Cystic Fibrosis: A Multiple Exocrinopathy Caused by Dysfunctions in a Multifunctional Transport Protein

Abstract

Cystic fibrosis (CF) is a lethal, autosomal recessive genetic disease caused by mutations in the CF gene that encodes a protein called CFTR (1,2). According to the latest available statistics from the CF Foundation (CFF Patient Registry Annual Data Report, August 1995), approximately 20,000 children and young adults in North America (excluding Canada) have been diagnosed with CF. This disease presents as a multiple exocrinopathy resulting in abnormalities in many exocrine tissues including the airways, lung, pancreas, liver, intestine, vas deferens, and sweat gland/duct (3,4). Mutations in the CFTR gene result in a plethora of clinical symptoms including thick, dehydrated airway mucus, chronic, recurrent, and tenacious lung infections with bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus, early-onset lung inflammation specific to infiltration by neutrophils, pancreatic insufficiency, bile duct obstruction, intestinal obstruction (meconium ileus), infertility in males, high sweat Cl, nasal polyp formation, and chronic sinusitis (3,4). The most common mutation is a deletion in a single phenylalanine residue at position 508 in the CFTR protein, the so-called DF508 mutation. This mutation accounts for more than 50% of the mutations isolated from CF patients worldwide; however, over 700 separate mutations in the CFTR gene have been identified as of late May 1997 by the CF Genetic Analysis Consortium. Mortality in CF patients is related to pulmonary disease (1– 4). The respiratory epithelium is covered by a periciliary fluid layer or airway surface liquid (ASL) that is produced in combination by columnar epithelial ion and water transport, secretion of mucin glycoproteins by goblet cells, and secretions from the submucosal glands (5). The composition, volume, and depth of this fluid layer are critical for the normal beating of the cilia that cover the apical surface of the airway epithelium (5). Atop the ASL lies the layer of airway mucus that is also produced from the secretions of the cells listed above (5). Secretion and absorption of fluid and electrolytes across the respiratory epithelium play critical roles in controlling the amount of mucus hydration and the depth of the periciliary layer (5). For example, in the mammalian fetus, secretory mechanisms predominate and the airways are filled completely with fluid (6). Shortly before, during, and immediately following birth, the absorptive pathways are activated and the secretory mechanisms are down-regulated, leading to a massive absorption of the lung fluid appropriate for air breathing (6). In CF, where Cl secretion is defective and Na absorption hyperactivated, the secreted mucus is too viscous and sticky in the airway, and it clogs the airways with such tenacity that conducting airways become obstructed (1–5). Moreover, the depth and composition of the ASL is affected such that ciliary beat is compromised, the mucus layer invades the ASL, and the micro-environment may become more ideal for bacterial infection. Treatment of the disease continues to improve mainly because of pancreatic enzyme replacement, nutritional management, and more potent and selective antibiotics (7). The median age for survival continues to increase (up to 31 years); however, therapies that correct the basic cellular defects that underlie these clinical phenotypes remain elusive (7).