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.
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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)