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    5522 results match your criteria American Journal of Respiratory Cell and Molecular Biology[Journal]

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    Genetic Ablation of p16(Ink4a) Does Not Protect Against Cellular Senescence in Mouse Models of COPD/Emphysema.
    Am J Respir Cell Mol Biol 2018 Feb 15. Epub 2018 Feb 15.
    University of Rochester Medical Center, Environmental Medicine,, Rochester, New York, United States ;
    Cigarette smoke (CS) affects DNA damage and cellular senescence signaling pathways in the pathogenesis of chronic obstructive pulmonary disease (COPD). p16(INK4a) (p16: a cyclin-dependent kinase inhibitor) is a key marker of cellular senescence, which is induced by CS in lung cells. It is thought that removal of p16 attenuates premature aging by removing senesced cells. Read More

    E-cadherin Loss Accelerates Tumor Progression and Metastasis in a Mouse Model of Lung Adenocarcinoma.
    Am J Respir Cell Mol Biol 2018 Feb 15. Epub 2018 Feb 15.
    Children's Hospital, Stem Cell Program, Boston, Massachusetts, United States ;
    Metastatic disease is the primary cause of death of lung cancer patients, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Read More

    Involvement of Alveolar Epithelial Cell Necroptosis in IPF Pathogenesis.
    Am J Respir Cell Mol Biol 2018 Feb 14. Epub 2018 Feb 14.
    Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea (the Republic of).
    Rationale: Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. Read More

    Intermittent Exposure to Cigarette Smoke Increases Lung Tumors and the Severity of Emphysema More Than Continuous Exposure.
    Am J Respir Cell Mol Biol 2018 Feb 14. Epub 2018 Feb 14.
    Keio University, School of Medicine, Division of Pulmonary Medicine, Department of Medicine, Shinjuku-ku, Japan.
    Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in COPD patients. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Read More

    Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema.
    Am J Respir Cell Mol Biol 2018 Feb 8. Epub 2018 Feb 8.
    Cincinnati Children's Hospital Medical Center, Critical Care, Cincinnati, Ohio, United States ;
    Rationale: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. Read More

    Loss of CDKN2B Promotes Fibrosis via Increased Fibroblast Differentiation Rather Than Proliferation.
    Am J Respir Cell Mol Biol 2018 Feb 8. Epub 2018 Feb 8.
    University of Michigan, Pulmonary and Critical Care Medicine, Ann Arbor, Michigan, United States ;
    Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by excessive scarring and fibroblast activation. We previously showed that fibroblasts from patients with IPF are hypermethylated at the CDKN2B gene locus resulting in decreased CDKN2B expression. Here, we examine how diminished CDKN2B expression in normal and IPF fibroblasts affect fibroblast function and how loss of CDKN2B contributes to IPF pathogenesis. Read More

    The LAM Lung Cell and Its Human Cell Models.
    Am J Respir Cell Mol Biol 2018 Feb 6. Epub 2018 Feb 6.
    NIH, CPB, Bethesda, Maryland, United States ;
    Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, affecting lungs, kidneys, and lymphatics. It is caused by the proliferation of abnormal smooth muscle-like LAM cells, with mutations and loss of heterozygosity in the tuberous sclerosis complex (TSC) 1 or, more frequently, 2 genes. Isolated pulmonary LAM cells have been difficult to maintain in culture and most studies of LAM lung cells involve mixtures of TSC2 wild-type and TSC2-null cells. Read More

    Deficient Follistatin-like 3 Secretion by Asthmatic Airway Epithelium Impairs Fibroblast Regulation and Fibroblast-to-myofibroblast Transition.
    Am J Respir Cell Mol Biol 2018 Feb 2. Epub 2018 Feb 2.
    University of Washington, Pediatrics, Division of Pulmonary Medicine, Seattle, Washington, United States ;
    Rationale: Bronchial epithelial cells (BECs) from healthy children inhibit human lung fibroblast (HLF) expression of collagen and fibroblast-myofibroblast transition (FMT) while asthmatic BECs do so less effectively, suggesting diminished epithelial-derived regulatory factors contribute to airway remodeling. Preliminary data demonstrated secretion of the activin A-inhibitor FSTL3 by healthy BECs was greater than that by asthmatic BECs.

    Objectives: Determine the relative secretion of FSTL3 and activin A by asthmatic and healthy BECs and if FSTL3 inhibits FMT. Read More

    Hypoxia Up-regulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α Dependent Manner.
    Am J Respir Cell Mol Biol 2018 Feb 2. Epub 2018 Feb 2.
    Indiana University School of Medicine, Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indianapolis, Indiana, United States.
    17β-estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible remain unknown. We hypothesized the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague Dawley rats or ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. Read More

    TRPV4-stimulation Releases ATP via Pannexin Channels in Human Pulmonary Fibroblasts.
    Am J Respir Cell Mol Biol 2018 Feb 2. Epub 2018 Feb 2.
    McMaster University, Medicine, Hamilton, Ontario, Canada ;
    We previously described several ionic conductances in human pulmonary fibroblasts (HPFs), including one activated by two structurally distinct TRPV4-channel agonists: 4α-phorbol-12,13-didecanoate (4αPDD) and GSK1016790A. However, the TRPV4-activated current exhibited peculiar properties: it developed slowly over many minutes, exhibited reversal potentials that could vary by tens of millivolts even within a given cell, and was not easily reversed by subsequent addition of two distinct TRPV4-selective blockers (RN-1734 or HC-067047). In this study, we characterized that conductance more carefully. Read More

    Upregulation and Nuclear Location of MMP28 in Alveolar Epithelium of Idiopathic Pulmonary Fibrosis.
    Am J Respir Cell Mol Biol 2018 Jan 26. Epub 2018 Jan 26.
    Universidad Nacional Autónoma de México, Facultad de Ciencias, México City, Mexico ;
    Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive aging-associated disease of unknown etiology. Growing body of evidence indicates that aberrant activated alveolar epithelial cells induce the expansion and activation of the fibroblast population leading to the destruction of the lung architecture. Some Matrix Metalloproteinases (MMPs) are upregulated in IPF, indicating that they may be important in the pathogenesis and/or progression of IPF. Read More

    Pseudomonas aeruginosa Biofilms: Host Response and Clinical Implications in Lung Infections.
    Am J Respir Cell Mol Biol 2018 Jan 26. Epub 2018 Jan 26.
    Atlanta VA Medical Center, 19998, Decatur, Georgia, United States.
    Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multi-drug resistant infections, especially in immunocompromised and hospitalized patients. P. aeruginosa is an important cause of nosocomial and ventilator-associated pneumonia characterized by high prevalence and fatality rates. Read More

    Platelets Play a Central Role in Sensitization to Allergen.
    Am J Respir Cell Mol Biol 2018 Jan 24. Epub 2018 Jan 24.
    King's College London, Institute of Pharmaceutical Science, London, United Kingdom of Great Britain and Northern Ireland ;
    Background: Platelet activation occurs in patients with allergic inflammation, and platelets can be activated directly by allergen via an IgE-dependent process. Platelets activate antigen-presenting cells (APCs) such as CD11c+ dendritic cells (DCs) in vitro. Whilst CD11c+ DCs are requisite for allergen sensitization, the role of platelets in this process is unknown. Read More

    Microparticulate Caspase-1 Regulates Gasdermin-D and Pulmonary Vascular Endothelial Cell Injury.
    Am J Respir Cell Mol Biol 2018 Jan 24. Epub 2018 Jan 24.
    The Ohio State University, Internal Medicine, Columbus, Ohio, United States ;
    Rationale: Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Caspases 1, 4 and 5 are essential for completion of the apoptotic program known as pyroptosis that also involves pro-inflammatory cytokines.

    Objectives: Because GSDM-D mediates pyroptotic death and is essential for pore formation, we hypothesized that it may direct caspase-1 encapsulated microparticle (MP) release and mediate endothelial cell death. Read More

    Interferon-β Improves Sepsis-related Alveolar Macrophage Dysfunction and Post-septic ARDS-related Mortality.
    Am J Respir Cell Mol Biol 2018 Jan 24. Epub 2018 Jan 24.
    Graduate School of Medicine, The University of Tokyo, Anesthesiology, Bunko-ku, Tokyo, Japan ;
    Interferon-β (IFNβ) is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFNβ for post-septic ARDS to better understand its pathogenesis in mice. Post-septic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFNβ 1 day earlier. Read More

    Digital Image Analyses on Whole Lung Slides in Mouse Models of Acute Pneumonia.
    Am J Respir Cell Mol Biol 2018 Jan 23. Epub 2018 Jan 23.
    Freie Universität Berlin, Department of Veterinary Pathology, Berlin, Germany ;
    Descriptive histopathology of mouse models of pneumonia is essential in assessing the outcome of infections, molecular manipulations or therapies in the context of whole lungs. Quantitative comparisons between experimental groups, however, have been limited to laborious stereology or ill-defined scoring systems that depend on the subjectivity of a more or less experienced observer. Here, we introduce self-learning digital image analyses that allow to transform optical information from whole mouse lung sections into statistically testable data. Read More

    βarrestin-2-dependent Signaling Promotes CCR4-mediated Chemotaxis of Murine T Helper Type 2 Cells.
    Am J Respir Cell Mol Biol 2018 Jan 23. Epub 2018 Jan 23.
    Duke University Schools of Nursing and Medicine, Durham, North Carolina, United States ;
    Allergic asthma is a complex inflammatory disease that leads to significant healthcare costs and reduction in quality of life. Although many cell types are implicated in the pathogenesis of asthma, CD4+ T helper type 2 cells (Th2) are centrally involved. We previously reported that the asthma phenotype is virtually absent in ovalbumin-sensitized and -challenged mice that lack global expression of βarrestin-2 and that CD4+ T cells from these mice displayed significantly reduced C-C motif chemokine 22 (CCL22)-mediated chemotaxis. Read More

    Riboflavin Metabolism Variation Among Clinical Isolates of Streptococcus pneumoniae Results in Differential Activation of MAIT Cells.
    Am J Respir Cell Mol Biol 2018 Jan 22. Epub 2018 Jan 22.
    Oregon Health & Sciences University, Portland, Oregon, United States.
    Streptococcus pneumoniae is an important bacterial pathogen that causes a range of non-invasive and invasive diseases. The mechanisms underlying variability in the ability of S. pneumoniae to transition from nasopharyngeal colonization to disease-causing pathogen are not well-defined. Read More

    R-spondin 2 is Upregulated in Idiopathic Pulmonary Fibrosis and Affects Fibroblasts Behavior.
    Am J Respir Cell Mol Biol 2018 Jan 18. Epub 2018 Jan 18.
    Instituto Nacional de Enfermedades Respiratorias, Mexico DF, Mexico ;
    Idiopathic pulmonary fibrosis (IPF) is characterized by the expansion of the myofibroblasts population, excessive extracellular matrix accumulation, and destruction of the lung parenchyma. The R-spondins family (RSPO) comprises a group of proteins essential for development. From them, RSPO2 is expressed primarily in the lungs and its mutations cause severe defects in the respiratory tract. Read More

    Novel Mechanism for Nicotinamide Phosphoribosyltransferase Inhibition of TNF-α-Mediated Apoptosis in Human Lung Endothelial Cells.
    Am J Respir Cell Mol Biol 2018 Jan 16. Epub 2018 Jan 16.
    University of Arizona, Arizona Health Sciences Center, Tucson, Arizona, United States ;
    Nicotinamide phosphoribosyltransferase (NAMPT) exists as both intracellular (iNAMPT) and extracellular (eNAMPT) proteins. eNAMPT is secreted into the blood and functions as a cytokine/enzyme (cytozyme) that activates NFκB signaling via ligation of the TLR4 receptor, further serving as a biomarker for inflammatory lung disorders such as the acute respiratory distress syndrome (ARDS). In contrast, iNAMPT is involved in nicotinamide mononucleotide (NMN) synthesis and has been implicated in the regulation of cellular apoptosis, although the exact mechanisms for this regulation are poorly understood. Read More

    Bronchiolitis Obliterans and Pulmonary Fibrosis After Sulfur Mustard Inhalation in Rats.
    Am J Respir Cell Mol Biol 2018 Jan 9. Epub 2018 Jan 9.
    University of Colorado at Denver - Anschutz Medical Campus, 129263, Pediatric Pulmonary Medicine, Aurora, Colorado, United States ;
    Rationale: Inhalation of powerful chemical agents, such as sulfur mustard (SM), can have debilitating pulmonary consequences, such as bronchiolitis obliterans (BO) and parenchymal fibrosis (PF). The underlying pathogenesis of disorders after SM inhalation is not clearly understood, resulting in a paucity of effective therapies.

    Objective: To evaluate the role of pro-fibrotic pathways involving TGF-β and PDGF in the development of BO and PF after inhalation injury sustained by SM, using a rat model. Read More

    IL-17 Plays a Role in RSV-induced Lung Inflammation and Emphysema in Elastase and LPS-injured Mice.
    Am J Respir Cell Mol Biol 2018 Jan 9. Epub 2018 Jan 9.
    Lovelace Respiratory Research Institute, Pathophysiology, Albuquerque, New Mexico, United States ;
    Respiratory syncytial virus (RSV) is associated with enhanced progression of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. However, little is known about the role of IL-17 in RSV-induced lung injury. We first investigated the role of RSV infection in enhancing mucous cell hyperplasia and airspace enlargement in the lungs of mice injured with elastase and lipopolysaccharide (E/LPS). Read More

    Bacterial-derived Neutrophilic Inflammation Drives Lung Remodeling in a Mouse Model of COPD.
    Am J Respir Cell Mol Biol 2018 Jan 9. Epub 2018 Jan 9.
    Vanderbilt University School of Medicine, Internal Medicine/Pulmonary and Critical Care Medicine, Nashville, Tennessee, United States ;
    Loss of secretory immunoglobulin A (SIgA) is common in the small airways of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease pathogenesis. Using mice that lack SIgA in the airways due to genetic deficiency of polymeric immunoglobulin receptor (pIgR-/- mice), we investigated the role of neutrophils in driving the fibrotic small airway wall remodeling and emphysema that develops spontaneously in these mice. By flow cytometry, we found an increase in the percentage of neutrophils among CD45+ cells in the lungs, as well as an increase in total neutrophils, in pIgR-/- mice compared to wild-type (WT) controls. Read More

    NO-independent sGC Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease.
    Am J Respir Cell Mol Biol 2017 Dec 21. Epub 2017 Dec 21.
    University of Pittsburgh Medical Center, Division Chief, Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, Pennsylvania, United States ;
    Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small molecule activator of oxidized sGC; which unlike endogenous NO and the sGC stimulator BAY 41-8543; preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator BAY 54-6544, sGC stimulator BAY 41-8543, sildenafil, or placebo for 4-12 weeks in a transgenic mouse model of SCD (BERK-SCD) and their hemizygous littermate controls (BERK-Hemi). Read More

    Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung.
    Am J Respir Cell Mol Biol 2017 Dec 21. Epub 2017 Dec 21.
    Eastern Virginia Medical School, 6040, Physiological Sciences, Norfolk, Virginia, United States ;
    [Rationale] The complement system plays a critical role in immune responses against pathogens. However, its identity and regulation in the lung are not fully understood. [Objectives] This study aims to explore the role of tripartite motif protein 72 (TRIM72) in regulating complement receptor (CR) of the immunoglobulin superfamily (CRIg) in alveolar macrophage (AM) and innate immunity of the lung. Read More

    PDE8 is Expressed in Human Airway Smooth Muscle and Selectively Regulates cAMP Signaling by βAR-AC6.
    Am J Respir Cell Mol Biol 2017 Dec 20. Epub 2017 Dec 20.
    Chapman University School of Pharmacy, Biomedical and Pharmaceutical Sciences, Irvine, California, United States ;
    Two cAMP signaling compartments centering around adenylyl cyclase (AC) exist in human airway smooth muscle (HASM) cells, one containing ßAR-AC6 and another containing E prostanoid receptors (EPR)-AC2. We hypothesized that different phosphodiesterase (PDE) isozymes selectively regulate cAMP signaling in each compartment. According to RNA-seq data, 18 of 24 PDE genes were expressed in primary HASM cells derived from age- and gender-matched donors with and without asthma. Read More

    Identification of Drug Candidates to Suppress Cigarette Smoke-induced Inflammation via cMap Analyses.
    Am J Respir Cell Mol Biol 2017 Dec 19. Epub 2017 Dec 19.
    McMaster University, Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada ;
    Cigarette smoking is the main risk factor for COPD, and to date, existing pharmacologic interventions have been ineffective at controlling inflammatory processes associated with the disease. To address this issue, we used the Connectivity Map (cMap) database to identify drug candidates with the potential to attenuate cigarette smoke-induced inflammation. We queried cMap using three independent, in house cohorts of healthy non-smokers and smokers. Read More

    Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.
    Am J Respir Cell Mol Biol 2017 Dec 12. Epub 2017 Dec 12.
    National Institute of Health Carlos III (ISCIII), Research Institute for Rare Diseases (IIER), Molecular Genetics, Madrid, Spain ;
    SERPINA1 gene is highly polymorphic, with more than one hundred variants described in databases. The SERPINA1 encodes alpha-1 antitrypsin (AAT) protein, and the severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. We report seven new variants in Spanish patients with AAT deficiency. Read More

    PD-1/PD-L1 Pathway Mediates the Alleviation of Pulmonary Fibrosis by Human Mesenchymal Stem Cells in Humanized Mice.
    Am J Respir Cell Mol Biol 2017 Dec 8. Epub 2017 Dec 8.
    The University of Hong Kong, Paediatrics, Hong Kong, Hong Kong ;
    Rationale: Pulmonary fibrosis is a chronic progressive lung disease with few treatments. Human mesenchymal stem cells (MSC) have been shown to be beneficial to pulmonary fibrosis as they have the immunomodulatory capacity. However, there is no reliable model to test the therapeutic effect of human MSC in vivo. Read More

    EphA2 Modulation Associates with Protective Effect of Prone Position in Ventilator-induced Lung Injury.
    Am J Respir Cell Mol Biol 2017 Dec 7. Epub 2017 Dec 7.
    Yonsei University College of Medicine, Internal Medicine, Seoul, Korea, Republic of ;
    The erythropoietin-producing hepatoma receptor tyrosine kinase A2 (EphA2) and its ligand ephrinA1 play a pivotal role in inflammation and tissue injury by modulating the epithelial and endothelial barrier integrity. Therefore, EphA2 receptor may be a potential therapeutic target for modulating ventilator-induced lung injury (VILI). To support this hypothesis, here we analyzed EphA2/ephrinA1 signaling in the process of VILI and determined the role of EphA2/ephrinA1 signaling in the protective mechanism of prone positioning in a VILI model. Read More

    The Rho Kinase Isoforms ROCK1 and ROCK2 Each Contribute to the Development of Experimental Pulmonary Fibrosis.
    Am J Respir Cell Mol Biol 2017 Dec 6. Epub 2017 Dec 6.
    Massachusetts General Hospital, Division of Pulmonary and Critical Care Medicine, Charlestown, Massachusetts, United States ;
    Pulmonary fibrosis is thought to result from dysregulated wound repair after repetitive lung injury. Many cellular responses to injury involve rearrangements of the actin cytoskeleton mediated by the two isoforms of the Rho-associated coiled coil forming protein kinase, ROCK1 and ROCK2. Additionally, profibrotic mediators such as transforming growth factor-beta (TGF-β), thrombin and lysophosphatidic acid (LPA) act through receptors that activate ROCK. Read More

    Systemic Markers of Adaptive and Innate Immunity are Associated with COPD Severity and Spirometric Disease Progression.
    Am J Respir Cell Mol Biol 2017 Dec 5. Epub 2017 Dec 5.
    Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, Massachusetts, United States ;
    The progression of chronic obstructive pulmonary disease (COPD) is associated with marked alterations in circulating immune cell populations, but no studies have characterized alterations in these cell types across the full spectrum of lung function impairment in current and former smokers. In 6,299 subjects from the COPDGene and ECLIPSE studies, we related Coulter blood counts and proportions to cross-sectional FEV1 adjusting for current smoking status. We also related cell count measures to three-year change in FEV1 in ECLIPSE subjects. Read More

    Whole Blood Gene Expression in Pulmonary Non-tuberculous Mycobacterial Infection.
    Am J Respir Cell Mol Biol 2017 Dec 5. Epub 2017 Dec 5.
    National Heart and Lung Institute, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland.
    Rationale: The factors predisposing towards the development of pulmonary non-tuberculous mycobacterial disease (pNTM) and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM but data are limited and inconsistent.

    Objectives: To use gene expression profiling to examine the host response to pNTM. Read More

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