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Baron, Rebecca

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Baron

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Rebecca

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Baron, Rebecca
Author's Publications: search.filters.isAuthorOfPublication.93e64457-c146-4a33-a244-0483be699306

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    Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation
    (John Wiley and Sons Inc., 2017) Santacruz, Lucia; Arciniegas, Antonio Jose Luis; Darrabie, Marcus; Mantilla, Jose G.; Baron, Rebecca; Bowles, Dawn E.; Mishra, Rajashree; Jacobs, Danny O.
    Abstract Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing V max and K m. Pharmacological activation of AMP‐activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF‐1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF‐1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia.
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    Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation
    (Public Library of Science, 2013) Nakahira, Kiichi; Kyung, Sun-Young; Rogers, Angela J.; Gazourian, Lee; Youn, Sojung; Massaro, Anthony; Quintana, Carolina; Osorio, Juan C.; Wang, Zhaoxi; Zhao, Yang; Lawler, Laurie A.; Christie, Jason D.; Meyer, Nuala J.; Causland, Finnian R. Mc.; Waikar, Sushrut S.; Waxman, Aaron; Chung, Raymond; Bueno, Raphael; Rosas, Ivan; Fredenburgh, Laura; Baron, Rebecca; Christiani, David; Hunninghake, Gary; Choi, Augustine M. K.
    Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Methods and Findings: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (β‰₯3,200 copies/Β΅l plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1Γ—10βˆ’7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9Γ—10βˆ’5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1Γ—10βˆ’4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Conclusions: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients. Please see later in the article for the Editors' Summary
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    Folliculin regulates cell–cell adhesion, AMPK, and mTORC1 in a cell‐type‐specific manner in lung‐derived cells
    (Wiley Periodicals, Inc., 2014) Khabibullin, Damir; Medvetz, Douglas A; Pinilla, Miguel; Hariharan, Venkatesh; Li, Chenggang; Hergrueter, Anja; Laucho Contreras, Maria; Zhang, Erik; Parkhitko, Andrey; Yu, Jane J; Owen, Caroline; Huang, Hayden; Baron, Rebecca; Henske, Elizabeth
    Abstract Germline loss‐of‐function BHD mutations cause cystic lung disease and hereditary pneumothorax, yet little is known about the impact of BHD mutations in the lung. Folliculin (FLCN), the product of the Birt–Hogg–Dube (BHD) gene, has been linked to altered cell–cell adhesion and to the AMPK and mTORC1 signaling pathways. We found that downregulation of FLCN in human bronchial epithelial (HBE) cells decreased the phosphorylation of ACC, a marker of AMPK activation, while downregulation of FLCN in small airway epithelial (SAEC) cells increased the activity of phospho‐S6, a marker of mTORC1 activation, highlighting the cell type–dependent functions of FLCN. Cell–cell adhesion forces were significantly increased in FLCN‐deficient HBE cells, consistent with prior findings in FLCN‐deficient human kidney‐derived cells. To determine how these altered cell–cell adhesion forces impact the lung, we exposed mice with heterozygous inactivation of Bhd (similarly to humans with germline inactivation of one BHD allele) to mechanical ventilation at high tidal volumes. Bhd+/βˆ’ mice exhibited a trend (P = 0.08) toward increased elastance after 6 h of ventilation at 24 cc/kg. Our results indicate that FLCN regulates the AMPK and mTORC1 pathways and cell–cell adhesion in a cell type–dependent manner. FLCN deficiency may impact the physiologic response to inflation‐induced mechanical stress, but further investigation is required. We hypothesize that FLCN‐dependent effects on signaling and cellular adhesion contribute to the pathogenesis of cystic lung disease in BHD patients.
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    Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators*
    (Lippincott Williams & Wilkins, 2016) Tsoyi, Konstantin; Hall, Sean R. R.; Dalli, Jesmond; Colas, Romain A.; Ghanta, Sailaja; Ith, Bonna; Coronata, Anna; Fredenburgh, Laura; Baron, Rebecca; Choi, Augustine M. K.; Serhan, Charles; Liu, Xiaoli; Perrella, Mark
    Objectives: Mesenchymal stromal cells are being investigated as a cell-based therapy for a number of disease processes, with promising results in animal models of systemic inflammation and sepsis. Studies are ongoing to determine ways to further improve the therapeutic potential of mesenchymal stromal cells. A gas molecule that improves outcome in experimental sepsis is carbon monoxide. We hypothesized that preconditioning of mesenchymal stromal cells with carbon monoxide ex vivo would promote further therapeutic benefit when cells are administered in vivo after the onset of polymicrobial sepsis in mice. Design: Animal study and primary cell culture. Setting: Laboratory investigation. Subjects: BALB/c mice. Interventions: Polymicrobial sepsis was induced by cecal ligation and puncture. Mesenchymal stromal cells, mesenchymal stromal cells-conditioned with carbon monoxide, fibroblasts, or fibroblasts-conditioned with carbon monoxide were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils, the production of specialized proresolving lipid mediators, and their importance for mesenchymal stromal cells function using gene silencing. Measurements and Main Results: Ex vivo preconditioning with carbon monoxide allowed mesenchymal stromal cells to be administered later after the onset of sepsis (6 hr), and yet maintain their therapeutic effect with increased survival. Carbon monoxide preconditioned mesenchymal stromal cells were also able to alleviate organ injury, improve bacterial clearance, and promote the resolution of inflammation. Mesenchymal stromal cells exposed to carbon monoxide, with docosahexaenoic acid substrate, produced specialized proresolving lipid mediators, particularly D-series resolvins, which promoted survival. Silencing of lipoxygenase pathways (5-lipoxygenase and 12/15-lipoxygenase), which are important enzymes for specialized proresolving lipid mediator biosynthesis, resulted in a loss of therapeutic benefit bestowed on mesenchymal stromal cells by carbon monoxide. Conclusions: Taken together, these data suggest that production of specialized proresolving lipid mediators contribute to improved mesenchymal stromal cell efficacy when exposed to carbon monoxide, resulting in an improved therapeutic response during sepsis.
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    Recent advances in understanding and treating ARDS
    (F1000Research, 2016) Baron, Rebecca; Levy, Bruce
    Acute respiratory distress syndrome represents a complex syndrome with considerable morbidity and mortality, for which there exist no targeted treatment strategies. However, recent advances in clinical care have improved outcomes, and we will review a number of these approaches here, as well as explore the mechanisms underlying the benefit of intervention that might point us in the direction toward future treatment and preventive strategies for this devastating syndrome.
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    Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites
    (2014) Platzer, Barbara; Baker, Kristi; Vera, Miguel Pinilla; Singer, Kathleen; Panduro, Marisella; Lexmond, Willem S.; Turner, Devin; Vargas, Sara; Kinet, Jean-Pierre; Maurer, Dieter; Baron, Rebecca; Blumberg, Richard; Fiebiger, Edda
    Antigen-mediated crosslinking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcΞ΅RI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcΞ΅RI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcΞ΅RI signals for DC function remain poorly understood. We show that humanized mice that express FcΞ΅RI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcΞ΅RI crosslinking fails to induce maturation or production of inflammatory mediators in human DCs and FcΞ΅RI-humanized DCs. Furthermore, conferring expression of FcΞ΅RI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcΞ΅RI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcΞ΅RI crosslinking on papain or LPS-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcΞ΅RI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.
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    Integrating Murine Gene Expression Studies to Understand Obstructive Lung Disease due to Chronic Inhaled Endotoxin
    (Public Library of Science, 2013) Lai, Peggy; Hofmann, Oliver; Baron, Rebecca; Cernadas, Manuela; Meng, Quanxin Ryan; Bresler, Herbert S.; Brass, David M.; Yang, Ivana V.; Schwartz, David A.; Christiani, David; Hide, Winston
    Rationale: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. Methods: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. Results: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. Conclusions: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development.
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    Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
    (Public Library of Science, 2010) Lopez-Guzman, Silvia; Riascos, Dario F.; Macias, Alvaro A.; Layne, Matthew D.; Harris, Cailin; Reeves, Raymond; Baron, Rebecca; Cheng, Guiying; Chung, Su Wol; von Andrian-Werburg, Ulrich; Perrella, Mark
    Background: The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes (β€œenhanceosomes”) that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs. Objectives: To determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules. Methodology/Principal Findings: Administration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-ΞΊB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-ΞΊB induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo. Conclusions/Significance: We describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.
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    Plasma surfactant protein-D as a diagnostic biomarker for acute respiratory distress syndrome: validation in US and Korean cohorts
    (BioMed Central, 2017) Park, Jinkyeong; Pabon, Maria; Choi, Augustine M. K.; Siempos, Ilias I.; Fredenburgh, Laura; Baron, Rebecca; Jeon, Kyeongman; Chung, Chi Ryang; Yang, Jeong Hoon; Park, Chi-Min; Suh, Gee Young
    Background: Acute respiratory distress syndrome (ARDS) is potentially underrecognized by clinicians. Early recognition and subsequent optimal treatment of patients with ARDS may be facilitated by usage of biomarkers. Surfactant protein D (SP-D), a marker of alveolar epithelial injury, has been proposed as a potentially useful biomarker for diagnosis of ARDS in a few studies. We tried to validate the performance of plasma SP-D levels for diagnosis of ARDS. Methods: We conducted a retrospective analysis using data from three (two in USA and one in Korea) prospective biobank cohorts involving 407 critically ill patients admitted to medical intensive care unit (ICU). A propensity score matched analysis (patients with versus without ARDS, matched 1:1) was carried out using significant variables from multiple logistic regression. The diagnostic accuracy of plasma SP-D as a diagnostic marker of ARDS was assessed by receiver operating characteristic curve analysis. Results: Out of the 407 subjects included in this study, 39 (10%) patients fulfilled ARDS criteria. Patients with ARDS had higher SP-D levels in plasma (p < 0.01) and higher hospital-mortality (p < 0.001) than those without ARDS. Thirty eight subjects with ARDS (cases) were successfully matched for propensity for ARDS with 38 subjects without ARDS (controls). Plasma levels of SP-D were higher in cases with ARDS compared to their matched controls without ARDS [median 20.8 ng/mL (interquartile range, 12.7–38.4) versus 7.9 (4.1–17.0); p = 0.001]. The area under the receiver operating characteristic curve for SP-D for the diagnosis of ARDS was 0.71 (95% confidence intervals, 0.60–0.83). A cut-off point of 12.7 ng/mL for SP-D yielded sensitivity of 74% and specificity of 63%. Conclusions: High levels of SP-D within 48 h after ICU admission might serve as a diagnostic marker for ARDS in patients hospitalized in medical ICU. Further prospective trials are required to validate the diagnostic role of SP-D in ARDS, and if its usefulness is greater in direct than in indirect ARDS, as well as across different strata of severity of ARDS.
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    An Immune Cell Signature of Bacterial Sepsis
    (Springer Science and Business Media LLC, 2020-02-17) Reyes, Miguel; Filbin, Michael; Bhattacharyya, Roby; Billman, Kianna; Eisenhaure, Thomas; Hung, Deborah; Levy, Bruce; Baron, Rebecca; Blainey, Paul; Goldberg, Marcia; Hacohen, Nir
    Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene expression studies have defined sepsis-associated molecular signatures but did not resolve changes in transcriptional states of specific cell types. Here, we used single-cell RNA sequencing to profile the blood of patients with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all patients and, based on clustering of their gene expression profiles, defined 16 immune cell states. We identified a unique CD14+ monocyte state that is expanded in septic patients and validated its power in discriminating septic patients from controls using public transcriptomic data from patients of different disease etiologies and multiple geographic locations (18 cohorts, n = 1,213 patients). We identified a panel of surface markers for isolation and quantification of the monocyte state, characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis.