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Jin-A Jung
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction, which causes most CF morbidity and mortality. This article reviews the pathophysiology of CF, recent animal models, and current treatment of CF.
Figures and Tables
Fig. 1
Model of cystic fibrosis airway host defense defects. (A) Cystic fibrosis (CF) airways exhibit 2 host defense defects at the genesis of the disease. On the left, loss of cystic fibrosis transmembrane conductance regulator (CFTR) channels that conduct chloride (Cl−) and bicarbonate (HCO3−) onto the airway surface causes the airway surface liquid pH to fall, and the acidic airway surface liquid inhibits the activity of antimicrobials. On the right, loss of CFTR channels in submucosal glands causes mucus to develop abnormal properties so that it does not break free after emerging and remains tethered to the gland ducts. (B) When bacteria enter noncystic fibrosis airways (top) they are killed by airway surface liquid antimicrobials, mucociliary transport sweeps them out of the lung, and other defenses including phagocytic cells eradicate them to maintain sterile lungs. In cystic fibrosis (bottom) antimicrobial activity and mucociliary transport are less effective than in noncystic fibrosis and other defenses may also be impaired. Eventually, the host defenses are overwhelmed, and bacteria proliferate, with inflammation, remodeling, immunity, and genetic changes in the bacteria influencing the species that will dominate. In addition, the resulting inflammation and airway remodeling may further enhance or impair host defense mechanisms. Airway insults will also affect host defenses. Adapted from Stoltz DA, et al. N Engl J Med 2015;372:351-62, with permission of the Massachusetts Medical Society.3
Fig. 2
Structural airway abnormalities in cystic fibrosis. Panel A shows 3-dimensional reconstructions from microcomputed tomography images of the laryngeal and upper tracheal region of non-cystic fibrosis (non-CF) and cystic fibrosis (CF) mice (6–8 weeks old). Cartilage ring structure (yellow) is disrupted, and the tracheal lumen (gray) is narrowed in cystic fibrosis mice. Panel B shows 3-dimensional reconstructions from optical coherence tomography (OCT) images of tracheal cartilage rings in noncystic fibrosis and cystic fibrosis newborn pigs. Individual cartilage rings are highlighted by different colors. Panel C shows 3-dimensional reconstructions from computed tomography images of ethmoid (red) and maxillary (green) sinuses in newborn noncystic fibrosis and cystic fibrosis pigs. Cystic fibrosis pigs have hypoplastic ethmoid sinuses. Panel D shows chest computed tomography (CT) image of a cystic fibrosis piglet on the day of birth and before airway infection, inflammation, and mucus obstruction. Air trapping (red arrows), a sign of airway obstruction, is already present. For comparison, Panel E shows air trapping on chest CT image from a 14-month-old human with cystic fibrosis. Murine tracheas were provided by Drs. Craig Hodges and Mitch Drumm (Case Western Reserve University) and analyzed by Ryan Adam (University of Iowa). OCT image acquisition and analysis were performed by Drs. Melissa Suter (Massachusetts General Hospital) and Eman Namati (University of Iowa). Sinus image analysis was performed by Dr. Eugene Chang and Tanner Wallen (University of Iowa). Adapted from Stoltz DA, et al. N Engl J Med 2015;372:351-62, with permission of the Massachusetts Medical Society.3
Fig. 3
Bacterial incidence in cystic fibrosis (from http://www.cff.org/). MRSA, methicillin-resistant Staphylococcus aureus.
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