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Cilia and Mucociliary Clearance Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Cilia and Mucociliary Clearance Ximena M. Bustamante-Marin and Lawrence E. Ostrowski Marsico Lung Institute, Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599 Correspondence: [email protected] Mucociliary clearance (MCC) is the primary innate defense mechanism of the lung. The functional components are the protective mucous layer, the airway surface liquid layer, and the cilia on the surface of ciliated cells. The cilia are specialized organelles that beat in metachronal waves to propel pathogens and inhaled particles trapped in the mucous layer out of the airways. In health this clearance mechanism is effective, but in patients with primary cilia dyskinesia (PCD) the cilia are abnormal, resulting in deficient MCC and chronic lung disease. This demonstrates the critical importance of the cilia for human health. In this review, we summarize the current knowledge of the components of the MCC apparatus, focusing on the role of cilia in MCC. he extensive epithelial surface of the respira- clearance (Wanner et al. 1996; Knowles and Ttory tract between the nose and the alveoli is Boucher 2002). The coordinated interaction of exposed daily to viral and bacterial pathogens, these components on the surface of the respira- particulates, and gaseous material with poten- tory tract results in MCC. tially harmful effects. In response to these chal- Proper ciliary function is absolutely re- lenges, humans have developed a series of de- quired for effective MCC. Cilia are specialized fense mechanisms to protect the airways from organelles that provide the force necessary to these insults, thereby maintaining the lungs in a transport foreign materials in the respiratory nearly sterile condition (Dickson and Huffnagle tract toward the mouth where they can be 2015). Lung defense involves cough, anatomical swallowed or expectorated. To accomplish this barriers, aerodynamic changes, and immune crucial function, the cilia beat in coordinated mechanisms; however, the primary defense metachronal waves at a beat frequency that has mechanism is mucociliary clearance (MCC). multiple physiological regulators. Much of what Healthy airway surfaces are lined by ciliated ep- we know about cilia structure and function has ithelial cells and covered with an airway surface been derived from studies performed using layer (ASL), which has two components, a mu- Chlamydomonas as a model, while the impor- cus layer that entraps inhaled particles and for- tance of cilia in maintaining airway clearance eign pathogens, and a low viscosity periciliary was revealed by clinical and pathological studies layer (PCL) that lubricates airway surfaces and of genetic and acquired forms of chronic airway facilitates ciliary beating for efficient mucus diseases, including primary ciliary dyskinesia Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028241 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028241 1 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press X.M. Bustamante-Marin and L.E. Ostrowski (PCD), cystic fibrosis (CF), asthma, and chronic is no increase in airway number. The alveoli obstructive pulmonary disease (COPD). In this increase in number after birth to reach the adult review, we summarize the current knowledge of range of 300 million by 2 years of age and the the components of MCC, with an emphasis on surface area of 75 to 100 m2 by adulthood the role of cilia in normal mucociliary trans- (Deutsch and Pinar 2002). port. We then briefly describe the health effects The result is a complex arrangement of or- of impaired MCC caused by genetic defects in gans and tissues that form the respiratory sys- cilia in patients with PCD. tem, which is divided into two parts. The upper airway or upper respiratory tract includes the nose and nasal passages, paranasal sinuses, the ORIGIN AND ORGANIZATION OF THE oral cavity, the pharynx, and the portion of RESPIRATORY TRACT the larynx above the vocal cords. The nose and In humans, the formation of the respiratory nasal cavity are the main external openings of system starts around the fourth week of gesta- the respiratory system. The oral cavity (mouth) tion. In the head, the nasal placodes develop acts as an alternative entry to the air, but it from the ectoderm at each side of the fronto- cannot filter the air of unwanted contaminants nasal prominence. They then become more as the nose does. Although the upper respirato- concave forming the nasal pit. The mesenchyme ry tract represents the entryway to the conduct- proliferates around the placode establishing the ing zone of the respiratory tract and plays an medial and lateral nasal prominences, while the important role in trapping and removing par- nasal pit becomes deeper, forming the nasal cav- ticulate matter, in this review we will focus on ities (Kim et al. 2004). The paranasal sinuses the lower respiratory tract. develop during late fetal life and in infancy as The lower airways, or lower respiratory tract, diverticula of the lateral nasal walls. The sinuses include the continuation of the conducting extend into the maxilla and reach their mature zone formed by the portion of the larynx below size in the early 20s. In the neck, the laryngo- the vocal cords, trachea, and within the lungs, tracheal groove emerges from the primitive pha- the bronchi, bronchioles, and the respiratory ryngeal floor. The endoderm lining the laryng- zone formed by respiratory bronchioles, alveo- otracheal groove forms the epithelium and lar ducts, and alveoli (Fig. 1A). On the surface of glands of the larynx, trachea, bronchi, and pul- each alveolus, the oxygen from the atmosphere monary lining epithelium (Panski 1982; Edgar required for cellular respiration is exchanged for et al. 2013). The primordial lung originates as a the carbon dioxide in the blood, which is re- protrusion from the laryngotracheal groove of leased into the atmosphere. the ventral foregut endoderm, which then pro- liferates, forming two lung buds surrounded by CELL TYPES IN THE LOWER RESPIRATORY the mesoderm in the primitive thoracic mesen- TRACT chyme. Each lung bud develops into left and right lungs, respectively, by undergoing branch- Studies in mice during branching morphogen- ing morphogenesis. This process is directed by esis of the lung showed that the terminal buds signals between the epithelial endoderm and the contain a population of multipotent epithelial surrounding mesoderm. Bronchial cartilage, progenitors characterized by high levels of smooth muscle, and other connective tissues Nmyc, Sox9, and cyclin D1 proteins (Okubo are derived from the mesenchyme. As the lung et al. 2005). These multipotent cells will give progresses through its phases of development, it rise to the major cell types of the conducting undergoes a complex series of epithelial–mes- airways, including basal stem cells (Rock et al. enchymal interactions regulated by homeobox 2009), neurosecretory cells (Kultschitsky or K- genes, transcription factors, hormones, and cells) (Becker and Silva 1981), ciliated cells, club growth factors (Chinoy 2003). During the post- cells, serous cells, goblet cells, intermediate cells, natal phase, lung growth is geometric, and there and brush cells (Reid and Jones 1980). The mu- 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028241 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Cilia and Mucociliary Clearance Lamina propia B Parasympathetic nerve ~ 12 mm lumen A diameter Capillary Secretory Cartilage cells plate Trachea Smooth Submucosal muscle gland Conducting zone C Bronchi Terminal bronchioles Bronchioles Respiratory bronchioles D Capillary Respiratory zone Alveoli Alveolar airspace Basal cell Ciliated cell Club cells Goblet cell Mucus cell Serous cell NE cell Alveolar cells Figure 1. Schematic representation of the airway epithelium. (A) The lower respiratory tract, functionally can be divided into conducting and respiratory zones. The adult human trachea has an internal diameter of 12 mm, cartilage plates, and smooth muscle. The trachea divides into right and left primary bronchi. A bronchus enters the lung at the hilum and then divides into bronchioles. After multiple bronchiolar branches (23 generations in humans), at the end of each respiratory bronchiole, the alveoli are found. (B) The trachea and most proximal airways are lined by a pseudostratified epithelium formed by ciliated and secretory cells. Basal cells are located in this region and they can generate secretory and ciliated cell lineages. (C) The small airways are lined by a simple cuboidal epithelium with fewer goblet cells, but are rich in club cells. (D) The alveoli are made of type I and type II alveolar cells. Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028241 3 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press X.M. Bustamante-Marin and L.E. Ostrowski cosa of the lower respiratory tract is a pseudo- mucosal glands contribute directly to mucocili- stratified columnar epithelium with numerous ary function. ciliated and goblet
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