46 results on '"Benjamin D. Medoff"'
Search Results
2. Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis
- Author
-
Yang Yang, Daniela M. Santos, Lorena Pantano, Rachel Knipe, Elizabeth Abe, Amanda Logue, Gina Pronzati, Katharine E. Black, Jillian J. Spinney, Francesca Giacona, Michael Bieler, Cedrickx Godbout, Paul Nicklin, David Wyatt, Andrew M. Tager, Peter Seither, Franziska E. Herrmann, and Benjamin D. Medoff
- Subjects
Cell Nucleus ,Pulmonary and Respiratory Medicine ,Pulmonary Fibrosis ,Clinical Biochemistry ,Cell Cycle Proteins ,YAP-Signaling Proteins ,Cell Biology ,Fibroblasts ,Phosphoproteins ,Idiopathic Pulmonary Fibrosis ,Mice ,Transforming Growth Factor beta ,Animals ,Humans ,Molecular Biology ,Original Research ,Adaptor Proteins, Signal Transducing ,Aurora Kinase A - Abstract
Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.
- Published
- 2022
3. Plasma Soluble Suppression of Tumorigenicity-2 Associates with Ventilator Liberation in Acute Hypoxemic Respiratory Failure
- Author
-
Jehan Alladina, Alexander Camacho, Sean D. Levy, R. Scott Harris, Benjamin D. Medoff, Sowmya R. Rao, Kelsey Brait, Kathryn A. Hibbert, Ednan K. Bajwa, James L. Januzzi, Josalyn L. Cho, and B. Taylor Thompson
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Time Factors ,Lung injury ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,0302 clinical medicine ,Odds Ratio ,Humans ,Medicine ,In patient ,Hospital Mortality ,030212 general & internal medicine ,Aged ,American Thoracic Society Documents ,Acute hypoxemic respiratory failure ,Interleukin-6 ,business.industry ,Patient Selection ,Editorials ,Middle Aged ,Hypoxemic respiratory failure ,Mechanical ventilator weaning ,Interleukin-1 Receptor-Like 1 Protein ,body regions ,030228 respiratory system ,Anesthesia ,Airway Extubation ,Liberation ,Female ,Respiratory Insufficiency ,business ,Ventilator Weaning ,Biomarkers - Abstract
Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect cli...
- Published
- 2021
4. Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome
- Author
-
Julian A. Villalba, Caroline F. Hilburn, Michelle A. Garlin, Grant A. Elliott, Yijia Li, Keiko Kunitoki, Sergio Poli, George A. Alba, Emilio Madrigal, Manuel Taso, Melissa C. Price, Alexis J. Aviles, Milagros Araujo-Medina, Liana Bonanno, Baris Boyraz, Samantha N. Champion, Cynthia K. Harris, Timothy L. Helland, Bailey Hutchison, Soma Jobbagy, Michael S. Marshall, Daniel J. Shepherd, Jaimie L. Barth, Yin P. Hung, Amy Ly, Lida P. Hariri, Sarah E. Turbett, Virginia M. Pierce, John A. Branda, Eric S. Rosenberg, Javier Mendez-Pena, Ivan Chebib, Ivy A. Rosales, Rex N. Smith, Miles A. Miller, Ivan O. Rosas, Charles C. Hardin, Lindsey R. Baden, Benjamin D. Medoff, Robert B. Colvin, Brent P. Little, James R. Stone, Mari Mino-Kenudson, and Angela R. Shih
- Subjects
Pulmonary and Respiratory Medicine ,Pulmonary Alveoli ,Respiratory Distress Syndrome ,COVID-19 ,Humans ,Pneumonia ,Vascular Diseases ,Critical Care and Intensive Care Medicine ,Lung - Published
- 2022
5. Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018
- Author
-
Daniel Okin, Jocelyn R. Farmer, Gabriel E. Molina, Michael Dougan, Yonina R. Murciano-Goroff, Aditya Bardia, Steven T. Chen, Benjamin D. Medoff, Rebecca Karp Leaf, Meghan J. Mooradian, Ian M. Allen, Alexander T. Faje, Tomas G. Neilan, Minh Mai, Sara R. Schoenfeld, Meghan E. Sise, Molly Thomas, Daniel A. Zlotoff, Leyre Zubiri, Kerry L. Reynolds, Yevgeniy R. Semenov, Minna J. Kohler, Mazen Nasrallah, Amanda C. Guidon, Justine V. Cohen, Michelle Rengarajan, Ryan J. Sullivan, Laura A. Petrillo, Sienna Durbin, and Alexandra-Chloé Villani
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Cohort Studies ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Neoplasms ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Aged ,Retrospective Studies ,Aged, 80 and over ,Inpatients ,business.industry ,Medical record ,Immuno‐oncology ,Retrospective cohort study ,Odds ratio ,Middle Aged ,Discontinuation ,Hospitalization ,Regimen ,Massachusetts ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Nivolumab ,business - Abstract
Background The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. Methods Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. Results In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. Conclusion This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. Implications for Practice The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.
- Published
- 2021
6. T cell-tropic HIV efficiently infects alveolar macrophages through contact with infected CD4+ T cells
- Author
-
Alejandro B. Balazs, Josalyn L. Cho, Björn Corleis, Abigail E. Schiff, Thomas J. Diefenbach, Stephanie Banning, Douglas S. Kwon, Amy K. Dickey, Alice H. Linder, Martin J. Deymier, Robert J. Wilkinson, Athe M. N. Tsibris, Shillah N Luhembo, Gerhard Walzl, Wendy A. Burgers, Benjamin D. Medoff, and Wellcome Trust
- Subjects
0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,T cell ,Science ,Cell ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,Virus-host interactions ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Retrovirus ,Virology ,Macrophages, Alveolar ,medicine ,Humans ,Monocytes and macrophages ,Multidisciplinary ,biology ,business.industry ,virus diseases ,biology.organism_classification ,Antiretroviral therapy ,In vitro ,3. Good health ,Chronic infection ,Viral Tropism ,030104 developmental biology ,medicine.anatomical_structure ,Mucosal immunology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Host-Pathogen Interactions ,Medicine ,Female ,business - Abstract
Alveolar macrophages (AMs) are critical for defense against airborne pathogens and AM dysfunction is thought to contribute to the increased burden of pulmonary infections observed in individuals living with HIV-1 (HIV). While HIV nucleic acids have been detected in AMs early in infection, circulating HIV during acute and chronic infection is usually CCR5 T cell-tropic (T-tropic) and enters macrophages inefficiently in vitro. The mechanism by which T-tropic viruses infect AMs remains unknown. We collected AMs by bronchoscopy performed in HIV-infected, antiretroviral therapy (ART)-naive and uninfected subjects. We found that viral constructs made with primary HIV envelope sequences isolated from both AMs and plasma were T-tropic and inefficiently infected macrophages. However, these isolates productively infected macrophages when co-cultured with HIV-infected CD4+ T cells. In addition, we provide evidence that T-tropic HIV is transmitted from infected CD4+ T cells to the AM cytosol. We conclude that AM-derived HIV isolates are T-tropic and can enter macrophages through contact with an infected CD4+ T cell, which results in productive infection of AMs. CD4+ T cell-dependent entry of HIV into AMs helps explain the presence of HIV in AMs despite inefficient cell-free infection, and may contribute to AM dysfunction in people living with HIV.
- Published
- 2021
7. Quantitative assessment of airway remodelling and response to allergen in asthma
- Author
-
R. Scott Harris, Andrew D. Luster, Daniel L. Hamilos, Benjamin D. Medoff, Jasmin A. Holz, Jason W. Griffith, Matthew B. Applegate, Alex Chee, Lida P. Hariri, Margit V. Szabari, Melissa J. Suter, David C. Adams, Josalyn L. Cho, and Alyssa J. Miller
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Vital capacity ,medicine.disease_cause ,Bronchial Provocation Tests ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Allergen ,Bronchoscopy ,Respiratory Hypersensitivity ,medicine ,Humans ,030212 general & internal medicine ,Airway Remodelling ,Lung ,Asthma ,business.industry ,Allergens ,respiratory system ,Airway obstruction ,medicine.disease ,Mucus ,Respiratory Function Tests ,respiratory tract diseases ,030228 respiratory system ,Immunology ,Airway Remodeling ,Female ,Airway ,business ,Tomography, Optical Coherence - Abstract
Background and objective In vivo evaluation of the microstructural differences between asthmatic and non-asthmatic airways and their functional consequences is relevant to understanding and, potentially, treating asthma. In this study, we use endobronchial optical coherence tomography to investigate how allergic airways with asthma differ from allergic non-asthmatic airways in baseline microstructure and in response to allergen challenge. Methods A total of 45 subjects completed the study, including 20 allergic, mildly asthmatic individuals, 22 non-asthmatic allergic controls and 3 healthy controls. A 3-cm airway segment in the right middle and right upper lobe were imaged in each subject immediately before and 24 h following segmental allergen challenge to the right middle lobe. Relationships between optical airway measurements (epithelial and mucosal thicknesses, mucosal buckling and mucus) and airway obstruction (FEV1 /FVC (forced expiratory volume in 1 s/forced vital capacity) and FEV1 % (FEV1 as a percentage of predictive value)) were investigated. Results Significant increases at baseline and in response to allergen were observed for all four of our imaging metrics in the asthmatic airways compared to the non-asthmatic airways. Epithelial thickness and mucosal buckling exhibited a significant relationship to FEV1 /FVC in the asthmatic group. Conclusion Simultaneous assessments of airway microstructure, buckling and mucus revealed both structural and functional differences between the mildly asthmatic and control groups, with airway buckling seeming to be the most relevant factor. The results of this study demonstrate that a comprehensive, microstructural approach to assessing the airways may be important in future asthma studies as well as in the monitoring and treatment of asthma.
- Published
- 2019
8. Diagnostic Accuracy of Endobronchial Optical Coherence Tomography for the Microscopic Diagnosis of Usual Interstitial Pneumonia
- Author
-
Harald C. Ott, John C. Wain, Paul A. VanderLaan, Benjamin W. Roop, Cameron D. Wright, Michael Lanuti, Henning A. Gaissert, Benjamin D. Medoff, Peter Caravan, Diane L. Davies, Maxwell L. Smith, Sarita R. Berigei, Hugh Auchincloss, Christopher R. Morse, Melissa J. Suter, Rebecca A Raphaely, Mari Mino-Kenudson, Sreyankar Nandy, Amita Sharma, Lida P. Hariri, Margit V. Szabari, Lloyd L. Liang, Ashok Muniappan, Andrew M. Tager, Colleen Keyes, Nora Horick, Maria L. Garcia-Moliner, Thomas V. Colby, and Angela R. Shih
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Diagnostic methods ,medicine.diagnostic_test ,business.industry ,Interstitial lung disease ,Diagnostic accuracy ,Original Articles ,respiratory system ,Critical Care and Intensive Care Medicine ,medicine.disease ,Usual interstitial pneumonitis ,Fibrosis ,humanities ,respiratory tract diseases ,Idiopathic pulmonary fibrosis ,Optical coherence tomography ,Usual interstitial pneumonia ,medicine ,In vivo microscopy ,Humans ,Radiology ,business ,Lung Diseases, Interstitial ,Tomography, Optical Coherence - Abstract
Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and Dl(CO) were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8–100.0%) and 100% (79.6–100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72–1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.
- Published
- 2021
9. Case 4-2021: A 70-Year-Old Woman with Dyspnea on Exertion and Abnormal Findings on Chest Imaging
- Author
-
Richard M. Schwartzstein, Benjamin D. Medoff, Justin F. Gainor, Lida P. Hariri, Yolonda L. Colson, and Amita Sharma
- Subjects
medicine.medical_specialty ,Lung Neoplasms ,Biopsy ,Physical Exertion ,Lung pathology ,Diagnosis, Differential ,Neuroendocrine Cells ,X ray computed ,medicine ,Humans ,Exertion ,Lung ,Aged ,Chest imaging ,Hyperplasia ,medicine.diagnostic_test ,business.industry ,General Medicine ,respiratory tract diseases ,Dyspnea ,Female ,Radiology ,business ,Tomography, X-Ray Computed ,Precancerous Conditions - Abstract
A Woman with Dyspnea on Exertion and Abnormal Findings on Chest Imaging A 70-year-old woman was evaluated because of increasing dyspnea on exertion and abnormal findings on chest imaging. Eleven ye...
- Published
- 2021
10. High-throughput human primary cell-based airway model for evaluating influenza, coronavirus, or other respiratory viruses in vitro
- Author
-
Jeffrey T. Borenstein, E E Marr, Robert W. Finberg, Jenna L. Balestrini, Jehan Alladina, Gaibler R, Hesham Azizgolshani, C A Wong, Brett C. Isenberg, R Fennell Fezzie, T J Mulhern, Benjamin D. Medoff, D M Burns, R J Luu, R. Maloney, Jonathan R. Coppeta, Ashley L. Gard, Pengpeng Liu, B P Cain, Jennifer P. Wang, and C. R. Miller
- Subjects
0301 basic medicine ,Science ,medicine.medical_treatment ,Cell Culture Techniques ,Bronchi ,Microbial Sensitivity Tests ,Respiratory Mucosa ,Biology ,medicine.disease_cause ,Antiviral Agents ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Pandemic ,Influenza, Human ,medicine ,Influenza A virus ,Humans ,Respiratory Tract Infections ,Coronavirus ,Multidisciplinary ,Protease ,Respiratory tract infections ,SARS-CoV-2 ,virus diseases ,COVID-19 ,Equipment Design ,Microfluidic Analytical Techniques ,Virology ,In vitro ,High-Throughput Screening Assays ,COVID-19 Drug Treatment ,030104 developmental biology ,Cell culture ,Viral infection ,Medicine ,Coronavirus Infections ,Immortalised cell line ,Biomedical engineering ,030217 neurology & neurosurgery - Abstract
Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air–liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.
- Published
- 2021
11. Association of obesity-related inflammatory pathways with lung function and exercise capacity
- Author
-
Jenna McNeill, Emily S. Lau, Robyn Farrell, Matthew Nayor, Emily K. Zern, Benjamin D. Medoff, Rohan R Bhat, John A. Sbarbaro, Rajeev Malhotra, Liana Brooks, Jennifer E. Ho, Mark W. Schoenike, Gregory D. Lewis, and Elizabeth Liu
- Subjects
Pulmonary and Respiratory Medicine ,Spirometry ,Leptin ,Male ,medicine.medical_specialty ,Adipokine ,Exercise intolerance ,Article ,Pulmonary function testing ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Medicine ,Humans ,030212 general & internal medicine ,Obesity ,Lung ,Inflammation ,Exercise Tolerance ,Adiponectin ,medicine.diagnostic_test ,business.industry ,Interleukin-6 ,Hemodynamics ,respiratory system ,medicine.disease ,Respiratory Function Tests ,C-Reactive Protein ,030228 respiratory system ,Cardiology ,Exercise Test ,Resistin ,Female ,medicine.symptom ,Inflammation Mediators ,Insulin Resistance ,business ,Signal Transduction - Abstract
BACKGROUND: Obesity has multifactorial effects on lung function and exercise capacity. The contributions of obesity-related inflammatory pathways to alterations in lung function remain unclear. RESEARCH QUESTION: To examine the association of obesity-related inflammatory pathways with pulmonary function, exercise capacity, and pulmonary-specific contributors to exercise intolerance. METHOD: We examined 695 patients who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring at Massachusetts General Hospital between December 2006–June 2017. We investigated the association of adiponectin, leptin, resistin, IL-6, CRP, and insulin resistance (HOMA-IR) with pulmonary function and exercise parameters using multivariable linear regression. RESULTS: Obesity-related inflammatory pathways were associated with worse lung function. Specifically, higher CRP, IL-6, and HOMA-IR were associated with lower percent predicted FEV(1) and FVC with a preserved FEV(1)/FVC ratio suggesting a restrictive physiology pattern (P≤0.001 for all). For example, a 1-SD higher natural-logged CRP level was associated with a nearly 5% lower percent predicted FEV(1) and FVC (beta −4.8, s.e. 0.9 for FEV1; beta −4.9, s.e. 0.8 for FVC; P
- Published
- 2021
12. Screening for YAP Inhibitors Identifies Statins as Modulators of Fibrosis
- Author
-
Royale Nichols, Jillian J Spinney, Michael Bieler, Katharine E. Black, Yufei Lin, Lida P. Hariri, Clemens K. Probst, Paul Nicklin, Benjamin D. Medoff, Lorena Pantano, Paula Grasberger, Peter Seither, David Wyatt, Daniela M. Santos, Gina Pronzati, and Andrew M. Tager
- Subjects
Pulmonary and Respiratory Medicine ,Cytoplasm ,Simvastatin ,Pulmonary Fibrosis ,Clinical Biochemistry ,Mevalonic Acid ,Cell Cycle Proteins ,Bleomycin ,Small Molecule Libraries ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,Mice ,Fibrosis ,Pulmonary fibrosis ,medicine ,Animals ,Humans ,Fibroblast ,Molecular Biology ,Original Research ,Adaptor Proteins, Signal Transducing ,Cell Nucleus ,Hippo signaling pathway ,biology ,business.industry ,YAP-Signaling Proteins ,Cell Biology ,Fibroblasts ,medicine.disease ,Phosphoproteins ,medicine.anatomical_structure ,chemistry ,HMG-CoA reductase ,biology.protein ,Cancer research ,Mevalonate pathway ,Acyl Coenzyme A ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Biomarkers ,Signal Transduction - Abstract
Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.
- Published
- 2020
13. PET Imaging Reveals Early Pulmonary Perfusion Abnormalities in HIV Infection Similar to Smoking
- Author
-
Tilo Winkler, Benjamin D. Medoff, Puja Kohli, Mamary Kone, Doreen DeFaria-Yeh, Vanessa J. Kelly, Douglas S. Kwon, R. Scott Harris, Josalyn L. Cho, Björn Corleis, and Kathryn A. Hibbert
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Pulmonary Circulation ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Subclinical infection ,COPD ,PET-CT ,business.industry ,Smoking ,Pet imaging ,Pulmonary ,Middle Aged ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,030228 respiratory system ,Lung disease ,Positron-Emission Tomography ,Breathing ,Cardiology ,Female ,business ,Perfusion - Abstract
Chronic obstructive pulmonary disease (COPD) is the most common noninfectious pulmonary disease among people living with HIV, independent of smoking. However, the cause for this enhanced susceptibility remains unclear, and the effects of HIV on pulmonary perfusion and ventilation are unknown. Methods: We used PET/CT in 46 smokers and nonsmokers, 23 of whom had documented HIV infection. Emphysema was assessed by CT and perfusion by (13)N ((13)NN) PET scans. After removal of image noise, vertical and axial gradients in perfusion were calculated. We tested for differences in the total spatial heterogeneity of perfusion (CV(2)(Qtotal)) and its components (CV(2)(Qtotal) = CV(2)(Qvgrad) [vertical gradient] + CV(2)(Qzgrad) [axial gradient] + CV(2)(Qr) [residual heterogeneity]) among groups. Results: There were no significant differences in demographic parameters among groups, and all subjects had minimal radiographic evidence of emphysema. Compared with controls, nonsmokers living with HIV had a significantly greater CV(2)(Qr)/CV(2)(Qtotal) (0.48 vs. 0.36, P = 0.05) and reduced CV(2)(Qvgrad)/CV(2)(Qtotal) (0.46 vs. 0.65, P = 0.038). Smokers also had a reduced CV(2)(Qvgrad)/CV(2)(Qtotal), however, there was no significant difference in CV(2)(Qvgrad)/CV(2)(Qtotal) between smokers living with and without HIV (0.39 vs. 0.34, P = 0.58), despite a decreased vertical perfusion gradient (Qv(grad)) in smokers living with HIV. Conclusion: In nonsmokers living with well-controlled HIV and minimal radiographic emphysema, HIV infection contributes to pulmonary perfusion abnormalities similar to smokers. These data indicate the onset of subclinical pulmonary perfusion abnormalities that could herald the development of significant lung disease in these susceptible individuals.
- Published
- 2020
14. Reply to Yaroshetskiy et al.: Acute Respiratory Distress Syndrome in COVID-19: Do All These Patients Definitely Require Intubation and Mechanical Ventilation?
- Author
-
C. Corey Hardin, Ari Moskowitz, Benjamin D. Medoff, B. Taylor Thompson, Jason H. Maley, Camille R. Petri, David R. Ziehr, Kathryn A. Hibbert, and Jehan Alladina
- Subjects
Pulmonary and Respiratory Medicine ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.medical_treatment ,Pneumonia, Viral ,Acute respiratory distress ,Critical Care and Intensive Care Medicine ,Cohort Studies ,Betacoronavirus ,Correspondence ,medicine ,Intubation, Intratracheal ,Intubation ,RESPIRATORY DISTRESS SYNDROME ADULT ,Humans ,Pandemics ,Mechanical ventilation ,Respiratory Distress Syndrome ,business.industry ,SARS-CoV-2 ,COVID-19 ,Respiration, Artificial ,Anesthesia ,business ,Coronavirus Infections - Published
- 2020
15. Reply to Epelbaum: Standards and Stereotypes in COVID-19
- Author
-
Benjamin D. Medoff, Camille R. Petri, C. Corey Hardin, Ari Moskowitz, David R. Ziehr, Jehan Alladina, Jason H. Maley, B. Taylor Thompson, and Kathryn A. Hibbert
- Subjects
Pulmonary and Respiratory Medicine ,2019-20 coronavirus outbreak ,biology ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,COVID-19 ,Critical Care and Intensive Care Medicine ,biology.organism_classification ,Respiration, Artificial ,Virology ,Cohort Studies ,Betacoronavirus ,Correspondence ,Pandemic ,Humans ,Medicine ,Coronavirus Infections ,business ,Pandemics ,Reference standards - Published
- 2020
16. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy
- Author
-
Bruno L. Cadilha, Ross D. Warner, Mauro Di Pilato, Sandra Misale, Edward Y. Kim, Alexandra-Chloé Villani, Benjamin D. Medoff, Matteo Ligorio, Thorsten R. Mempel, Davide Seruggia, Valentina Zappulli, Vinidhra Mani, Jasper N. Prüßmann, Shariq M. Usmani, Francesco Marangoni, Esteban Carrizosa, and Mazen Nasrallah
- Subjects
0301 basic medicine ,Adaptive Immune Resistance ,Regulatory T cell stability ,CARD11 ,Major histocompatibility complex ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Article ,Autoimmunity ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,PD-1 ,MALT1 Paracaspase ,medicine ,Humans ,CBM complex ,Multidisciplinary ,biology ,Effector ,CARMA1/CARD11 ,Immune checkpoint ,3. Good health ,Tumor inflammation ,030104 developmental biology ,Tumor microenvironment ,biology.protein ,Cancer research ,Immune Checkpoint Therapy ,030215 immunology - Abstract
Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy.
- Published
- 2019
- Full Text
- View/download PDF
17. Vascular permeability in the fibrotic lung
- Author
-
Sydney B. Montesi, Rachel S. Knipe, Clemens K. Probst, Barry S. Shea, and Benjamin D. Medoff
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Vascular permeability ,Disease ,Lung injury ,Article ,Capillary Permeability ,Pathogenesis ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Fibrosis ,medicine ,Humans ,Lung ,business.industry ,Bacterial pneumonia ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Immunology ,business - Abstract
Idiopathic pulmonary fibrosis (IPF) is thought to result from aberrant tissue repair processes in response to chronic or repetitive lung injury. The origin and nature of the injury, as well as its cellular and molecular targets, are likely heterogeneous, which complicates accurate pre-clinical modelling of the disease and makes therapeutic targeting a challenge. Efforts are underway to identify central pathways in fibrogenesis which may allow targeting of aberrant repair processes regardless of the initial injury stimulus. Dysregulated endothelial permeability and vascular leak have long been studied for their role in acute lung injury and repair. Evidence that these processes are of importance to the pathogenesis of fibrotic lung disease is growing. Endothelial permeability is increased in non-fibrosing lung diseases, but it resolves in a self-limited fashion in conditions such as bacterial pneumonia and acute respiratory distress syndrome. In progressive fibrosing diseases such as IPF, permeability appears to persist, however, and may also predict mortality. In this hypothesis-generating review, we summarise available data on the role of endothelial permeability in IPF and focus on the deleterious consequences of sustained endothelial hyperpermeability in response to and during pulmonary inflammation and fibrosis. We propose that persistent permeability and vascular leak in the lung have the potential to establish and amplify the pro-fibrotic environment. Therapeutic interventions aimed at recognising and “plugging” the leak may therefore be of significant benefit for preventing the transition from lung injury to fibrosis and should be areas for future research.
- Published
- 2020
18. CARMA3 Mediates Allergic Lung Inflammation in Response to Alternaria alternata
- Author
-
Benjamin Causton, Benjamin D. Medoff, Jayaraj Rajagopal, Ramnik J. Xavier, Katherine Discipio, Josalyn L. Cho, Ana Pardo-Saganta, Tristan Kooistra, and Jacob Gillis
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_treatment ,Clinical Biochemistry ,Inflammation ,Alternaria alternata ,Alternariosis ,Allergic inflammation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Cells, Cultured ,biology ,Innate lymphoid cell ,Alternaria ,Cell Biology ,Pneumonia ,respiratory system ,Allergens ,biology.organism_classification ,Asthma ,respiratory tract diseases ,CARD Signaling Adaptor Proteins ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,Immunology ,Respiratory epithelium ,medicine.symptom ,030215 immunology - Abstract
The airway epithelial cell (AEC) response to allergens helps initiate and propagate allergic inflammation in asthma. CARMA3 is a scaffold protein that mediates G protein-coupled receptor-induced NF-κB activation in airway epithelium. In this study, we demonstrate that mice with CARMA3-deficient AECs have reduced airway inflammation, as well as reduced type 2 cytokine levels in response to Alternaria alternata. These mice also have reduced production of IL-33 and IL-25, and reduced numbers of innate lymphoid cells in the lung. We also show that CARMA3-deficient human AECs have decreased production of proasthmatic mediators in response to A. alternata. Finally, we show that CARMA3 interacts with inositol 1,4,5-trisphosphate receptors in AECs, and that inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release. In conclusion, we show that CARMA3 signaling in AECs helps mediate A. alternata-induced allergic airway inflammation, and that CARMA3 is an important signaling molecule for type 2 immune responses in the lung.
- Published
- 2018
19. HIV-1 and SIV Infection Are Associated with Early Loss of Lung Interstitial CD4+ T Cells and Dissemination of Pulmonary Tuberculosis
- Author
-
Allison N. Bucsan, Douglas S. Kwon, Andrew M. Tager, Deepak Kaushal, Gregory S. Olson, Antonella C. Lisanti-Park, Abigail E. Schiff, Samantha J. Gates, Björn Corleis, Shabaana A. Khader, Andrew D. Luster, Benjamin D. Medoff, Alice H. Linder, Maud Deruaz, Brittany A. Bowman, Vladimir Vrbanac, and Jeffrey M. Paer
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Programmed cell death ,Tuberculosis ,viruses ,Population ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,Mycobacterium tuberculosis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Humans ,education ,lcsh:QH301-705.5 ,Lung ,Tuberculosis, Pulmonary ,education.field_of_study ,biology ,business.industry ,Coinfection ,virus diseases ,Simian immunodeficiency virus ,respiratory system ,medicine.disease ,biology.organism_classification ,Macaca mulatta ,In vitro ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,HEK293 Cells ,lcsh:Biology (General) ,Immunology ,HIV-1 ,Female ,Simian Immunodeficiency Virus ,business ,030217 neurology & neurosurgery - Abstract
SUMMARY Lung interstitial CD4+ T cells are critical for protection against pulmonary infections, but the fate of this population during HIV-1 infection is not well described. We studied CD4+ T cells in the setting of HIV-1 infection in human lung tissue, humanized mice, and a Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) nonhuman primate co-infection model. Infection with a CCR5-tropic strain of HIV-1 or SIV results in severe and rapid loss of lung interstitial CD4+ T cells but not blood or lung alveolar CD4+ T cells. This is accompanied by high HIV-1 production in these cells in vitro and in vivo. Importantly, during early SIV infection, loss of lung interstitial CD4+ T cells is associated with increased dissemination of pulmonary Mtb infection. We show that lung interstitial CD4+ T cells serve as an efficient target for HIV-1 and SIV infection that leads to their early depletion and an increased risk of disseminated tuberculosis., Graphical Abstract, In Brief Corleis et al. show that lung parenchymal CD4+ T cells are permissive to HIV-1-dependent cell death. CD4+ T cell loss is highly significant in the interstitium but not the alveolar space, and loss of interstitial CD4+ T cells is associated with extrapulmonary dissemination of M. tuberculosis.
- Published
- 2019
20. Fat, fire and muscle – The role of adiponectin in pulmonary vascular inflammation and remodeling
- Author
-
Benjamin D. Medoff
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Hypertension, Pulmonary ,Adipose tissue ,Inflammation ,Pathogenesis ,Mice ,Risk Factors ,medicine.artery ,Internal medicine ,Adipocytes ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Obesity ,Lung ,Adiponectin ,business.industry ,Biochemistry (medical) ,Hypoxia (medical) ,medicine.disease ,Pulmonary hypertension ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Adipose Tissue ,Pulmonary artery ,Immunology ,medicine.symptom ,business - Abstract
Pulmonary hypertension is a life-threatening condition that results from a heterogeneous group of diseases, many of which demonstrate characteristic pathologic changes of pulmonary vascular inflammation and remodeling. Recent clinical studies indicate obesity to be a risk factor for the development of pulmonary hypertension; however, the mechanisms leading to this association are unknown. Adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may directly influence the pathogenesis of pulmonary hypertension. One of these mediators is adiponectin, a protein with a wide range of metabolic, anti-inflammatory, and anti-proliferative activities. Paradoxically, adiponectin is present in high concentration in the serum of lean healthy individuals, but decreases in obesity. Studies suggest that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Most notably, experimental studies show that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice deficient in adiponectin develop a spontaneous lung vascular phenotype characterized by age-dependent increases in peri-vascular inflammatory cells and elevated pulmonary artery pressures. Emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and anti-proliferative actions on cells in the lung. This review aims to synthesize the existing data related to adiponectin's effects on the pulmonary vasculature and to discuss how changes in adiponectin levels might contribute to the development of pulmonary hypertension.
- Published
- 2013
21. Birefringence microscopy platform for assessing airway smooth muscle structure and function in vivo
- Author
-
Daniel L. Hamilos, Margit V. Szabari, Melissa J. Suter, Alyssa J. Miller, Benjamin D. Medoff, Lida P. Hariri, Brett E. Bouma, David C. Adams, Yan Wang, R. Scott Harris, Jason W. Griffith, Josalyn L. Cho, Andrew D. Luster, Jasmin A. Holz, and Martin Villiger
- Subjects
Pathology ,medicine.medical_specialty ,genetic structures ,Muscle Relaxation ,Confocal ,Respiratory System ,Sus scrofa ,Biology ,01 natural sciences ,Article ,010309 optics ,03 medical and health sciences ,Dogs ,Imaging, Three-Dimensional ,0302 clinical medicine ,Optical coherence tomography ,In vivo ,0103 physical sciences ,Microscopy ,Endomicroscopy ,medicine ,Animals ,Humans ,Birefringence ,medicine.diagnostic_test ,Muscle, Smooth ,General Medicine ,Airway smooth muscle ,respiratory system ,musculoskeletal system ,Asthma ,respiratory tract diseases ,Cartilage ,Muscle relaxation ,030228 respiratory system ,Case-Control Studies ,Tomography, Optical Coherence ,Ex vivo ,Muscle Contraction ,Biomedical engineering - Abstract
The inability to visualize airway smooth muscle (ASM) cells in vivo is a major obstacle in understanding their role in normal physiology and diseases. At present, there is no imaging modality available to assess ASM in vivo. Confocal endomicroscopy lacks the penetration depth and field of view, and conventional optical coherence tomography (OCT) does not have sufficient contrast to differentiate ASM from surrounding tissues. We have developed a birefringence microscopy platform which leverages the micro-organization of tissue to add further dimension to traditional OCT. We have utilized this technology to validate ASM measurements in ex vivo swine and canine studies, visualize and characterize volumetric representations of ASM in vivo, and to quantify and predict ASM contractile force as a function of optical retardation. We provide in vivo images and volumetric assessments of ASM in living humans and document structural disease variations in subjects with mild asthma. The opportunity to link inflammatory responses to ASM responses, and to link ASM responses to clinical responses and outcomes could lead to an increased understanding of diseases of the airway and ultimately to improved patient outcomes.
- Published
- 2016
22. Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation
- Author
-
Josalyn L. Cho, Jason W. Griffith, Giorgia Radicioni, Morris Ling, Lucas Faustino, Melissa J. Suter, Benjamin D. Medoff, David C. Adams, Aylwin Ng, Richard C. Boucher, Roshi Afshar, Mehmet Kesimer, Andre K. Han, James J. Moon, Amina A. Ford, Andrew D. Luster, William W. Kwok, Sabina A. Islam, Daniel L. Hamilos, R. S. Harris, and Ramnik J. Xavier
- Subjects
0301 basic medicine ,Adult ,medicine.medical_treatment ,Inflammation ,medicine.disease_cause ,Article ,Airborne allergen ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Allergen ,Th2 Cells ,medicine ,Hypersensitivity ,Humans ,Lung ,Sensitization ,Asthma ,business.industry ,Muscle, Smooth ,General Medicine ,Allergens ,respiratory system ,medicine.disease ,respiratory tract diseases ,Mucus ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Phenotype ,030228 respiratory system ,Immunology ,Cytokines ,medicine.symptom ,business ,Airway - Abstract
Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. In this study, we utilized segmental allergen challenge (SAC) of allergic asthmatics (AA) and allergic non-asthmatic controls (AC) to determine if there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin and increased MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-registered optical coherence tomography (OR-OCT). Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation.
- Published
- 2016
- Full Text
- View/download PDF
23. 18F-FDG Uptake Rate Is a Biomarker of Eosinophilic Inflammation and Airway Response in Asthma
- Author
-
Chanikarn Wongviriyawong, Jose G. Venegas, Nicolas de Prost, Benjamin D. Medoff, Daniel L. Hamilos, Roshi Afshar, Tilo Winkler, Marcos F. Vidal Melo, R. Scott Harris, Andrew D. Luster, Guido Musch, Josalyn L. Cho, and Mamary Kone
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Respiratory System ,Cell Count ,Bronchoalveolar Lavage ,Multimodal Imaging ,Ventilation/perfusion ratio ,Gastroenterology ,Atopy ,Young Adult ,Fluorodeoxyglucose F18 ,Internal medicine ,Ventilation-Perfusion Ratio ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Respiratory system ,Asthma ,Inflammation ,Lung ,medicine.diagnostic_test ,business.industry ,Biological Transport ,Allergens ,respiratory system ,Eosinophil ,medicine.disease ,respiratory tract diseases ,Eosinophils ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Positron-Emission Tomography ,Cats ,Feasibility Studies ,Female ,Tomography, X-Ray Computed ,Airway ,business ,Biomarkers - Abstract
In asthma, the relationship among airway inflammation, airway hyperresponsiveness, and lung function is poorly understood. Methods to noninvasively assess these relationships in human subjects are needed. We sought to determine whether (18)F-FDG uptake rate (K(i), min(-1)) could serve as a biomarker of eosinophilic inflammation and local lung function.We used PET/CT to assess regional pulmonary perfusion (Q), specific ventilation per unit volume (sV(A)), fractional gas content (Fgas), airway wall thickness, and regional K(i) 10 h after segmental allergen challenge to the right middle lobe in 6 asthmatic subjects with demonstrated atopy. Q, sV(A), and Fgas in the allergen-challenged lobe were compared with the right upper lobe, where diluent was applied as a control. The airway wall thickness aspect ratio (ω) of the allergen-challenged airway was compared with those of similarly sized airways from unaffected areas of the lung. Differences in K(i) between allergen and diluent segments were compared with those in cell counts obtained 24 h after the allergen challenge by a bronchoalveolar lavage of the respective segments.We found systematic reductions in regional Q, sV(A), and Fgas and increased ω in all subjects. The ratio of eosinophil count (allergen to diluent) was linearly related (R(2) = 0.9917, P0.001) to the ratio of K(i).Regional K(i) measured with PET is a noninvasive and highly predictive biomarker of eosinophilic airway inflammation and its functional effects. This method may serve to help in the understanding of allergic inflammation and test the therapeutic effectiveness of novel drugs or treatments.
- Published
- 2011
24. Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway
- Author
-
Craig M. Lilly, Benjamin D. Medoff, Seddon Y. Thomas, Andrew D. Luster, and Aleena Banerji
- Subjects
Adult ,Male ,Receptors, CCR6 ,Chemokine ,Receptors, CXCR3 ,T-Lymphocytes ,T cell ,Immunology ,Epitopes, T-Lymphocyte ,Bronchi ,chemical and pharmacologic phenomena ,C-C chemokine receptor type 6 ,CXCR3 ,Interferon-gamma ,Chemokine receptor ,Antigen ,Cell Movement ,T-Lymphocyte Subsets ,medicine ,Animals ,Humans ,Immunology and Allergy ,Receptor ,biology ,Gene Expression Profiling ,hemic and immune systems ,Allergens ,Middle Aged ,respiratory system ,Natural killer T cell ,Asthma ,respiratory tract diseases ,Killer Cells, Natural ,medicine.anatomical_structure ,biology.protein ,Female ,Receptors, Chemokine ,Interleukin-4 ,Bronchoalveolar Lavage Fluid - Abstract
Human allergic asthma is a chronic inflammatory disease of the airways thought to be driven by allergen-specific Th2 cells, which are recruited into the lung in response to inhaled allergen. To identify chemoattractant receptors that control this homing pattern, we used endobronchial segmental allergen challenge in human atopic asthmatics to define the pattern of chemoattractant receptor expression on recruited T cells as well as the numbers of recruited CD1d-restricted NKT cells and levels of chemokines in the bronchoalveolar (BAL) fluid. CD1d-restricted NKT cells comprised only a small minority of BAL T cells before or after Ag challenge. BAL T cells were enriched in their expression of specific chemoattractant receptors compared with peripheral blood T cells prechallenge, including CCR5, CCR6, CXCR3, CXCR4, and BLT1. Surprisingly, following segmental allergen challenge, no chemoattractant receptor was specifically increased. However, CCR6 and CXCR3, which were expressed on virtually all CD4+ BAL T cells prechallenge, were markedly decreased on all recruited BAL T cells following Ag challenge, suggesting that these receptors were internalized following encounter with ligand in the airway. Our data therefore suggests a role for CCR6 and CXCR3, in conjunction with other chemoattractant receptors, in the recruitment of inflammatory T cells into the BAL during the allergic asthmatic response.
- Published
- 2007
25. Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge
- Author
-
Tilo Winkler, Vanessa J. Kelly, R. Scott Harris, Benjamin D. Medoff, Daniel L. Hamilos, Roshi Afshar, Mamary Kone, Josalyn L. Cho, Andrew D. Luster, and Jose G. Venegas
- Subjects
Adult ,Male ,lcsh:Medicine ,Inflammation ,Disease ,Respiratory physiology ,Multimodal Imaging ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,immune system diseases ,medicine ,Hypersensitivity ,Humans ,Young adult ,lcsh:Science ,Lung ,Asthma ,Multidisciplinary ,rhinorrhea ,business.industry ,lcsh:R ,respiratory system ,Allergens ,Middle Aged ,medicine.disease ,3. Good health ,respiratory tract diseases ,medicine.anatomical_structure ,030228 respiratory system ,Positron-Emission Tomography ,Immunology ,lcsh:Q ,Female ,medicine.symptom ,Airway ,business ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery ,Research Article - Abstract
Background Allergic non-asthmatic (ANA) adults experience upper airway symptoms of allergic disease such as rhinorrhea, congestion and sneezing without symptoms of asthma. The aim of this study was to utilize PET-CT functional imaging to determine whether allergen challenge elicits a pulmonary response in ANA subjects or whether their allergic disease is truly isolated to the upper airways. Methods In 6 ANA subjects, bronchoalveolar lavages (BAL) were performed at baseline and 24h after instillation of an allergen and a diluent in separate lung lobes. After instillation (10h), functional imaging was performed to quantify and compare regional perfusion, ventilation, fractional gas content (Fgas), and glucose uptake rate (Ki) between the baseline, diluent and allergen lobes. BAL cell counts were also compared. Results In ANA subjects, compared to the baseline and diluent lobes, perfusion and ventilation were significantly lower in the allergen lobe (median [inter-quartile range], baseline vs. diluent vs. allergen: Mean-normalized perfusion; 0.87 [0.85–0.97] vs. 0.90 [0.86–0.98] vs. 0.59 [0.55–0.67]; p
- Published
- 2015
26. Oligomerization of CXCL10 Is Necessary for Endothelial Cell Presentation and In Vivo Activity
- Author
-
Gabriele S. V. Campanella, Lindsay A. Manice, Benjamin D. Medoff, Richard A. Colvin, Ralph Weissleder, Jan Grimm, Gregory R. Wojtkiewicz, and Andrew D. Luster
- Subjects
Chemokine ,Ovalbumin ,Lymphocyte ,Immunology ,Antigen-Presenting Cells ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,CXCR3 ,Cell Line ,Mice ,Cell Line, Tumor ,Cell Adhesion ,Intubation, Intratracheal ,medicine ,Animals ,Humans ,Immunology and Allergy ,CXCL10 ,Receptor ,Cell Line, Transformed ,Antigen Presentation ,biology ,Egg Proteins ,Chemotaxis ,Molecular biology ,Peptide Fragments ,Cell biology ,Chemokine CXCL10 ,Mice, Inbred C57BL ,Endothelial stem cell ,Chemotaxis, Leukocyte ,medicine.anatomical_structure ,biology.protein ,Endothelium, Vascular ,Chemokines, CXC ,CD8 - Abstract
The chemokine IFN-γ-inducible protein of 10 kDa (IP-10; CXCL10) plays an important role in the recruitment of activated T lymphocytes into sites of inflammation by interacting with the G protein-coupled receptor CXCR3. IP-10, like other chemokines, forms oligomers, the role of which has not yet been explored. In this study, we used a monomeric IP-10 mutant to elucidate the functional significance of oligomerization. Although monomeric IP-10 had reduced binding affinity for CXCR3 and heparin, it was able to induce in vitro chemotaxis of activated T cells with the same efficacy as wild-type IP-10. However, monomeric IP-10 was unable to induce recruitment of activated CD8+ T cells into the airways of mice after intratracheal instillation. Use of a different IP-10 mutant demonstrated that this inability was due to lack of oligomerization rather than reduced CXCR3 or heparin binding. Molecular imaging demonstrated that both wild-type and monomeric IP-10 were retained in the lung after intratracheal instillation. However, in vitro binding assays indicated that wild-type, but not monomeric, IP-10 was retained on endothelial cells and could induce transendothelial chemotaxis of activated T cells. We therefore propose that oligomerization of IP-10 is required for presentation on endothelial cells and subsequent transendothelial migration, an essential step for lymphocyte recruitment in vivo.
- Published
- 2006
27. CXCR3 and Its Ligands in a Murine Model of Obliterative Bronchiolitis: Regulation and Function
- Author
-
Edward Seung, Benjamin D. Medoff, Andrew D. Luster, Ryan Jackobek, Terry K. Means, Leo C. Ginns, Joshua M. Farber, and John C. Wain
- Subjects
Chemokine ,Pathology ,medicine.medical_specialty ,Receptors, CXCR3 ,Pulmonary Fibrosis ,medicine.medical_treatment ,Immunology ,Ligands ,CXCR3 ,Chemokine CXCL9 ,Interferon-gamma ,Mice ,stomatognathic system ,immune system diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,CXCL10 ,Lung transplantation ,Lymphocytes ,Bronchiolitis Obliterans ,Lung ,Mice, Knockout ,Mice, Inbred BALB C ,medicine.diagnostic_test ,biology ,respiratory system ,medicine.disease ,Up-Regulation ,Chemokine CXCL10 ,Mice, Inbred C57BL ,Trachea ,Transplantation ,Disease Models, Animal ,stomatognathic diseases ,STAT1 Transcription Factor ,Bronchoalveolar lavage ,Bronchiolitis ,Reperfusion Injury ,Cell Migration Inhibition ,biology.protein ,CXCL9 ,Receptors, Chemokine ,Chemokines, CXC ,Gene Deletion - Abstract
Lung transplantation remains the only effective therapy for patients with end-stage lung disease, but survival is limited by the development of obliterative bronchiolitis (OB). The chemokine receptor CXCR3 and two of its ligands, CXCL9 and CXCL10, have been identified as important mediators of OB. However, the relative contribution of CXCL9 and CXCL10 to the development of OB and the mechanism of regulation of these chemokines has not been well defined. In this study, we demonstrate that CXCL9 and CXCL10 are up-regulated in unique patterns following tracheal transplantation in mice. In these experiments, CXCL9 expression peaked 7 days posttransplant, while CXCL10 expression peaked at 1 day and then again 7 days posttransplant. Expression of CXCL10 was also up-regulated in a novel murine model of lung ischemia, and in bronchoalveolar lavage fluid taken from human lungs 24 h after lung transplantation. In further analysis, we found that 3 h after transplantation CXCL10 is donor tissue derived and not dependent on IFN-γ or STAT1, while 24 h after transplantation CXCL10 is from recipient tissue and regulated by IFN-γ and STAT1. Expression of both CXCL9 and CXCL10 7 days posttransplant is regulated by IFN-γ and STAT1. Finally, we demonstrate that deletion of CXCR3 in recipients reduces airway obliteration. However, deletion of either CXCL9 or CXCL10 did not affect airway obliteration. These data show that in this murine model of obliterative bronchiolitis, these chemokines are differentially regulated following transplantation, and that deletion of either chemokine alone does not affect the development of airway obliteration.
- Published
- 2006
28. BLT1-mediated T cell trafficking is critical for rejection and obliterative bronchiolitis after lung transplantation
- Author
-
Benjamin D. Medoff, Andrew M. Tager, Andrew H. Lichtman, Gabriele S. V. Campanella, Sabina A. Islam, Edward Seung, John C. Wain, Seddon Y. Thomas, Leo C. Ginns, Andrew D. Luster, Terry K. Means, and Nir Grabie
- Subjects
Graft Rejection ,Ovalbumin ,T cell ,medicine.medical_treatment ,Immunology ,Receptors, Leukotriene B4 ,Bronchiolitis obliterans ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Biology ,Article ,Effector T-Lymphocyte ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,Lung transplantation ,Bronchiolitis Obliterans ,030304 developmental biology ,Mice, Knockout ,Mice, Inbred BALB C ,0303 health sciences ,Lung ,Base Sequence ,T lymphocyte ,respiratory system ,medicine.disease ,respiratory tract diseases ,3. Good health ,Mice, Inbred C57BL ,Trachea ,Transplantation ,Disease Models, Animal ,medicine.anatomical_structure ,Collagen ,CD8 ,Lung Transplantation ,030215 immunology - Abstract
Leukotriene B4 is a lipid mediator that recently has been shown to have potent chemotactic activity for effector T lymphocytes mediated through its receptor, BLT1. Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model. In addition, we used BLT1-deficient mice and a BLT1 antagonist in two tracheal transplant models of lung transplantation to demonstrate the importance of BLT1 for the recruitment of T cells into tracheal allografts. We also show that BLT1-mediated CD8+ T cell recruitment plays an important role in the development of airway fibroproliferation and obliteration. Finally, in human studies of lung transplant recipients, we found that BLT1 is up-regulated on T lymphocytes isolated from the airways of patients with obliterative bronchiolitis. These data demonstrate that BLT1 contributes to the development of lung rejection and obliterative bronchiolitis by mediating effector T lymphocyte trafficking into the lung. This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation.
- Published
- 2005
29. Use of recruitment maneuvers and high positive end-expiratory pressure in a patient with acute respiratory distress syndrome
- Author
-
Marcelo B. P. Amato, Dean R. Hess, Jose G. Venegas, Benjamin D. Medoff, H. Kesselman, and R. S. Harris
- Subjects
Adult ,Respiratory Distress Syndrome ,medicine.medical_specialty ,ARDS ,Time Factors ,Critical Care ,Streptococcus pyogenes ,business.industry ,Acute respiratory distress ,Critical Care and Intensive Care Medicine ,medicine.disease ,Combined Modality Therapy ,Tertiary care ,Positive-Pressure Respiration ,Medical intensive care unit ,Recruitment maneuver ,Sepsis ,Streptococcal Infections ,medicine ,Humans ,Female ,Intensive care medicine ,business ,Positive end-expiratory pressure - Abstract
To present the use of a novel high-pressure recruitment maneuver followed by high levels of positive end-expiratory pressure in a patient with the acute respiratory distress syndrome (ARDS).Observations in one patient.The medical intensive care unit at a tertiary care university teaching hospital.A 32-yr-old woman with severe ARDS secondary to streptococcal sepsis.The patient had severe gas exchange abnormalities because of acute lung injury and marked lung collapse. Attempts to optimize recruitment based on the inflation pressure-volume (PV) curve were not sufficient to avoid dependent lung collapse. We used a recruitment maneuver using 40 cm H2O of positive end-expiratory pressure (PEEP) and 20 cm H2O of pressure controlled ventilation above PEEP for 2 mins to successfully recruit the lung. The recruitment was maintained with 25 cm H2O of PEEP, which was much higher than the PEEP predicted by the lower inflection point (P(Flex)) of the PV curve.Recruitment was assessed by improvements in oxygenation and by computed tomography of the chest. With the recruitment maneuvers, the patient had a dramatic improvement in gas exchange and we were able to demonstrate nearly complete recruitment of the lung by computed tomography. A PV curve was measured that demonstrated a P(Flex) of 16-18 cm H2O.Accumulating data suggest that the maximization and maintenance of lung recruitment may reduce lung parenchymal injury from positive pressure ventilation in ARDS. We demonstrate that in this case PEEP alone was not adequate to recruit the injured lung and that a high-pressure recruitment maneuver was required. After recruitment, high-level PEEP was needed to prevent derecruitment and this level of PEEP was not adequately predicted by the P(Flex) of the PV curve.
- Published
- 2000
30. Lung T Cells in HIV Infection. Driven to Exhaustion?
- Author
-
Benjamin D. Medoff and Josalyn L. Cho
- Subjects
CD4-Positive T-Lymphocytes ,Lung Diseases ,Pulmonary and Respiratory Medicine ,Lung ,business.industry ,Human immunodeficiency virus (HIV) ,virus diseases ,HIV Infections ,CD8-Positive T-Lymphocytes ,Critical Care and Intensive Care Medicine ,medicine.disease_cause ,medicine.anatomical_structure ,Immunology ,HIV-1 ,medicine ,Humans ,Original Article ,business - Abstract
Rationale: Lymphocytic alveolitis in HIV-1–infected individuals is associated with multiple pulmonary complications and a poor prognosis. Although lymphocytic alveolitis has been associated with viremia and an increased number of CD8+ T cells in the lung, its exact cause is unknown.
- Published
- 2015
31. Systemic oxygen extraction during incremental exercise in patients with severe chronic obstructive pulmonary disease
- Author
-
Deborah H. Markowitz, Leo C. Ginns, David M. Systrom, Benjamin D. Medoff, Paul P. Pappagianopoulos, and David A. Oelberg
- Subjects
Male ,medicine.medical_specialty ,Physiology ,Radionuclide ventriculography ,Physical exercise ,Incremental exercise ,Oxygen Consumption ,Physiology (medical) ,Internal medicine ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Lung Diseases, Obstructive ,Exercise physiology ,Exercise ,Aged ,COPD ,business.industry ,Lactate threshold ,Hemodynamics ,Public Health, Environmental and Occupational Health ,General Medicine ,Middle Aged ,medicine.disease ,Respiratory Function Tests ,Surgery ,Exercise Test ,Cardiology ,Arterial blood ,Acidosis, Lactic ,Female ,Blood Gas Analysis ,business ,Respiratory minute volume - Abstract
To determine if decreased systemic oxygen (O2) extraction contributes to the exercise limit in severe chronic obstructive pulmonary disease (COPD), 40 consecutive incremental cycle ergometer exercise tests performed by such patients, from which a "log-log" lactate threshold (LT) was identified, were compared to those of 8 patients with left ventricular failure (LVF) and 10 normal controls. Pulmonary gas exchange and minute ventilation were measured continuously and arterial blood gas tensions, pH, and lactate concentrations were sampled each minute. Cardiac output (Qc) was measured by first-pass radionuclide ventriculography. The systemic O2 extraction ratio (O2ER) was calculated as arterial - mixed venous O2 content difference (CaO2 - CvO2)/CaO2. Peak exercise O2 uptake (VO2peak) was markedly reduced in both COPD and LVF [41 (3) and 42 (3)% predicted, respectively], compared to controls [89 (2)% predicted, P0.0001 for each]. Similarly, the LT occurred at a low percentage of predicted maximal oxygen consumption in both COPD and LVF [25 (2) and 27 (3)%] compared to normals [46 (3)%, P0.0001 for each]. The systemic O2ER at peak exercise was severely reduced in COPD [0.36 (0.02)] compared to the other groups [P0.0001 for each], for whom it was nearly identical [0.58 (0.03) vs 0.63 (0.04), LVF vs control, P0.05]. In the COPD group, an early LT correlated with reduced systemic O2ER at peak exercise (r = 0.64, P0.0001), but not with any index of systemic O2 delivery. These data suggest that lactic acidemia during exercise in patients with severe COPD is better related to abnormal systemic O2 extraction than to its delivery and contributes to the exercise limit.
- Published
- 1998
32. The Role of CARMA1 in T Cells
- Author
-
Benjamin D. Medoff, Ravisankar A. Ramadas, and Marly I. Roche
- Subjects
Guanylate kinase ,T cell ,ZAP70 ,T-Lymphocytes ,Immunology ,T-cell receptor ,Receptors, Antigen, T-Cell ,Guanylate cyclase 2C ,Membrane-associated guanylate kinase ,Biology ,Article ,Cell biology ,CARD Signaling Adaptor Proteins ,medicine.anatomical_structure ,Guanylate Cyclase ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Signal transduction ,Signal Transduction - Abstract
Caspase recruitment domain-containing membrane-associated guanylate kinase protein-1 (CARMA1), a member of the membrane associated guanylate kinase (MAGUK) family of kinases, is essential for T lymphocyte activation and proliferation via T-cell receptor (TCR) mediated NF-κB activation. Recent studies suggest a broader role for CARMA1 regulating other T-cell functions as well as a role in non-TCR-mediated signaling pathways important for lymphocyte development and functions. In addition, CARMA1 has been shown to be an important component in the pathogenesis of several human diseases. Thus, comprehensively defining its mechanisms of action and regulation could reveal novel therapeutic targets for T-cell-mediated diseases and lymphoproliferative disorders.
- Published
- 2013
33. Volumetric Optical Frequency Domain Imaging of Pulmonary Pathology With Precise Correlation to Histopathology
- Author
-
Guillermo J. Tearney, Matthew B. Applegate, Benjamin D. Medoff, Lida P. Hariri, Eugene J. Mark, Mari Mino-Kenudson, Melissa J. Suter, Andrew D. Luster, and Brett E. Bouma
- Subjects
Pulmonary and Respiratory Medicine ,Lung Diseases ,medicine.medical_specialty ,Pathology ,Lung Neoplasms ,Hamartoma ,Pulmonary Fibrosis ,Adenocarcinoma ,Critical Care and Intensive Care Medicine ,Bronchoscopy ,medicine ,Bronchial Biopsy ,Humans ,Pulmonary pathology ,Lung cancer ,Original Research ,Alveolar Wall ,Lamina propria ,Lung ,business.industry ,respiratory system ,medicine.disease ,Adenocarcinoma, Mucinous ,Carcinoma, Adenoid Cystic ,medicine.anatomical_structure ,Carcinoma, Squamous Cell ,Histopathology ,Radiology ,Cardiology and Cardiovascular Medicine ,business ,Tomography, Optical Coherence - Abstract
Background Lung cancer is the leading cause of cancer-related mortality. Radiology and bronchoscopy techniques do not have the necessary resolution to evaluate lung lesions on the microscopic scale, which is critical for diagnosis. Bronchial biopsy specimens can be limited by sampling error and small size. Optical frequency domain imaging (OFDI) provides volumetric views of tissue microstructure at near-histologic resolution and may be useful for evaluating pulmonary lesions to increase diagnostic accuracy. Bronchoscopic OFDI has been evaluated in vivo, but a lack of correlated histopathology has limited the ability to develop accurate image interpretation criteria. Methods We performed OFDI through two approaches (airway-centered and parenchymal imaging) in 22 ex vivo lung specimens, using tissue dye to precisely correlate imaging and histology. Results OFDI of normal airway allowed visualization of epithelium, lamina propria, cartilage, and alveolar attachments. Carcinomas exhibited architectural disarray, loss of normal airway and alveolar structure, and rapid light attenuation. Squamous cell carcinomas showed nested architecture. Atypical glandular formation was appreciated in adenocarcinomas, and uniform trabecular gland formation was seen in salivary gland carcinomas. Mucinous adenocarcinomas showed alveolar wall thickening with intraalveolar mucin. Interstitial fibrosis was visualized as signal-dense tissue, with an interstitial distribution in mild interstitial fibrotic disease and a diffuse subpleural pattern with cystic space formation in usual interstitial pneumonitis. Conclusions To our knowledge, this study is the first demonstration of volumetric OFDI with precise correlation to histopathology in lung pathology. We anticipate that OFDI may play a role in assessing airway and parenchymal pathology, providing fresh insights into the volumetric features of pulmonary disease.
- Published
- 2012
34. Variant alveolar lipoproteinosis: a syndrome with distinct clinical and pathological features
- Author
-
Michiya, Nishino, Benjamin D, Medoff, Eugene J, Mark, Osamu, Matsubara, Walter J, O'Donnell, Paul F, Currier, and Richard L, Kradin
- Subjects
Adult ,Immunosuppression Therapy ,Male ,Adolescent ,Middle Aged ,Pulmonary Alveolar Proteinosis ,Bronchoalveolar Lavage ,Young Adult ,Dyspnea ,Cough ,Macrophages, Alveolar ,Humans ,Female ,Bronchoalveolar Lavage Fluid ,Lung ,Retrospective Studies - Abstract
Pulmonary alveolar proteinosis (PAP) is a rare condition in which pulmonary macrophages fail to clear surfactant, resulting in the alveolar accumulation of lipoproteinaceous debris. The histopathology of PAP is typified by diffuse filling of terminal airways with eosinophilic, PAS/diastase (PAS/D)-positive acellular material. We present five patients who showed histopathological changes in the lungs consistent with mild PAP. However, these cases were notable for the abundance of degenerating alveolar macrophages, weak PAS staining of lipoproteinaceous material and paucity of lamellated bodies on ultrastructural examination. Only one patient showed the CT finding of mosaiform 'crazy-paving' and the opalescent bronchoalveolar lavage fluid characteristic of PAP. In one case, therapeutic lung lavage based on a presumptive diagnosis of PAP exacerbated respiratory distress. Three patients showed partial or near-complete resolution of disease in response to high-dose corticosteroid therapy, a treatment approach that is generally ineffective in PAP. We conclude that distinguishing 'variant alveolar lipoproteinosis' from classical PAP is clinically important. Despite the otherwise typical appearance of lipoproteinaceous alveolar material in lung biopsies, the presence of degenerating foamy macrophages and atypical histochemical, ultrastructural and radiographic features suggest a steroid-responsive form of proteinosis that is likely pathogenetically distinct and may not be amenable to whole-lung lavage.
- Published
- 2011
35. Adiponectin Lowers Glucose Production by Increasing SOGA
- Author
-
Rachael B, Cowherd, Rachael B, Cowerd, Melissa M, Asmar, J McKee, Alderman, Elizabeth A, Alderman, Alaina L, Garland, Walker H, Busby, Wanda M, Bodnar, Ivan, Rusyn, Benjamin D, Medoff, Roland, Tisch, Elizabeth, Mayer-Davis, James A, Swenberg, Steven H, Zeisel, and Terry P, Combs
- Subjects
Blood Glucose ,Autophagosome ,medicine.medical_treatment ,Autophagy-Related Proteins ,Mice, Obese ,AMP-Activated Protein Kinases ,Mice ,AMP-activated protein kinase ,Mice, Inbred NOD ,Insulin ,Cloning, Molecular ,Intracellular Signaling Peptides and Proteins ,Middle Aged ,medicine.anatomical_structure ,Liver ,Female ,Rabbits ,Adiponectin ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,Adult ,medicine.medical_specialty ,Molecular Sequence Data ,Mice, Transgenic ,Biology ,Pathology and Forensic Medicine ,Young Adult ,Commentaries ,Lysosome ,Internal medicine ,medicine ,Autophagy ,Hypoglycemic Agents ,Animals ,Humans ,Amino Acid Sequence ,Gluconeogenesis ,AMPK ,nutritional and metabolic diseases ,Peptide Fragments ,Mice, Inbred C57BL ,Insulin receptor ,Endocrinology ,Glucose ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,biology.protein ,Regular Articles - Abstract
Adiponectin is a hormone that lowers glucose production by increasing liver insulin sensitivity. Insulin blocks the generation of biochemical intermediates for glucose production by inhibiting autophagy. However, autophagy is stimulated by an essential mediator of adiponectin action, AMPK. This deadlock led to our hypothesis that adiponectin inhibits autophagy through a novel mediator. Mass spectrometry revealed a novel protein that we call suppressor of glucose by autophagy (SOGA) in adiponectin-treated hepatoma cells. Adiponectin increased SOGA in hepatocytes, and siRNA knockdown of SOGA blocked adiponectin inhibition of glucose production. Furthermore, knockdown of SOGA increased late autophagosome and lysosome staining and the secretion of valine, an amino acid that cannot be synthesized or metabolized by liver cells, suggesting that SOGA inhibits autophagy. SOGA decreased in response to AICAR, an activator of AMPK, and LY294002, an inhibitor of the insulin signaling intermediate, PI3K. AICAR reduction of SOGA was blocked by adiponectin; however, adiponectin did not increase SOGA during PI3K inhibition, suggesting that adiponectin increases SOGA through the insulin signaling pathway. SOGA contains an internal signal peptide that enables the secretion of a circulating fragment of SOGA, providing a surrogate marker for intracellular SOGA levels. Circulating SOGA increased in parallel with adiponectin and insulin activity in both humans and mice. These results suggest that adiponectin-mediated increases in SOGA contribute to the inhibition of glucose production.
- Published
- 2010
36. Case records of the Massachusetts General Hospital. Case 16-2010. A 48-year-old man with a cough and pain in the left shoulder
- Author
-
Benjamin D, Medoff, Gerald F, Abbott, and Abner, Louissaint
- Subjects
Diagnosis, Differential ,Male ,Radiography ,Scapula ,Histiocytosis, Langerhans-Cell ,Cough ,Smoking ,Humans ,Pain ,Smoking Cessation ,Bone Diseases ,Middle Aged ,Lung - Published
- 2010
37. Allergic asthma: a tale of many T cells
- Author
-
Benjamin D. Medoff, Roshi Afshar, and Andrew D. Luster
- Subjects
Allergy ,T cell ,Immunology ,Pathogenesis ,Mice ,immune system diseases ,T-Lymphocyte Subsets ,Immunopathology ,medicine ,Immunology and Allergy ,Animals ,Humans ,Asthma ,business.industry ,Respiratory disease ,Interleukin-17 ,Receptors, Antigen, T-Cell, gamma-delta ,T lymphocyte ,respiratory system ,Allergens ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Cytokines ,Interleukin 17 ,business - Abstract
Asthma is a common immune-mediated disorder characterized by reversible airway inflammation, mucus production, and variable airflow obstruction with airways hyperresponsiveness (AHR). In most cases the airway inflammation characteristic of asthma is thought to result from an allergic-type reaction to an inhaled substance from the environment (so-called allergic asthma). In allergic asthma, allergen exposure stimulates eosinophilic inflammation of the airways associated with infiltration of T cells. Although the recruitment of eosinophils into the airways is an important component in the pathogenesis of asthma, the trafficking of T lymphocytes into the airways is now believed to establish and orchestrate the asthmatic inflammatory response. This review explores the roles of various T cell subsets in the pathogenesis of allergic airway inflammation and highlights the contributions of these cells in regulating asthma.
- Published
- 2008
38. CARMA3 Mediates Lysophosphatidic Acid–Stimulated Cytokine Secretion by Bronchial Epithelial Cells
- Author
-
Benjamin D. Medoff, Merran C. Derby, Zhifang Cao, Joe C. Adams, Kelley A Wittbold, Ramnik J. Xavier, Aimee Landry, and Barry P. Sandall
- Subjects
Pulmonary and Respiratory Medicine ,Chemokine ,Thymic stromal lymphopoietin ,Clinical Biochemistry ,Stimulation ,Bronchi ,Respiratory Mucosa ,Allergic inflammation ,chemistry.chemical_compound ,Mice ,Thymic Stromal Lymphopoietin ,Lysophosphatidic acid ,Animals ,Humans ,Protein Isoforms ,Molecular Biology ,Caspase ,Cells, Cultured ,Chemokine CCL20 ,biology ,NF-kappa B ,Epithelial Cells ,Cell Biology ,Articles ,respiratory system ,Asthma ,Cell biology ,CCL20 ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,chemistry ,Immunology ,biology.protein ,Cytokines ,Cytokine secretion ,RNA Interference ,Lysophospholipids - Abstract
NF-kappaB activation in bronchial epithelial cells is important for the development of allergic airway inflammation, and may control the expression of critical mediators of allergic inflammation such as thymic stromal lymphopoietin (TSLP) and the chemokine CCL20. Members of the caspase recruitment domain (CARD) family of proteins are differentially expressed in tissue and help mediate NF-kappaB activity in response to numerous stimuli. Here we demonstrate that CARMA3 (CARD10) is specifically expressed in human airway epithelial cells, and that expression of CARMA3 in these cells leads to activation of NF-kappaB. CARMA3 has recently been shown to mediate NF-kappaB activation in embryonic fibroblasts after stimulation with lysophosphatidic acid (LPA), a bioactive lipid-mediator that is elevated in the lungs of individuals with asthma. Consistent with this, we demonstrate that stimulation of airway epithelial cells with LPA leads to increased expression of TSLP and CCL20. We then show that inhibition of CARMA3 activity in airway epithelial cells reduces LPA-mediated NF-kappaB activity and the production of TSLP and CCL20. In conclusion, these data demonstrate that LPA stimulates TSLP and CCL20 expression in bronchial epithelial cells via CARMA3-mediated NF-kappaB activation.
- Published
- 2008
39. Invasive and noninvasive ventilation in patients with asthma
- Author
-
Benjamin D, Medoff
- Subjects
Epinephrine ,Respiration ,Conscious Sedation ,Tidal Volume ,Humans ,Paralysis ,Hypoventilation ,Respiration, Artificial ,Asthma - Abstract
Despite recent advances in our ability to manage asthma, there continues to be a small but important incidence of patients who present with severe asthma exacerbations that require ventilatory support. Mechanical ventilation in these patients is difficult and can be associated with substantial morbidity. Unfortunately, there is little in the way of randomized controlled trials to guide our therapeutic decisions in these patients. The goal is to provide adequate gas exchange while minimizing hyperinflation and ventilator-induced lung injury and administering aggressive therapy to reduce airway inflammation and bronchoconstriction. Although there is controversy on exactly what is the optimal method for mechanical ventilation in asthma, most experts agree that a general approach based on controlled hypoventilation is ideal.
- Published
- 2008
40. T cell trafficking in allergic asthma: the ins and outs
- Author
-
Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster
- Subjects
Chemokine ,T cell ,T-Lymphocytes ,Immunology ,Immune system ,medicine ,Immunology and Allergy ,Eosinophilia ,Animals ,Humans ,Lung ,Asthma ,biology ,business.industry ,Chemotaxis ,Models, Immunological ,respiratory system ,medicine.disease ,Mucus ,respiratory tract diseases ,medicine.anatomical_structure ,biology.protein ,Lymph Nodes ,medicine.symptom ,Chemokines ,Airway ,business - Abstract
T cells are critical mediators of the allergic airway inflammation seen in asthma. Pathogenic allergen-specific T cells are generated in regional lymph nodes and are then recruited into the airway by chemoattractants produced by the asthmatic lung. These recruited effector T cells and their products then mediate the cardinal features of asthma: airway eosinophilia, mucus hypersecretion, and airway hyperreactivity. There has been considerable progress in delineating the molecular mechanisms that control T cell trafficking into peripheral tissue, including the asthmatic lung. In this review, we summarize these advances and formulate them into a working model that proposes that T cell trafficking into and out of the allergic lung is controlled by several discrete regulatory pathways that involve the collaboration of innate and acquired immune cells.
- Published
- 2008
41. Pathogenic T-cell recruitment into the airway in human disease
- Author
-
Leo C. Ginns, Seddon Y. Thomas, Andrew D. Luster, Benjamin D. Medoff, Aleena Banerji, Craig M. Lilly, John C. Wain, and Hui Zhang
- Subjects
Lung Diseases ,General Neuroscience ,T-Lymphocytes ,Bronchial Diseases ,Biology ,General Biochemistry, Genetics and Molecular Biology ,CCL5 ,CCL20 ,Chemokine receptor ,Chemotaxis, Leukocyte ,History and Philosophy of Science ,Immunology ,CCL17 ,CXCL10 ,Animals ,Humans ,CXC chemokine receptors ,CCL13 ,CC chemokine receptors - Abstract
Effector T cells significantly contribute to inflammatory diseases. These cells are recruited into tissue, where they orchestrate an inflammatory response that can either protect against infection or sometimes stimulate human disease. The recruitment of T cells into tissue from the blood and lymphoid compartments is an active process controlled by chemokines and the chemokine receptors expressed on distinct effector T-cell subsets. Thus, the chemokines secreted in the tissue will determine the specific types of T lymphocyte recruited into that tissue based on the chemokine receptors expressed on these cells. It follows that the chemokine receptor profile on T cells isolated from the lungs of patients with inflammatory pulmonary disease will define the subtype of pathogenic T lymphocytes mediating the disease process and will identify the mechanisms that recruit these cells into the lung. This article reviews data from both human and animal studies that define the chemokine receptors involved in the recruitment of T lymphocytes into the lung in various inflammatory pulmonary diseases, including asthma, obliterative bronchiolitis, sarcoidosis, and chronic eosinophilic pneumonia. We then speculate on the potential role of these chemokine receptors in the pathogenesis of these disorders and potential novel therapeutic approaches suggested by these data.
- Published
- 2006
42. The leukotriene B4 lipid chemoattractant receptor BLT1 defines antigen-primed T cells in humans
- Author
-
Terry K. Means, Andrew M. Tager, Christian Brander, Craig M. Lilly, Benjamin D. Medoff, Seddon Y. Thomas, Sabina A. Islam, Andrew D. Luster, and Christoph Hess
- Subjects
Receptors, CCR6 ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Receptors, CCR2 ,T-Lymphocytes ,Immunology ,Receptors, Leukotriene B4 ,Biology ,Protein Serine-Threonine Kinases ,Lymphocyte Activation ,Biochemistry ,Leukotriene B4 ,CCL5 ,Receptors, Interleukin-8A ,Interleukin 21 ,Interferon-gamma ,CCL17 ,Cytotoxic T cell ,Humans ,IL-2 receptor ,Antigen-presenting cell ,Cells, Cultured ,Chemokines, Cytokines, and Interleukins ,Inflammation ,Receptors, Purinergic P2 ,Cell Biology ,Hematology ,HLA-DR Antigens ,Natural killer T cell ,ADP-ribosyl Cyclase 1 ,Asthma ,Case-Control Studies ,Acute Disease ,Interleukin 12 ,Receptors, Chemokine ,Interleukin-4 ,Bronchoalveolar Lavage Fluid - Abstract
We have recently shown that the leukotriene B4 (LTB4)–BLT1 pathway is important in early effector T-cell recruitment in mouse models of inflammation. Here we characterize the phenotype and function of human peripheral blood BLT1+ T cells in health and illustrate their involvement in asthma and acute infection. In healthy individuals, BLT1+ T cells are a rare peripheral blood T-cell population enriched for the activation markers CD38 and HLA-DR. Compared with BLT1– T cells, a larger proportion of peripheral blood BLT1+ T cells express the effector cytokines IFNγ and IL-4 and inflammatory chemokine receptors, CCR1, CCR2, CCR6, and CXCR1. Consequently, in healthy individuals peripheral blood BLT1+ T cells are a rare antigen-primed T-cell subset with unique phenotypic, migratory, and functional properties. BLT1 expression on T cells is tightly regulated by inflammation and only transiently expressed after naive T-cell activation by dendritic cells. Although rare in the peripheral blood of healthy individuals, BLT1+ T cells are markedly increased in frequency in the peripheral blood in response to acute Epstein-Barr virus (EBV) infection and moderately increased in the airways of asymptomatic allergic asthmatics. Our studies provide novel insights into the LTB4-BLT1 lipid chemoattractant pathway in human T-cell responses, and how it may link innate and adaptive immunity.
- Published
- 2005
43. Case records of the Massachusetts General Hospital. Case 17-2005. A 22-year-old woman with back and leg pain and respiratory failure
- Author
-
Benjamin D, Medoff, Jo-Anne O, Shepard, R Neal, Smith, and Alexander, Kratz
- Subjects
Adult ,Leg ,Respiratory Distress Syndrome ,Exchange Transfusion, Whole Blood ,Pain ,Nausea ,Anemia, Sickle Cell ,Radiography ,Fatal Outcome ,Back Pain ,Bone Marrow ,Infarction ,Humans ,Female ,Pulmonary Embolism ,Bone Marrow Diseases ,Lung - Published
- 2005
44. Pulmonary mechanics and graphics during positive pressure ventilation
- Author
-
Benjamin D. Medoff, Dean R. Hess, and Michael B. Fessler
- Subjects
medicine.medical_specialty ,Pulmonary mechanics ,business.industry ,Airway Resistance ,Respiratory physiology ,Pulmonary compliance ,Positive-Pressure Respiration, Intrinsic ,Positive-Pressure Respiration ,Anesthesiology and Pain Medicine ,Airway resistance ,Esophagus ,Internal medicine ,medicine ,Cardiology ,Respiratory Mechanics ,Humans ,business ,Positive pressure ventilation ,Pulmonary Ventilation ,Lung Compliance - Published
- 1999
45. Breathing reserve at the lactate threshold to differentiate a pulmonary mechanical from cardiovascular limit to exercise
- Author
-
David A. Oelberg, David J. Kanarek, David M. Systrom, and Benjamin D. Medoff
- Subjects
Pulmonary and Respiratory Medicine ,Lung Diseases ,Male ,medicine.medical_specialty ,Cardiac output ,Heart Diseases ,Radionuclide ventriculography ,Critical Care and Intensive Care Medicine ,Maximal Voluntary Ventilation ,Predictive Value of Tests ,Ventriculography, First-Pass ,Internal medicine ,Medicine ,Humans ,Exercise physiology ,Cardiac Output ,Exercise ,business.industry ,Lactate threshold ,VO2 max ,Middle Aged ,Physical therapy ,Breathing ,Cardiology ,Exercise Test ,Lactates ,Respiratory Mechanics ,Female ,Cardiology and Cardiovascular Medicine ,business ,Respiratory minute volume - Abstract
Criteria used to define the respective roles of pulmonary mechanics and cardiovascular disease in limiting exercise performance are usually obtained at peak exercise, but are dependent on maximal patient effort. To differentiate heart from lung disease during a less effort-dependent domain of exercise, the predictive value of the breathing reserve index (BRI=minute ventilation [VE]/maximal voluntary ventilation [MVV]) at the lactate threshold (LT) was evaluated.Thirty-two patients with COPD and a pulmonary mechanical limit (PML) to exercise defined by classic criteria at maximum oxygen uptake (VO2max) were compared with 29 patients with a cardiovascular limit (CVL) and 12 normal control subjects. Expired gases and VE were measured breath by breath using a commercially available metabolic cart (Model 2001; MedGraphics Corp; St. Paul, Minn). Arterial blood gases, pH, and lactate were sampled each minute during exercise, and cardiac output (Q) was measured by first-pass radionuclide ventriculography (System 77; Baird Corp; Bedford, Mass) at rest and peak exercise.For all patients, the BRI at lactate threshold (BRILT) correlated with the BRI at VO2max (BRIMAX) (r=0.85, p0.0001). The BRILT was higher for PML (0.73+/-0.03, mean+/-SEM) vs CVL (0.27+/-0.02, p0.0001), and vs control subjects (0.24+/-0.03, p0.0001). A BRILTor = 0.42 predicted a PML at maximum exercise, with a sensitivity of 96.9%, a specificity of 95.1%, a positive predictive value of 93.9%, and a negative predictive value of 97.5%.The BRILT, a variable measured during the submaximal realm of exercise, can distinguish a PML from CVL.
- Published
- 1998
46. Sildenafil Can Increase the Response to Inhaled Nitric Oxide
- Author
-
William E. Hurford, Benjamin D. Medoff, Kevin C. Dennehy, Dean R. Hess, and Luca M. Bigatello
- Subjects
medicine.medical_specialty ,Phosphodiesterase Inhibitors ,Sildenafil ,Hypertension, Pulmonary ,Nitric Oxide ,Heart Septal Defects, Atrial ,Piperazines ,Sildenafil Citrate ,Nitric oxide ,chemistry.chemical_compound ,3',5'-Cyclic-GMP Phosphodiesterases ,Internal medicine ,Administration, Inhalation ,medicine ,Humans ,Sulfones ,Hypoxia ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,biology ,Inhalation ,Phosphoric Diester Hydrolases ,Pulmonary Gas Exchange ,business.industry ,Drug Synergism ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Anesthesiology and Pain Medicine ,Endocrinology ,chemistry ,Purines ,Enzyme inhibitor ,cGMP-specific phosphodiesterase type 5 ,biology.protein ,Female ,Congenital disease ,business - Published
- 2000
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.