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PubMed2001

Mechanisms of insulin resistance in cystic fibrosis.

Cystic fibrosis (CF) is associated with a high incidence of diabetes. Studies evaluating causes of CF-related diabetes (CFRD) have consistently documented decreased insulin secretion. In patients with CFRD, insulin sensitivity has been documented to be decreased, but controversy exists in patients with normal or impaired glucose tolerance (IGT). We undertook this study 1) to reexplore insulin sensitivity in patients with IGT and 2) to evaluate potential mechanisms of insulin resistance in CF, including GLUT-4 translocation, elevation of serum cytokines, and free fatty acid (FFA) levels. We recruited nine CF subjects with impaired glucose tolerance (IGTCF) and nine age-, gender-, and body mass index-matched control volunteers. Each underwent a hyperinsulinemic euglycemic clamp (200 mU. m(-2). min(-1)) to measure insulin sensitivity. A muscle biopsy was obtained at maximal insulin stimulation for measure of GLUT-4 translocation with sucrose gradients. An oral glucose tolerance test and National Institutes of Health (NIH) clinical status scores were measured in all volunteers. We also measured tumor necrosis factor (TNF)-alpha levels and FFA in all subjects. Additionally, we report the results of TNF-alpha and FFA in 32 CF patients previously studied by our group. Results were that glucose disposal rate (GDR) was significantly lower in the CFIGT subjects than in controls, indicative of impaired insulin action. GLUT-4 translocation was impaired in CF and correlated with GDR. TNF-alpha levels were higher in all CF subjects than in controls and correlated with GDR. There was no difference in FFA between CF and control subjects. Modified NIH clinical status scores were inversely correlated with GDR and TNF-alpha levels. We conclude that IGTCF patients have decreased peripheral insulin sensitivity. Mechanisms include elevation of TNF-alpha and impaired translocation of GLUT-4.

Adult↗
PubMed2005

Altered O-glycosylation and sulfation of airway mucins associated with cystic fibrosis.

Cystic fibrosis (CF) is the most lethal genetic disorder in Caucasians and is characterized by the production of excessive amounts of viscous mucus secretions in the airways of patients, leading to airway obstruction, chronic bacterial infections, and respiratory failure. Previous studies indicate that CF-derived airway mucins are glycosylated and sulfated differently compared with mucins from nondiseased (ND) individuals. To address unresolved questions about mucin glycosylation and sulfation, we examined O-glycan structures in mucins purified from mucus secretions of two CF donors versus two ND donors. All mucins contained galactose (Gal), N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), fucose (Fuc), and sialic acid (Neu5Ac). However, CF mucins had higher sugar content and more O-glycans compared with ND mucins. Both ND and CF mucins contained GlcNAc-6-sulfate (GlcNAc-6-Sul), Gal-6-Sul, and Gal-3-Sul, but CF mucins had higher amounts of the 6-sulfated species. O-glycans were released from CF and ND mucins and derivatized with 2-aminobenzamide (2-AB), separated by ion exchange chromatography, and quantified by fluorescence. There was nearly a two-fold increase in sulfation and sialylation in CF compared with ND mucin. High performance liquid chromatography (HPLC) profiles of glycans showed differences between the two CF samples compared with the two ND samples. Glycan compositions were defined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Unexpectedly, 260 compositional types of O-glycans were identified, and CF mucins contained a higher proportion of sialylated and sulfated O-glycans compared with ND mucins. These profound structural differences in mucin glycosylation in CF patients may contribute to inflammatory responses and increased pathogenesis by Pseudomonas aeruginosa.

Acetylgalactosamine↗
PubMed1998

Lef1 transcription factor expression defines airway progenitor cell targets for in utero gene therapy of submucosal gland in cystic fibrosis.

Cystic fibrosis (CF) has emerged as a paradigm disorder for assessing the utility of gene therapy in the treatment of genetic diseases. It is hypothesized that submucosal glands may play an important role in the pathophysiology of CF lung disease. However, this region poses several significant obstacles for gene therapy due to its inaccessibility from the lumen of adult proximal airways. In utero gene therapy to correct submucosal gland dysfunction in CF provides an attractive alternative strategy to target gland progenitor cells prior to gland formation and morphogenesis. Such approaches will require the use of integrating vectors capable of transducing expanding stem-cell/progenitor-cell populations in the lung. We described a newborn-ferret model of the proximal airway which was used to evaluate the phenotypic characteristics of submucosal gland progenitors and to test gene therapy strategies for targeting these cell types. To this end, we have isolated the ferret cDNA to the lymphoid enhancing factor 1 (Lef1) and have demonstrated that its mRNA expression specifically defines a subset of surface airway epithelial progenitor cells involved in the formation of primordial submucosal gland buds and subsequent gland morphogenesis. Such findings suggest that the transcriptional switch regulating activation of Lef1 expression defines the phenotype of early submucosal gland progenitor cells. In an effort to prove the principle of gene targeting to this progenitor-cell population, we evaluated the efficiency of recombinant retroviral vectors to target submucosal glands in a xenograft model system. Findings from these studies demonstrated successful gene targeting to progenitor cells of submucosal gland buds which was stable throughout subsequent gland development. In summary, these studies have provided evidence for the existence of phenotypically distinct submucosal gland progenitor cells which represent appropriate targets for gene therapy of submucosal glands in CF.

Amino Acid Sequence↗
PubMed2006

IL-8 and IFN-gamma in tear fluid of patients with cystic fibrosis.

Cystic fibrosis (CF) is inherited as an autosomal recessive disorder. It is caused by mutations in the protein-coding gene of chromosome 7, resulting in chronic pulmonary disease and pancreatic insufficiency. The disease affects all secretory epithelia, including the eye. The pathogenesis of ocular changes in CF is still unknown, but the involvement of immunologic processes in patients with CF has been studied in recent years. We measured interleukin-8 (IL-8) and interferon-gamma (IFN-gamma) levels in tears in a group of patients and a group of normal controls to determine if the levels of these cytokines are elevated in CF. The levels of these cytokines in tears and the clinical severity of CF and eye disease were compared. Tear samples were collected from 24 patients with CF at the department of pediatric diseases, Medical University of Bialystok, Poland. Cytokine levels were determined by ELISA. Ophthalmic examinations, including tests for keratoconjunctivitis sicca (dry eye), were used to study the ocular surface. The tear levels of IL-8 and IFN-gamma in the CF patients were significantly higher than those in controls. The clinical severity of CF correlated significantly with the IL-8 and IFN-gamma levels. We found positive correlation between the tear levels of IFN-gamma and dry eye findings in CF patients. Our results suggest that the inflammatory cytokines IL-8 and IFN-gamma may play key roles in the regulation of ocular surface inflammation and the immunologic reaction in patients with CF. The tear levels of IL-8 and IFN-gamma may be candidate markers for evaluation of the clinical status of CF and eye disease. These findings help to provide a new insight into the pathogenesis of dry eye in patients with CF and provide potential targets for therapy.

Adolescent↗
PubMed1998

Lung transplantation for cystic fibrosis.

Cystic fibrosis (CF) is an inherited disease in which the fundamental physiological defect is failure of cAMP regulation of chloride transport. More than 90% of patients with CF will die of chronic, suppurative, obstructive lung disease, with the median survival in the United States currently being 29 years of age. Currently, although other therapies are being aggressively investigated, bilateral lung transplantation offers the only hope for short-term and mid-term survival in patients with CF and end-stage pulmonary disease. Since 1989, 103 bilateral sequential lung transplants (BLT) for CF have been performed at our institution (46 pediatric, 48 adult, 9 redo) at a mean age of 21+/-10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplantation, and in 15% of adults. The hospital mortality rate was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival rates are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1+/-1.6 years). Mean forced expiratory volume in 1 second increased from 25%+/-9% pretransplantation to 79%+/-35% 1 year posttransplantation. Acute rejection occurred 1.7 times per patient-year, with the majority of these episodes taking place the first 6 months posttransplantation. Need for treatment of lower respiratory infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population, and was associated with an early mortality of 33%. Eight living donor transplants (4 primary transplants, 4 redo transplants) were performed with an early survival of 87.5%. Patients with end-stage CF can undergo BLT with morbidity and mortality comparable with that observed in pulmonary transplantation for other disease entities.

Adolescent↗
PubMed1989

Prolactin, human nutrition and evolution, and the relation to cystic fibrosis.

Cystic fibrosis (CF) is a lethal, genetically transmitted disease of Caucasian populations. Its prevalence is highest (ca 1:2000 live births) among Western and Central Europeans and their descendants. Major clinical symptoms are chronic, obstructive, pulmonary disease, impaired intestinal digestion and absorption and elevated concentration of salt in sweat. The last is important, not only for diagnosis, but because it is an example of an electrolyte transport defect present in other epithelial tissues. Numerous other clinical manifestations are generally present. The history of prolactin (PRL), especially its role in osmoregulation, is outlined and related to the symptomatology and electrolyte defect of CF. Data are presented showing the relation of PRL to regulation of sweat electrolytes and its presence and probable synthesis in the coil of the human sweat gland. The basic biochemical defect of CF has not yet been elucidated, but recent research has shown that it is probably an abnormality of a regulatory factor. We propose that PRL is a likely candidate. The large variety of functions of PRL, in particular the regulation of the transport of sodium and chloride across epithelial membranes, and the regulation of mucus production, can be matched to the major disease symptomatology. Additionally, every other one of the multiple abnormalities of CF can be associated with described activities of PRL. In lower vertebrates epithelial tissues regulated by PRL are phylogenetic progenitors of affected tissues in CF. In the human, these tissues contain cells of the Diffuse Neuroendocrine System, or APUD cells, that show PRL-like immunoreactivity, or overt synthesis of the hormone. Thus, the regulatory activity of these tissues could be paracrine. The geographic distribution and the dietary habits of early Caucasians are examined. It appears that the Neolithic revolution, with the necessity of adapting to agriculturally produced foods, i.e. milk and wheat, could have brought about the genetic selection of post-translational variants of PRL. It is suggested that the combination of two or more of these mutations in the same individual may be responsible for CF. This is illustrated with proposed models of CF inheritance. We conclude by postulating that PRL acts at the level of the target cell by triggering (in conjunction with a steroid) the gene expression of unique proteins; these act as intermediaries of PRL activity; two or more abnormalities of these proteins when present in an individual produce CF; the protein abnormalities are the consequence of nutritional and ecological pressure.

Biological Evolution↗
PubMed1997

Dornase alfa. A review of pharmacoeconomic and quality-of-life aspects of its use in cystic fibrosis.

Cystic fibrosis (CF) is a fatal hereditary disease; patients with CF have an average lifespan of 30 years. By cleaving neutrophil-derived DNA, dornase alfa (recombinant human deoxyribonuclease I) decreases the adhesiveness and visco-elasticity of sputum in the infected lungs of patients with CF. As a result, respiratory function is improved in patients with all degrees of disease severity, and the relative risk of pulmonary exacerbations is reduced in patients with mild to moderate disease. Resource utilisation (days spent in hospital or receiving parenteral antibiotics) in patients with mild to moderate disease is also reduced by dornase alfa, as evidenced by a placebo-controlled trial in > 900 patients. Cost savings generated by these reductions in resource use during 24 weeks of dornase alfa therapy offset about 17 to 37.5% of the acquisition cost of the drug, depending on local cost data for various countries. Reductions in resource utilisation with dornase alfa have not been observed in patients with severe disease. Available cost-effectiveness and cost-utility analyses are not fully published. One analysis estimated that the incremental cost of avoiding one hospitalisation was about $Can 15,000 relative to standard therapy after 1 year of treatment. Informal analysis in the UK suggests a cost per quality-adjusted life-year of 25,000 Pounds for dornase alfa. Some quality-of-life (QOL) domains (mainly cough frequency and chest congestion) have shown modest improvement in patients treated with dornase alfa, mainly those with mild CF. Persuasive evidence of QOL benefit is lacking in those with more severe disease. Identifying patients most likely to benefit from dornase alfa therapy is essential to maximise clinical and cost benefits. The lack of a demonstrated reduction in resource utilisation in patients with severe CF makes its use more difficult to justify economically in this group than in those with less severe disease. However, in the absence of other treatments for this group, economic considerations must be weighed against clinical benefits. In conclusion, the acquisition cost of dornase alfa is partially offset by savings gained by reducing resource utilisation in patients with mild to moderate CF, and the drug appears to improve quality of life in some patients, mostly those with less severe disease. However, in the absence of guidance from definitive cost-effectiveness analyses, individual healthcare providers must make their own decisions about how best to provide dornase alfa to patients with CF in a rational and cost-justifiable manner.

Cystic Fibrosis↗
PubMed2004

Management of osteoporosis in adults with cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease that causes respiratory failure within the Caucasian population. The life span of patients with CF has gradually increased from a median of 2 years of age to >30 years. Concurrent with this increased lifespan, a variety of other nutritional, endocrine and bone issues have been recognised. Decreased absorption of fat-soluble vitamins (D and K in particular) because of pancreatic insufficiency, altered sex hormone production, chronic inflammation, a lack of physical activity, glucocorticoid treatment and an intrinsic hyper-resorptive bone physiology are some of the factors that contribute to the prominence of bone disease within the CF population. In some series, three-quarters of adult patients with CF have osteopenia or osteoporosis. Lung transplantation is one viable treatment for patients with end-stage CF, which requires a lifetime of antirejection medication. Immunosuppressant therapies have a detrimental effect on bone mineral density (BMD). To combat the multifactorial nature of CF-related bone disease, advances in nutritional and vitamin supplementation, and anti-resorptive and anabolic therapies have evolved. Chronic vitamin D depletion contributes to bone disease in the CF population. The isoform of vitamin D that is the best and safest supplement, with the lowest cost, has yet to be identified. However, it is clear that many patients with CF who receive the standard of care (i.e. two daily combination vitamin A, D, E and K tablets [ADEKs]) may still be vitamin D-deficient. More aggressive supplementation needs to be individualised, with close monitoring of serum 25-hydroxyvitamin D levels. Similarly, routine calcium supplementation may be important, and evidence is accumulating that vitamin K also plays an important role in maximising and maintaining BMD. Early recognition and treatment of delayed puberty in adolescents and hypogonadism in adults with hormone replacement therapy is recommended to maintain BMD in patients with CF. Bisphosphonates, including pamidronic acid, etidronic acid and alendronic acid, reduce bone resorption by inhibiting the recruitment and function of osteoclasts. Pamidronic acid is beneficial in improving BMD in CF patients before and after transplantation. Bisphosphonate therapy and minimisation of glucocorticoid dosage have been shown to be efficacious in glucocorticoid-induced osteoporosis. Teriparatide is the first US FDA-approved anabolic growth agent for bone, and has been shown to increase BMD and decrease fracture incidence in postmenopausal women. Teriparatide may offer a new avenue for treating bone disease in CF since many patients may have poor bone formation as well as accelerated bone breakdown. Numerous clinical trials are underway to optimise treatment of CF osteoporosis.

Adult↗
PubMed1982

[Myocardial fibrosis in cystic fibrosis. A new case report (author's transl)].

We report the case of a 9 month-old infant in whom acute heart failure was the presenting symptom of cystic fibrosis. Post-mortem examination showed lesions of myocardial fibrosis associated with typical lesions of cystic fibrosis in the pancreas. Hypoproteinemia and anemia were present and earlier could have suggested the correct diagnosis before the episode of acute heart failure. The analogy of the histologic myocardial changes in cystic fibrosis and in congenital lipomatosis of the pancreas suggests a common pathogeny related to the deficiency of the exocrine secretion of the pancreas.

Cardiomyopathies↗
PubMed1992

Chloride channels, Golgi pH and cystic fibrosis.

Cystic fibrosis (CF) is associated with a defect in a cAMP-activated chloride channel in secretory epithelia, which leads to decreased fluid secretion. In addition, many mucus glycoproteins show decreased sialylation but increased sulphation. We have recently shown that the pH of intracellular organelles is elevated in CF cells, due to defective chloride conductance in the vesicle membranes. We postulate that this may affect the activity of sialyl-, fucosyl- and sulphotransferases, and thus explain the abnormal glycosylation. Defects in sialylation of glycolipids might also generate receptors for Pseudomonas, which infects the respiratory tract of CF patients.

Journal Article↗
PubMed2003

Genetics of cystic fibrosis.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cyclic adenosine monophosphate (cAMP)-induced chloride channel and appears capable of regulating other ion channels. Mutations affect CFTR through a variety of molecular mechanisms, which can produce little or no functional gene product at the apical membrane. More than 1000 different disease-causing mutations within the CFTR gene have been described. The potential of a mutation to contribute to the phenotype depends on its type, localization in the gene, and the molecular mechanism as well as on interactions with secondary modifying factors. Genetic testing can confirm a clinical diagnosis of CF and can be used for infants with meconium ileus, for carrier detection in individuals with positive family history and partners of proven CF carriers, and for prenatal diagnostic testing if both parents are carriers. Studies of clinical phenotype in correlation with CFTR genotype have revealed a very complex relationship demonstrating that some phenotypic features are closely determined by the underlying mutations, whereas others are modulated by modifier genes, epigenetic mechanisms, and environment.

Journal Article↗
PubMed2003

The status of gene therapy for cystic fibrosis.

Cystic fibrosis (CF) has been a primary focus for gene therapy of lung diseases because the genetic cause is known and the airway epithelium is accessible for direct deoxyribonucleic acid (DNA) delivery. Soon after the mutated gene was identified in 1989, investigators demonstrated that transfer of a normal copy of the CF gene corrected ion transport abnormalities, thus validating the potential for use of gene therapy for this autosomal recessive disease. However, subsequent studies in a variety of in vitro and animal models, and more limited human studies, have revealed several obstacles to gene therapy for CF: (1) The incomplete understanding of CF lung disease pathogenesis, particularly the relative importance of ion transport and other cellular abnormalities (including glycoconjugate processing, pH regulation of intracellular organelles, and membrane trafficking), and of surface epithelial versus submucosal gland CF transmembrane regulator (CFTR) expression, generates uncertainty as to the necessary target cells for gene transfer and the optimum end point(s) for short-term human studies. (2) The airway epithelium has protective barriers against viral infection that impair gene transfer with several vectors, including recombinant viruses and DNA conjugates. Improvement in DNA transfer technology will be necessary for successful gene therapy. (3) Immune responses to recombinant viruses and inflammatory effects of bacterial DNA are only partially understood and appear to limit efficacy, particularly with repeated administration. Identification of these obstacles is prerequisite for progress, and recent studies with novel DNA delivery methods appear promising.

Journal Article↗
PubMed2004

Nutrition for patients with cystic fibrosis.

Cystic fibrosis (CF) is the most frequent, lethal genetic disorder among northern Europeans. The etiology of this autosomal recessive disease is known to be a defect in the cAMP activation of chloride (Cl-) channels in secretory cells in many organs of the body. Although this defect usually leads to severe lung disease, many of these patients also have nutritional deficiencies. Nutrition is one of the key components in the management of CF. Patients are at high risk for malnutrition, which may result in accelerated progression of the disease and increased morbidity. This review will discuss nutrition recommendations for calories, protein, vitamins and minerals, and enteral and parenteral nutrition support practices.

Journal Article↗
PubMed1998

Ongoing planned clinical trials investigating the pulmonary management of cystic fibrosis.

Cystic fibrosis (CF) is a genetic disease where abnormalities in ion transport lead to poor clearance of viscoelastic secretions and a susceptibility to bacterial colonisation. Once established the infection/inflammatory cascade appears to be self-perpetuating. Treatment is therefore based on a number of strategies. Recently, advances have been concentrated at correcting the gene defect. Other strategies include correction of the ion transport defect. These may be crucial in patients if started before there is significant pulmonary disease. Developments aimed at improving the rheological properties of secretions, controlling airway infection and inflammation are essential once bronchopulmonary sepsis is established. This report looks at some of the clinical trials that are ongoing or planned in the treatment of pulmonary disease in CF.

Journal Article↗