Cystic fibrosis (CF) is a common genetic disease for which the gene was identified within the last decade. Pulmonary disease predominates in this ultimately fatal disease and current therapy only slows the progression. CF transmembrane regulator (CFTR), the gene product, is an integral membrane glycoprotein that normally functions as a chloride channel in epithelial cells. The most common mutation, deltaF508, results in mislocalization and altered glycosylation of CFTR. Altered fucosylation and sialylation are hallmarks of both membrane and secreted glycoproteins in CF and the focus here is on these investigations. Oligosaccharides from CF membrane glycoproteins have the Lewis x, selectin ligand in terminal positions. In addition, two major bacterial pathogens in CF, Pseudomonas aeruginosa and Haemophilus influenzae, have binding proteins, which recognize fucose in alpha1,3 linkage and asialoglycoconjugates. We speculate that the altered terminal glycosylation of airway epithelial glycoproteins in CF contributes to the chronic infection and robust inflammatory response in the CF lung. Understanding the effects of mutant CFTR on glycosylation may provide further insight into the regulation of glycoconjugate processing as well as therapy for CF.
Peptides with potent broad-spectrum antibiotic activity have been identified in many animal species. Recent investigations have demonstrated that epithelial cells are a site of antibiotic peptide expression, suggesting that these peptides contribute to host defense at mucosal surfaces. Expression of tracheal antimicrobial peptide (TAP), a member of the -defensin family of peptides, is inducible in cultured tracheal epithelial cells (TEC) upon challenge with bacterial lipopolysaccharide (LPS) (G. Diamond, J. P. Russell, and C. L. Bevins, Proc. Natl. Acad. Sci. USA, in press). In this study, an anchored reverse transcriptase PCR strategy was used to determine if TAP was the sole -defensin isoform expressed upon stimulation of the cells with LPS. In addition to TAP, a second class of cDNA clones which encoded lingual antimicrobial peptide (LAP), a -defensin peptide recently isolated from a different mucosal site, the bovine tongue, was identified (B. S. Schonwetter, E. D. Stolzenberg, and M. Zasloff, Science 267:1645-1648, 1995). Northern (RNA) blot analysis demonstrated in vivo expression of LAP mRNA in tracheal mucosa. Levels of LAP mRNA were higher in cultured TEC challenged with either LPS or tumor necrosis factor alpha than in control cells. Thus, a response of TEC exposed to inflammatory mediators is induction of antibiotic-encoding genes, including both TAP and LAP. This work complements the in vivo studies of Schonwetter et al. (cited above), which showed elevated levels of LAP mRNA in squamous epithelial cells of the tongue near sites of tissue injury and inflammation, by suggesting possible mediators of the in vivo observation. Together these lines of investigations support the hypothesis that inducible expression of endogenous antibiotic peptides by inflammatory mediators characterizes local defense of mammalian mucosal surfaces.
FFM, fat-free mass SF, skinfold TBW, total body water FQ, food quotient RQ, respiratory quotient 2H 2 0 , deuterium oxide rC0 2 , mean daily CO 2 production Abbreviations CF, cystic fibrosis REE, resting energy expenditure TEE, total energy expenditure FVC, forced vital capacity FEV.. forced expiratory volume in 1 s FEF 25-75' forced expiratory flow between 0.25 and 0.75 s 2H, deuterium 180,oxygen-18 BW, body weight ABSTRACT. Increased energy expenditure, poor dietary intake, and fat malabsorption in patients with cystic fibrosis (CF) frequently lead to growth failure and malnutrition, which are associated with pulmonary failure and decreased survival. The study purpose was to understand better the energy expenditure and requirements in the mild pulmonary disease state in children. Resting and total energy expenditure were measured in 6-to 9-yr-old, pancreaticinsufficient children with CF (n =25) and control children (n = 25) of similar age, gender, and weight. The effect of the most common genotype, homozygousaF508, on energy expenditure was also investigated. Dietary intake, degree of fat malabsorption, body composition, physical activity, and clinical status were determined. The CF group had a 9% increase in resting energy expenditure, which was not related to genotype or severity of lung disease. Both CF genotype subgroups (aF508 homozygous and all others) had a similar, modest resting energy expenditure increase. Total energy expenditure was increased by 12% in the entire CF group and by 23% in the aF508 homozygous CF subgroup compared with controls. The total energy expenditure increase in aF508 homozygous children may be related to increased voluntary physical activity, reflecting no activity reduction associated with lung disease, or to an unidentified genotype-related mechanism. The clinical implication is that a detailed physical activity assessment should be evaluated along with resting energy expenditure, either measured or estimated by equations, when daily energy needs are being determined for children with CF. (Pediatr Res 35: 451-460, 1994) CF, a common lethal genetic disorder with an autosomal recessive pattern of inheritance, is caused by mutations in the CF transmembrane conductance regulator gene (1-3). Generalized exocrine gland dysfunction results in abnormalities in several organ systems (4). In addition to the excessive losses of sodium chloride in sweat, abnormal mucus in the lungs contributes to the development of chronic obstruction, infection, and inflammation. Exocrine pancreatic insufficiency occurs in more than 85% of patients with CF, and, despite enzyme replacement therapy, malabsorption of fat and micronutrients may occur. According to a 1990 CF Foundation report, about 50% of patients cared for in the 114 organized CF centers had growth failure, with weight and/or height less than the 10th percentile for age and gender (5). CF-related growth failure is often attributed to chronic lung disease, although this causal relationship is not established.Malnutrition may be caused b...
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