J, McGovern J, Lee CJ, Peng XY, Pivarnik T, Sun H, Walia A, Woo S, Yu S, Antin-Ozerkis DE, Sauler M, Kaminski N, Herzog EL, and Ryu C
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Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA)., Objectives: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor., Methods: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease., Measurements and Main Results: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis., Conclusions: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.
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- 2024
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12. cGAS Expression is Enhanced in Systemic Sclerosis Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation.
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Yu S, Hu B, Sun Y, Peng XY, Lee CJ, Woo S, McGovern J, Zielonka J, Saber T, Ghincea A, Gandhi S, Walia A, Pivarnik T, Ishikawa G, Shuai S, Sun H, Gunes BI, Kujawski S, Perez S, Odell W, Hinchcliff M, Varga J, Bostwick CF, Sauler M, Gomez JL, Ryu C, and Herzog EL
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Objective: The lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The innate immune DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model., Methods: Expression and localization of cGAS, cytokines, and type 1 interferons were evaluated in SSc-ILD lung tissues, bronchoalveolar lavage (BAL), and isolated lung fibroblasts. CGAS activation was assessed in a publicly available SSc-ILD single cell RNA sequencing dataset. Production of cytokines, type 1 interferons, and αSMA elicited by TGFβ1 or local substrate stiffness were measured in normal human lung fibroblasts (NHLFs) via qRT-PCR, ELISA, and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human PCLS, and the bleomycin pulmonary fibrosis model., Results: SSc-ILD lung tissue and BAL are enriched for cGAS, cytokines, and type 1 interferons. The cGAS pathway shows constitutive activation in SSc-ILD fibroblasts and is inducible in NHLFs by TGFβ1 or mechanical stimuli. In these settings, and in human PCLS, cGAS expression is paralleled by the production of cytokines, type 1 interferons, and αSMA that are mitigated by a small molecule cGAS inhibitor. These findings are recapitulated in the bleomycin mouse model., Conclusion: cGAS signaling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc-ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.
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- 2024
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13. Lung Transcriptomics Links Emphysema to Barrier Dysfunction and Macrophage Subpopulations.
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Lu R, Gregory A, Suryadevara R, Xu Z, Jain D, Morrow JD, Hobbs BD, Yun JH, Lichtblau N, Chase R, Curtis JL, Sauler M, Bartholmai BJ, Silverman EK, Hersh CP, Castaldi PJ, and Boueiz A
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Rationale: While many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort., Objectives: Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung samples., Methods: Using RNA-sequencing data from 446 samples in the Lung Tissue Research Consortium (LTRC) and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of chest computed tomography-quantified emphysema. We also leveraged publicly available lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses., Measurements and Main Results: In the bulk lung RNA-seq analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared differentially expressed genes and biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and distinct pathway activities were observed among various macrophage subpopulations., Conclusions: This study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung.
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- 2024
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14. Cell type-specific expression of angiotensin receptors in the human lung with implications for health, aging, and chronic disease.
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Benjamin KJ, Sauler M, Poonyagariyagorn H, and Neptune ER
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The renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung, AGTR1 and AGTR2 , using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes for AGTR1 and a subtype of alveolar epithelial type 2 cells for AGTR2 . In the context of disease, we further pinpoint AGTR2 localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2
B ) and AGTR1 localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, finding AGTR2 associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway's role in lung homeostasis and constructing rational approaches for targeting specific lung disorders., Competing Interests: Competing interest The authors declare no competing interests.- Published
- 2024
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