Repair and remodeling of airway epithelium after injury in chronic obstructive pulmonary disease

Current Pulmonology Reports, Jun 2013

Chronic obstructive pulmonary disease (COPD) is thought to develop as a result of chronic exposure to cigarette smoke, occupational or other environmental hazards, and it comprises both airways and parenchyma. Acute infections or chronic colonization of airways with bacteria may also contribute to development and/or progression of COPD lung disease. Airway epithelium is the primary target for the inhaled environmental factors and pathogens. The repetitive injury as a result of chronic exposure to environmental factors may result in persistent activation of pathways involved in airway epithelial repair, such as epithelial to mesenchymal transition, altered migration and proliferation of progenitor cells, and abnormal redifferentiation leading to airway remodeling. Development of model systems that mimic chronic airways disease as observed in COPD is required to understand the molecular mechanisms underlying the abnormal airway epithelial repair that are specific to COPD, and to also develop novel therapies focused on airway epithelial repair.

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Repair and remodeling of airway epithelium after injury in chronic obstructive pulmonary disease

Shyamala Ganesan Uma S. Sajjan 0 ) Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 W. Medical Center Dr. , Ann Arbor, MI 48109-5688, USA Chronic obstructive pulmonary disease (COPD) is thought to develop as a result of chronic exposure to cigarette smoke, occupational or other environmental hazards, and it comprises both airways and parenchyma. Acute infections or chronic colonization of airways with bacteria may also contribute to development and/or progression of COPD lung disease. Airway epithelium is the primary target for the inhaled environmental factors and pathogens. The repetitive injury as a result of chronic exposure to environmental factors may result in persistent activation of pathways involved in airway epithelial repair, such as epithelial to mesenchymal transition, altered migration and proliferation of progenitor cells, and abnormal redifferentiation leading to airway remodeling. Development of model systems that mimic chronic airways disease as observed in COPD is required to understand the molecular mechanisms underlying the abnormal airway epithelial repair that are specific to COPD, and to also develop novel therapies focused on airway epithelial repair. - Chronic obstructive pulmonary disease (COPD) is a multifactorial disease and is primarily characterized by airflow limitation that is progressive and often not reversible. Structural and functional changes in both airway and alveolar epithelium contribute to airflow limitation. Cigarette smoke, one of the major risk factors for development of COPD, induces structural and functional changes in airway epithelium in vitro and in vivo [1 , 2 , 3, 4 , 5]. Airway epithelium that lines the respiratory tract protects the lungs from external environmental insults, and therefore alteration in structure and function can have a profound impact on host defense against invading pathogens and particulates, and also repair process following an injury. Mounting evidence in recent years has suggested that airway epithelium is indeed both a site of disease initiation and a driver of disease progression [6, 7]. This is due to the understanding of various mechanisms by which epithelium maintains homeostasis after injury and how repeated injury leads to disproportionate activation of repair signals promoting airway disease. Epithelium lining the trachea and bronchi (proximal airways) is pseudostratified and is made up of three major cell types: ciliated cells, non-ciliated secretory cells, and basal cells. As the bronchi branches into bronchioles and to terminal bronchioles, the epithelium gradually changes from pseudostratified to simple cuboidal epithelium, and the number of ciliated, goblet, and basal cells gradually decline and non-ciliated cells called Clara cells becomes the major cell type [8]. In the proximal airway and cartilaginous bronchioles, the invagination of epithelium forms submucosal glands, which are characterized by a variable proportion of ciliated cells, goblet cells, and serous cells. Other minor cell types that are present in conducting airways are: 1.) chemosensory or brush cells that contain apical tufts of microvilli and are thought to play a role in regulation of both airway surface fluid secretion and breathing [9, 10]; and 2.) pulmonary neuroendocrine cells, which are typically tall and pyramidal in shape and extend from the basal lamina of the epithelium and possess microvilli [11, 12]. Ciliated cells and secretory cells are the major cell types that contribute to mucociliary clearance function of airway epithelium. Mucociliary clearance depends on the cilia and composition of the airway surface liquid (ASL) lining the airway surface. ASL is made up of two layers, an upper viscoelastic layer of mucins secreted by the goblet cells and submucosal glands, and a lower periciliary layer containing large membrane-bound glyocproteins, as well as tethered mucins (muc-1, muc-4 and muc-16) [13, 14]. The periciliary layer is relatively less viscous, and acts as a lubricating layer for cilia to beat. Hydration of ASL is regulated by the coordinated activity of Chloride secretion (Cl-) and Sodium (Na+) absorption channels. The combination of Clsecretion and reduced reabsorption of Na+ favors normal ASL hydration and efficient mucociliary clearance. In normal airways, the coordinated functioning of ATP-activated cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated Cl- channel (CaCC), outwardly rectifying Cl- channel (ORCC), Cl- channel 2 (CLC2), and epithelial Na+ channel (ENaC) regulate ASL hydration [15]. CFTR negatively regulates ENac, and therefore absent or dsyfunctional CFTR increases ENaC activity leading to hyperabsorption of Na+, an increased driving force for fluid reabsorption resulting in reduced ASL depth and impaired mucociliary clearance, as observed in the chronic airway disease, cystic fibrosis [15]. In addition, aquaporins that regulate transcellular water tr (...truncated)


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Shyamala Ganesan, Uma S. Sajjan. Repair and remodeling of airway epithelium after injury in chronic obstructive pulmonary disease, Current Pulmonology Reports, 2013, pp. 145-154, Volume 2, Issue 3, DOI: 10.1007/s13665-013-0052-2