DOCSLIB.ORG

The Role and Importance of Club Cells (Clara Cells) in the Pathogenesis of Some Respiratory Diseases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role and Importance of Club Cells (Clara Cells) in the Pathogenesis of Some Respiratory Diseases THORACIC SURGERY DOI: 10.5114/kitp.2016.58961 The role and importance of club cells (Clara cells) in the pathogenesis of some respiratory diseases Wojciech Rokicki, Marek Rokicki, Jacek Wojtacha, Agata Dżeljijli Department of Thoracic Surgery, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Poland Kardiochirurgia i Torakochirurgia Polska 2016; 13 (1): 26-30 Abstract Streszczenie The report presents the cellular structure of the respiratory W pracy omówiono komórkową budowę układu oddechowego system as well as the history of club cells (Clara cells), their wraz z historią odkryć komórek oskrzelikowych zwanych komór- ultrastructure, and location in the airways and human organs. kami Clary. Przedstawiono ich rozmieszczenie w drogach odde- The authors discuss the biochemical structure of proteins se- chowych i narządach człowieka. W dalszej kolejności scharak- creted by these cells and their importance for the integrity teryzowano ultrastrukturę komórek Clary. Omówiono budowę and regeneration of the airway epithelium. Their role as pro- biochemiczną i znaczenie białek wydzielanych przez te komórki genitor cells for the airway epithelium and their involvement dla integralności i odnowy nabłonka dróg oddechowych. Podkre- in the bio transformation of toxic xenobiotics introduced into ślono ich rolę jako komórek progenitorowych dla nabłonka dróg the lungs during breathing is emphasized. oddechowych, a także udział w biotransformacji wprowadzanych This is followed by a discussion of the clinical aspects associat- do płuc z powietrzem oddechowym toksycznych ksenobiotyków. ed with club cells, demonstrating that tracking the serum con- W drugiej części pracy przedstawiono aspekty kliniczne związa- centration of club cell-secreted proteins is helpful in the diag- ne z komórkami Clary, wykazując, że śledzenie surowiczego stę- nosis of a number of lung tissue diseases. Finally, suggestions żenia białek przez nie wydzielanych jest pomocne w diagnostyce are provided regarding the possible use of proteins secreted szeregu schorzeń tkanki płucnej. Na koniec wysunięto sugestie by club cells in the treatment of serious respiratory conditions. o możliwym zastosowaniu białek wydzielanych przez komórki Key words: club cells, Clara cells, xenobiotic detoxification, pro- Clary w leczeniu poważnych schorzeń układu oddechowego. genitor cells. Słowa kluczowe: komórki maczugowate, komórki Clary, de- toksykacja ksenobiotyków, komórki progenitorowe. The respiratory system of mammals is comprised of • undifferentiated basal cells with high mitotic potential, two anatomical parts: the conducting zone that transports • small granule cells belonging to the group of APUD cells the air to the lungs and the respiratory zone responsible for which regulate the secretory function of goblet cells and gas exchange. The conducting zone includes the trachea, glands in the mucous membrane. bronchi (main, lobar, segmental), and bronchioles. In the respiratory bronchioles, forming the margin be- The respiratory zone is the lung parenchyma proper, tween the conducting and respiratory zones, the following which consists of the respiratory bronchioles, alveolar ducts, types of cells can be distinguished: and pulmonary alveoli. Respiratory bronchioles form the mar- • ciliated cells (the most common), gin between the conducting and respiratory zones. Biologi- • microvillar cells (few), cally, each of the three regions is constructed of different epi- • small granule cells (few), thelial cells which have various physiological functions. • bronchiolar cells known as club cells or Clara cells (CCs). The epithelium lining the primary airways includes In the pulmonary alveolar epithelium, the following cell the following types of cells: types can be distinguished: • ciliated cells with approximately 250 cilia on the apical • type I pneumocytes, surface, • type II pneumocytes, • goblet (or beaker) cells which produce and secrete mucus, • type III pneumocytes (rare), • brush cells with numerous microvilli on the surface, • numerous pulmonary macrophages [1]. Address for correspondence: Prof. Wojciech Rokicki, Department of Thoracic Surgery, 13 3-go Maja St., 41-800 Zabrze, Poland, phone: +48 508233466, e-mail: [email protected] 26 Kardiochirurgia i Torakochirurgia Polska 2016; 13 (1) THORACIC SURGERY Bronchiolar cells were first described in 1881 by Rudolph Human protein CC16 (mass: 15.8 kDa) secreted by CCs Albert von Kölliker, a Swiss physician, anatomist, and physi- is a homodimer without sugar residues; each unit is com- ologist, but his discovery was forgotten for decades. As late posed of 70 amino acid residues bound with covalent bonds. as in 1937, the Austrian anatomic pathologist, Max Clara Its structure includes a hydrophobic pocket for binding li- described a specific type of cells present in the bronchial pophobic ligands, such as e.g., biphenols. It is resistant to epithelium; the cells were initially called Clara cells, but are the action of proteases, low temperature, and pH changes. now known as club cells (CCs) or bronchiolar exocrine cells. It has also been demonstrated that, due to its relatively low Max Clara was an ardent Nazi supporter and joined molecular mass, the protein is catabolized in renal distal tu- NSDAP (Nationalsozialistische Deutsche Arbeitpartei) in 1935; bules [9]. In humans, the gene encoding CCSP has 3 short the results of his studies were based on the examination of exons and 2 introns (4.1 kb in length). Its genes are located lung samples acquired from prisoners murdered in concen- on chromosome 11q12.3-13.1 in the vicinity of other genes as- tration camps around Dresden. After the end of World War II sociated with inflammatory and immune processes [10, 11]. in 1945, he became a persona non grata in German scientific Apart from this protein, CCs also secrete many essential circles. In 1950, he left Germany for Turkey, where he became substances, including the KL-6 protein and a number of glyco- a professor at the University of Istanbul [2]. proteins, lipids, and proteins providing chemical and physical Club cells (CCs) are cubical in shape, and their surface protection for both pulmonary surfactant and small airways. facing the bronchiolar lumen is bulging; they do not have The protective role of protein CC16 has been demon- cilia or secrete mucus, which is why they are also known strated in experimental studies on mice. According to as bronchiolar cells or non-ciliated non-mucous secretory the observations, its deficiency is associated with increased cells of the bronchiolar epithelium [3]. Examination with susceptibility of lungs to viral infections and oxidative an electron microscope reveals the smooth and rough en- stress. Labeling the serum concentration of CC16 has been doplasmic reticulum located primarily in the apical part of employed to demonstrate CC damage in various acute and the cell. A large number of mitochondria is present, also chronic lung diseases [12]. located mostly in the apical part of the cell. The significant Additionally, it has been shown that the protein’s ex- number of these organelles attests to the high level of their pression is significantly enhanced by some transcription metabolic activity. Each cell also contains approximately factors stimulated by cytokines, particularly by interferon 6 dense membrane-coated granularities, approx. 0.3 µm gamma. In turn, in neoplastic cells of the respiratory and in size, located primarily near the basement membrane. urinary system, protein CC16 functions as an antagonist of Chemically, the granularities are proteins, glycoproteins, the CC10/UG phenotype, creating two forms outside and and lipids. The Golgi apparatus is well developed. The cen- inside the cellular regulator encompassing both inflamma- trally located cell nucleus forms approx. 30% of the cell; it is tion and neoplastic transformation [9]. very wrinkled and contains many nucleoli. The apical part of A study in 2014 demonstrated that, in preterm infants, the cytoplasm contains small amounts of secretory granu- an increase in the serum concentration of protein KL-6 se- larities. Additionally, CCs contain substantial amounts of creted by CCs to more than 79 µg/ml is a good indicator of cytochrome P-450 working jointly with mixed-function oxi- advanced bronchopulmonary dysplasia, much more sensi- dases. CCs produce and secrete a number of substances in tive than the concentration of protein CC16 alone. The re- both an apocrine and a merocrine manner [3, 4]. The secre- sults prove that labeling the concentration of both these tory activity of CCs is stimulated by adrenergic fibers [5]. proteins concurrently results in a clear increase in their pre- In physiological conditions, CCs constitute approxi- dictive value in diagnosing dysplasia [13]. mately 9% of the total population of airway epithelial cells Furthermore, it has been observed that the proinflam- in human lungs; in terms of distribution, they are practi- matory cytokine TNF-α very clearly induces the production cally absent in the mucous membrane of the proximal seg- and secretion of proteins by CCs, thus significantly modu- ments of the bronchial tree (the trachea and the primary, lating the inflammatory response in the airways [14]. lobar, and segmental bronchi). Approximately 11-22% of Despite constantly conducted large-scale studies in- CCs are located in the terminal bronchioles. In physiologi- volving both physiological and pathological conditions, cal conditions, they constitute
Load more

Recommended publications
  • Lung Organoids and Their Use to Study Cell-Cell Interaction
    Curr Pathobiol Rep (2017) 5:223–231 DOI 10.1007/s40139-017-0137-7 ORGANOID CULTURES (M HUCH, SECTION EDITOR) Lung Organoids and Their Use To Study Cell-Cell Interaction Marko Z. Nikolić1 & Emma L. Rawlins1 Published online: 24 April 2017 # The Author(s) 2017. This article is an open access publication Abstract types which self-organise through cell sorting and spatially Purpose of Review The lung research field has pioneered the restricted lineage commitment in a manner reminiscent of use of organoids for the study of cell-cell interactions. the native organ with some degree of organ functionality [1, Recent Findings The use of organoids for airway basal cells is 2]. Organoids have also been referred to as “mini-organs” and routine. However, the development of organoids for the other enable in vitro modelling of organ development, disease regions of the lung is still in its infancy. Such cultures usually modelling and drug screening. The 3D culture preserves na- rely on cell-cell interactions between the stem cells and a tive DNA integrity and prevents the cells from being trans- putative niche cell for their growth and differentiation. formed [13]. Organoids were first successfully derived from Summary The use of co-culture organoid systems has facili- mouse small intestine using single Lgr5+ stem cells [3]. These tated the in vitro cultivation of previously inaccessible stem organoids were entirely epithelial illustrating that organoids cell populations, providing a novel method for dissecting the can be built without a non-epithelial cellular niche. The molecular requirements of these cell-cell interactions. Future organoid was structured as crypt-villus units, with a similar technology development will allow the growth of epithelial- stem cell hierarchy to in vivo, showing epithelial cell interac- only organoids in more defined media and also the introduc- tions are sufficient for the creation of crypt-villus units.
    [Show full text]
  • Systematic Review of Drug Effects in Humans and Models with Surfactant-Processing Disease
    REVIEW DRUG EFFECTS Systematic review of drug effects in humans and models with surfactant-processing disease Dymph Klay1, Thijs W. Hoffman1, Ankie M. Harmsze2, Jan C. Grutters1,3 and Coline H.M. van Moorsel1,3 Affiliations: 1Interstitial Lung Disease Center of Excellence, Dept of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands. 2Dept of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands. 3Division of Heart and Lung, University Medical Center Utrecht, Utrecht, The Netherlands. Correspondence: Coline H.M. van Moorsel, Interstitial Lung Disease Center of Excellence, St Antonius Hospital, Koekoekslaan 1, Nieuwegein, 3435CM, The Netherlands. E-mail: [email protected] @ERSpublications Drug effects in disease models of surfactant-processing disease are highly dependent on mutation http://ow.ly/ZYZH30k3RkK Cite this article as: Klay D, Hoffman TW, Harmsze AM, et al. Systematic review of drug effects in humans and models with surfactant-processing disease. Eur Respir Rev 2018; 27: 170135 [https://doi.org/10.1183/ 16000617.0135-2017]. ABSTRACT Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky–Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations. We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation.
    [Show full text]
  • University of Groningen Developmental and Pathological Roles of BMP/Follistatin-Like 1 in the Lung Tania, Navessa
    University of Groningen Developmental and pathological roles of BMP/follistatin-like 1 in the lung Tania, Navessa IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Tania, N. (2017). Developmental and pathological roles of BMP/follistatin-like 1 in the lung. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 CHAPTER 7 1 Variant club cell differentiation is driven by bone morphogenetic protein 4 in adult human airway epithelium: Implications for goblet cell metaplasia and basal cell hyperplasia in COPD Navessa P.
    [Show full text]
  • University of Groningen Lung Epithelial Cell Differentiation in Human and Mouse Song, Juan
    University of Groningen Lung epithelial cell differentiation in human and mouse Song, Juan IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Song, J. (2016). Lung epithelial cell differentiation in human and mouse: Environment, epigenetics and epigenetic editing. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 Chapter 2 Smoking during pregnancy inhibits ciliated cell differentiation and up regulates secretory cell related genes in neonatal offspring Junjun Cao 1,2,3 , Juan Song 1,2 , Marjan Reinders-Luinge 1,2 , Wierd Kooistra 1,2 , Kim van der Sloot 1,2 , Xia Huo 3, Wim Timens 1,2 , Susanne Krauss-Etschmann 4 and Machteld N.
    [Show full text]
  • Differentiation of Club Cells to Alveolar Epithelial Cells in Vitro
    Differentiation of Club Cells to Alveolar Epithelial Cells In Vitro The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Zheng, Dahai; Soh, Boon-Seng; Yin, Lu; Hu, Guangan; Chen, Qingfeng; Choi, Hyungwon; Han, Jongyoon; Chow, Vincent T. K. and Chen, Jianzhu. “Differentiation of Club Cells to Alveolar Epithelial Cells In Vitro.” Scientific Reports 7 (January 2017): 41661 © 2017 The Author(s) As Published http://dx.doi.org/10.1038/srep41661 Publisher Nature Publishing Group Version Final published version Citable link http://hdl.handle.net/1721.1/110075 Terms of Use Creative Commons Attribution 4.0 International License Detailed Terms http://creativecommons.org/licenses/by/4.0/ www.nature.com/scientificreports OPEN Differentiation of Club Cells to Alveolar Epithelial Cells In Vitro Dahai Zheng1,2, Boon-Seng Soh2,3, Lu Yin4, Guangan Hu5, Qingfeng Chen2, Hyungwon Choi6, Jongyoon Han4,7, Vincent T. K. Chow8 & Jianzhu Chen1,5 Received: 18 November 2016 Club cells are known to function as regional progenitor cells to repair the bronchiolar epithelium in Accepted: 21 December 2016 response to lung damage. By lineage tracing in mice, we have shown recently that club cells also give Published: 27 January 2017 rise to alveolar type 2 cells (AT2s) and alveolar type 1 cells (AT1s) during the repair of the damaged alveolar epithelium. Here, we show that when highly purified, anatomically and phenotypically confirmed club cells are seeded in 3-dimensional culture either in bulk or individually, they proliferate and differentiate into both AT2- and AT1-like cells and form alveolar-like structures.
    [Show full text]
  • Club Cells, CC10 and Self-Control at the Epithelial Surface
    EDITORIAL | EXPERIMENTAL STUDIES Club cells, CC10 and self-control at the epithelial surface Pieter S. Hiemstra1 and Arnaud Bourdin2 Affiliations: 1Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. 2Dept of Respiratory Diseases, Hoˆpital Arnaud de Villeneuve, Montpellier, France. Correspondence: Arnaud Bourdin, CHRU, Respiratory Dept, Hoˆpital Arnaud de Villeneuve, Montpellier, 34295, France. E-mail: [email protected] @ERSpublications CC10, at physiological concentrations, may contribute to the maintenance of homeostasis in the peripheral airways http://ow.ly/yQHBy There has been a recent marked increase in our insight into mechanisms that control inflammation, unwanted immune responses and tissue injury. This is illustrated by the wealth of literature on the role of regulatory T- and B-cells in lung disease, but also by studies on anti-inflammatory cytokines such as interleukin (IL)-10, and products of microbial metabolism such as short-chain fatty acids. The airway epithelium also shows clear signs of self-control, and studies on the club cell 10-kDa protein (CC10; also known as e.g. club cell secretory protein or secretoglobin family 1A member 1 (SCGB1A1)) have identified it as one of the mediators involved [1]. CC10 is a main product of club cells, which are especially abundant in the peripheral airways where they contribute to maintenance of airway integrity and repair [2]. The consequences of injury to the small airways are clear from the involvement of small airway dysfunction in an increasing number of lung diseases. Moreover, a defect in the relative abundance of CC10-expressing cells in the peripheral airways of patients with asthma, chronic obstructive pulmonary disease (COPD) and post- transplant obliterative bronchiolitis was reported [3–5].
    [Show full text]
  • Inhibition of Gabrp Reduces the Differentiation of Airway Epithelial Progenitor Cells Into Goblet Cells
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 720, 2021 Inhibition of Gabrp reduces the differentiation of airway epithelial progenitor cells into goblet cells AN WANG1*, QIUYANG ZHANG2*, YONGMEI WANG3*, XUE LI2, KUAN LI2, YU LI2, JIANHAI WANG2, LI LI4 and HUAIYONG CHEN1,2,5 1Department of Basic Medicine, Haihe Clinical College of Tianjin Medical University; 2Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases; Departments of 3Pathology and 4Respiratory Medicine, Tianjin University Haihe Hospital; 5Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin 300350, P.R. China Received September 4, 2020; Accepted March 12, 2021 DOI: 10.3892/etm.2021.10152 Abstract. Bronchial asthma is an intractable pulmonary in the organoid‑forming ability of mouse Club cells in the disease that affects millions of individuals worldwide, with the presence of Gabrp antagonist bicuculline methiodide (BMI). overproduction of mucus contributing to high morbidity and Furthermore, the RT‑qPCR results indicated that the mRNA mortality. Gamma‑aminobutyric acid (GABA) is associated levels of chloride channel accessory 3, pseudogene (Clca3p), with goblet cell hyperplasia in the lungs of primate models and mucin (Muc)5Ac and Muc5B were significantly decreased in Club cells serve as airway epithelial progenitor cells that may BMI organoid cultures. These results suggested that blocking differentiate into goblet and ciliated cells. In the present study, GABA signaling through Gabrp inhibits mouse Club cell it was investigated whether the GABAA receptor pi (Gabrp) proliferation, as well as differentiation into goblet cells. is essential for Club cell proliferation and differentiation in Therefore, targeting GABA/Gabrp signaling may represent mice.
    [Show full text]
  • I Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair. by Alicia Marie
    Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair. by Alicia Marie Farin Department of Cell Biology Duke University Date:_______________________ Approved: ___________________________ Barry Stripp, Supervisor ___________________________ Brigid Hogan, Co-Chair ___________________________ Terry Lechler, Co-Chair ___________________________ David Kirsch ___________________________ Mark Onaitis Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell Biology in the Graduate School of Duke University 2016 i v ABSTRACT Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair. by Alicia Marie Farin Department of Cell Biology Duke University Date:_______________________ Approved: ___________________________ Barry Stripp, Supervisor ___________________________ Brigid Hogan, Co-Chair ___________________________ Terry Lechler, Co-Chair ___________________________ David Kirsch ___________________________ Mark Onaitis An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell Biology in the Graduate School of Duke University 2016 Copyright by Alicia Marie Farin 2016 Abstract The lungs are vital organs whose airways are lined with a continuous layer of epithelial cells. Epithelial cells in the distal most part of the lung, the alveolar space, are specialized to facilitate gas exchange. Proximal to the alveoli is the airway epithelium,
    [Show full text]
  • Club Cell-Specific Role of Programmed Cell Death 5 in Pulmonary Fibrosis
    ARTICLE https://doi.org/10.1038/s41467-021-23277-8 OPEN Club cell-specific role of programmed cell death 5 in pulmonary fibrosis Soo-Yeon Park1,7, Jung Yeon Hong2,7, Soo Yeon Lee1, Seung-Hyun Lee 1, Mi Jeong Kim1, Soo Yeon Kim2, Kyung Won Kim 2, Hyo Sup Shim 3, Moo Suk Park 4, Chun Geun Lee 5,6, Jack A. Elias 5, ✉ ✉ Myung Hyun Sohn 2 & Ho-Geun Yoon 1 Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary 1234567890():,; function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β- induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF. 1 Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea. 2 Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea. 3 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. 4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
    [Show full text]
  • Download File
    Genetic regulation of pulmonary progenitor cell differentiation Maria R. Stupnikov Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Maria R. Stupnikov All rights reserved ABSTRACT Genetic regulation of pulmonary progenitor cell differentiation Maria R. Stupnikov The respiratory system represents a major interface between the body and the external environment. Its design includes a tree-like network of conducting tubules (airways) that carries air to millions of alveoli, where gas exchange occurs. The conducting airways are characterized by their great diversity in epithelial cell types with multiple populations of secretory, multiciliated, and neuroendocrine cells. How these different cell types arise and how these populations are balanced are questions still not well understood. Aberrant patterns of airway epithelial differentiation have been described in various human pulmonary diseases, chronic bronchitis, asthma, neuroendocrine hyperplasia of infancy, and others. The goal of this thesis is to investigate mechanisms of regulation of airway epithelial cell fate in the developing lung epithelium. More specifically, these studies focus on Notch signaling and address a long unresolved issue whether the different Notch ligands (Jagged and Delta) have distinct roles in the epithelial differentiation program of the extrapulmonary and intrapulmonary airways. Moreover, these studies investigate the ontogeny of the bHLH transcription factor Ascl1 and identify its targets in the developing airways as potential regulators of neuroepithelial body (NEB) size and maturation. My studies provide evidence that the Notch ligand families Jag and Dll are required for the specification and formation of different cell lineages in the developing airway epithelia.
    [Show full text]
  • An Obligatory Role for Club Cells in Preventing Obliterative Bronchiolitis in Lung Transplants
    An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants Zhiyi Liu, … , Steven L. Brody, Andrew E. Gelman JCI Insight. 2019. https://doi.org/10.1172/jci.insight.124732. Research In-Press Preview Immunology Transplantation Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions and poorly regenerate club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex-vivo analysis reveals a specific role for alloantigen-primed effector CD8+ T cells in preventing club cell proliferation and maintenance. Taken together, we demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a new model to identify the underlying mechanisms of OB. Find the latest version: https://jci.me/124732/pdf An Obligatory Role for Club Cells in Preventing Obliterative Bronchiolitis in Lung Transplants Zhiyi Liu1,5, Fuyi Liao1, Davide Scozzi1, Yuka Furuya3, Kaitlyn N.
    [Show full text]
  • Surfactant Protein D, Club Cell Protein 16, Pulmonary and Activation
    Lock-Johansson et al. Respiratory Research 2014, 15:147 http://respiratory-research.com/content/15/1/147 REVIEW Open Access Surfactant protein D, Club cell protein 16, Pulmonary and activation-regulated chemokine, C-reactive protein, and Fibrinogen biomarker variation in chronic obstructive lung disease Sofie Lock-Johansson1, Jørgen Vestbo2,3 and Grith Lykke Sorensen1* Abstract Chronic obstructive pulmonary disease (COPD) is a multifaceted condition that cannot be fully described by the severity of airway obstruction. The limitations of spirometry and clinical history have prompted researchers to investigate a multitude of surrogate biomarkers of disease for the assessment of patients, prediction of risk, and guidance of treatment. The aim of this review is to provide a comprehensive summary of observations for a selection of recently investigated pulmonary inflammatory biomarkers (Surfactant protein D (SP-D), Club cell protein 16 (CC-16), and Pulmonary and activation-regulated chemokine (PARC/CCL-18)) and systemic inflammatory biomarkers (C-reactive protein (CRP) and fibrinogen) with COPD. The relevance of these biomarkers for COPD is discussed in terms of their biological plausibility, their independent association to disease and hard clinical outcomes, their modification by interventions, and whether changes in clinical outcomes are reflected by changes in the biomarker. Keywords: COPD, Biomarker, SP-D, CC-16, PARC/CCL-18, CRP, Fibrinogen Introduction with regards to sensitivity, accuracy, precision and re- Chronic obstructive pulmonary disease (COPD) is a com- producibility [5]. Surfactant protein D (SP-D), club cell mon disease worldwide [1] and is forecasted to be the 3rd protein 16 (CC-16, previously named Clara cell pro- leading cause of death globally in 2030 [2].
    [Show full text]