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PubMed1978

The biologic activities of cystic fibrosis serum. II. Ultrastructural aspects of the effect of cystic fibrosis sera and calcium ionophore A23187 on rabbit tracheal explants.

Ultrastructural and cytochemical observations indicate that both cystic fibrosis (CF) sera and calcium ionophore A23187 induce a swelling or an increase in the size and possibly the number of secondary lysosomes and an increase in mucus secretion in epithelium of the rabbit tracheal bioassay system. Extended incubation of the rabbit tracheal explants with either CF or control sera produces a cytotoxic effect on the tracheal epithelium, but only after the termination of the normal bioassay time period. Comparative ultrastructural study of the effect of both CF sera and calcium ionophore A23187 on the rabbit tracheal bioassay system indicates that increased membrane permeability to calcium may be important in the production of the ciliary dyskinesia response by CF serum factor(s) in the rabbit tracheal bioassay system.

Animals↗
PubMed1993

[Cellular expression of CFTR in cystic fibrosis: defective cyclic AMP-dependent regulation of glycoconjugate secretion in cystic fibrosis fetal tracheal epithelial cells transfected by SV40 large T oncogene].

Epithelial tracheal cells isolated from two fetuses with cystic fibrosis (CF) and non-CF fetus (control) were transfected with a plasmid vector recombined with the large T oncogene of SV40. All transfected cells expressed SV40 antigen and exhibited an epithelial morphology (junctional complex, cytokeratins). CFT cells retained the mutations of the CF gene, one heterozygous for the S549N/N1303K substitutions (CFT-1 cells), the other homozygous for the deletion delta F508 (CFT-2 cells). Accordingly, these CFT cells exhibited the defective beta-adrenergic regulation of chloride conductance. We compared the responsiveness of control (NT-1 cells) and CF cells (CFT-1 and CFT-2 cells) to agonists of the protein kinase A (PKA)-dependent pathway for stimulation of glycoconjugate secretion. We show that the isoproterenol (10(-5) M) and forskolin (10(-5) M) markedly increased the cAMP content and the PKA activity of all three cell lines. In contrast, these effectors produced an increase in glycoconjugate secretion in control cells, but not in CFT-1 and CFT-2 cells. In conclusion, our results indicate that CFT cells do not respond to agonists of the PKA-dependent pathway for stimulation of both glycoconjugate secretion and chloride transport, which suggests the involvement of CFTR in these two processes.

Cells, Cultured↗
PubMed1991

Down-regulation of cystic fibrosis gene mRNA transcript levels and induction of the cystic fibrosis chloride secretory phenotype in epithelial cells by phorbol ester.

To evaluate the hypothesis that phorbol myristate acetate (PMA) might modulate the expression of the cystic fibrosis (CF) gene in epithelial cells, we examined the effect of PMA on CF mRNA levels and regulation of Cl- secretion. Strikingly, PMA down-regulated CF mRNA transcript numbers in a dose- and time-dependent manner. Importantly, in parallel with the reduction of CF mRNA levels, PMA-treated cells were unable to up-regulate Cl- secretion in a normal fashion in response to forskolin, an effect which was also dose- and time-dependent. Thus, PMA is capable of modulating expression of the CF gene and induces T84 cells to adopt the "CF phenotype" in regard to regulation of Cl- ion transport.

Blotting, Northern↗
PubMed2002

The cystic fibrosis mutation G551D alters the non-Michaelis-Menten behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) channel and abolishes the inhibitory Genistein binding site.

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) channel activity explains most of the manifestations of the cystic fibrosis (CF) disease. To understand the consequences of CF mutations on CFTR channel activity, we compared the pharmacological properties of wild-type (wt) and G551D-CFTR. Dose-dependent relationships of wt-CFTR activated by genistein follows a non-Michaelis-Menten behavior consistent with the presence of two binding sites. With phosphorylated CFTR, a high affinity site for genistein is the activator (K(s) approximately 3 microm), whereas a second site of low affinity (K(i) approximately 75 microm) is the inhibitor. With non-phosphorylated CFTR, K(s) was increased (K(s) approximately 12 microm), but K(i) was not affected (K(i) approximately 70 microm). In G551D-CFTR cells, channel activity was recovered by co-application of forskolin and genistein in a dose-dependent manner. A further stimulation of G551D-CFTR channel activity was measured at concentrations from 30 microm to 1 mm. The dose response is described by a classical Michaelis-Menten kinetics with only a single apparent site (K(m) approximately 11 microm). Our results suggest glycine 551 in NBD1 as an important location within the low affinity inhibitory site for genistein and offers new evidence for pharmacological alteration caused by an NBD1 mutation of CFTR. This study also reveals how a mutation of an ion channel converts a non-Michaelis-Menten behavior (two binding sites) into a classical Michaelis-Menten model (one binding site).

Animals↗
PubMed1997

Phylogenetic analysis of cystic fibrosis transmembrane conductance regulator gene in mammalian species argues for the development of a rabbit model for cystic fibrosis.

The species-specific pattern of cystic fibrosis transmembrane conductance regulator (CFTR) expression was investigated in order to identify species closely related to man which can be used as potential cystic fibrosis (CF) animal models. To this purpose, the nucleotide sequences of the CFTR promoter region of eight mammalian species representing four different orders (Primates, Artiodactyla, Lagomorpha and Rodentia) were analyzed. Distance matrices and unrooted trees of the CFTR promoter region sequences yielded two deeply separated groups, one including man (Homo sapiens), nonhuman primates (Hylobates lar, Macaca fascicularis, Saimiri sciureus), cow (Bos taurus), and rabbit (Oryctolagus cuniculus) and the other including the rodents (Rattus norvegicus, Mus musculus). Divergences between rodent and nonrodent groups have been observed in putative cis transcriptional regulatory elements and can be involved in the differences of pattern of expression between these two groups. Comparison of the available CFTR cDNA sequences enabled us to root the tree with a noneutherian outgroup and to perform a phylogenetic analysis. This analysis did not detect any base composition bias and supported polyphyletic Glires. Although a long-branch attraction artifact cannot be completely excluded, these findings converge toward the recent statement (Graur, Duret, and Gouy 1996) that Lagomorpha is more closely related to Primates than to Rodentia. In addition, the phenylalanine residue in exon 10 involved in the most common CF mutation in man is conserved in rabbit. These phylogenetic analyses as well as anatomical and developmental data suggest that, once rabbit embryonic stem cells become available, the rabbit will provide a suitable tool for both gene transfer and pharmacological investigations and could lead to a better CF model than the current murine models.

Animals↗
PubMed1979

Protease deficiency in plasma of patients with cystic fibrosis. Reduced reaction of 4-methylumbelliferylguanidinobenzoate with plasma of patients with cystic fibrosis.

Protease activity in plasma is assayed using 4-methylumbelliferylguanidinobenzoate. The assay is modified by carrying out the reaction in the presence and absence of benzamidine, a competitive inhibitor of trypsin-like proteases. The parameters of the assay are described in detail. Using this assay, our earlier demonstration of a deficiency of protease activity in plasma of patients with cystic fibrosis is confirmed. The activity, corrected for the nonspecific hydrolysis of 4-methylumbelliferylguanidinobenzoate by benzamidine, is expressed as nanomoles of 4-methylumbelliferone released per milliliter plasma. Under standard conditions, the activity in plasma activated with chloroform-ellagic acid was 127.2 +/- 23.1 in 7 controls, 70.4 +/- 11.7 in 11 obligate heterozygotes, and 48.7 +/- 16.6 in 12 patients with cystic fibrosis. Identical results were obtained when unactivated plasma was used. These data demonstrate that the judicious use of specific inhibitors such as benzamidine might be useful in assaying low levels of protease activity in crude systems.

Benzamidines↗
PubMed2005

Response to acute lung infection with mucoid Pseudomonas aeruginosa in cystic fibrosis mice.

RATIONALE: Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator gene, which codes for a chloride channel, but the role of this chloride channel in inflammation induced by lung infection with Pseudomonas aeruginosa remains to be defined. OBJECTIVES: We tested the hypothesis that loss of this chloride channel alone is sufficient to cause excessive inflammation in response to inflammatory stimuli. METHODS: We investigated the response of cystic fibrosis and wild-type mice to mucoid P. aeruginosa administered by insufflation. MEASUREMENTS: The host responses measured included survival, weight change, lung morphometry, bacterial clearance, and inflammatory mediators, and cell counts were assessed in bronchoalveolar lavage fluid. MAIN RESULTS: Depending on the dose administered and frequency of dosing, cystic fibrosis mice experienced significantly higher mortality rates, greater weight loss, higher lung pathology scores, and higher inflammatory mediator and neutrophil levels compared with wild-type mice, even after the bacteria had been cleared. Surprisingly, bacteria were cleared just as rapidly in cystic fibrosis mice as in wild-type mice, and sepsis was not observed. Chronic lung infections could not be established with mucoid P. aeruginosa in either cystic fibrosis or wild-type mice. CONCLUSIONS: Absence of this chloride channel alone appears sufficient for exaggerated inflammation and excess mortality compared with wild-type controls in the face of mucoid P. aeruginosa lung infection. To establish chronic infection, additional factors such as bacterial trapping or poor clearance may be required.

Animals↗
PubMedDate not supplied

Chloride and potassium channels in cystic fibrosis airway epithelia.

Cystic fibrosis, the most common lethal genetic disease in Caucasians, is characterized by a decreased permeability in sweat gland duct and airway epithelia. In sweat duct epithelium, a decreased Cl- permeability accounts for the abnormally increased salt content of sweat. In airway epithelia a decreased Cl- permeability, and possibly increased sodium absorption, may account for the abnormal respiratory tract fluid. The Cl- impermeability has been localized to the apical membrane of cystic fibrosis airway epithelial cells. The finding that hormonally regulated Cl- channels make the apical membrane Cl- permeable in normal airway epithelial cells suggested abnormal Cl- channel function in cystic fibrosis. Here we report that excised, cell-free patches of membrane from cystic fibrosis epithelial cells contain Cl- channels that have the same conductive properties as Cl- channels from normal cells. However, Cl- channels from cystic fibrosis cells did not open when they were attached to the cell. These findings suggest defective regulation of Cl- channels in cystic fibrosis epithelia; to begin to address this issue, we performed two studies. First, we found that isoprenaline, which stimulates Cl- secretion, increases cellular levels of cyclic AMP in a similar manner in cystic fibrosis and non-cystic fibrosis epithelial cells. Second, we show that adrenergic agonists open calcium-activated potassium channels, indirectly suggesting that calcium-dependent stimulus-response coupling is intact in cystic fibrosis. These data suggest defective regulation of Cl- channels at a site distal to cAMP accumulation.

Calcium↗
PubMed1996

Mutant cystic fibrosis transmembrane conductance regulator inhibits acidification and apoptosis in C127 cells: possible relevance to cystic fibrosis.

We have shown elsewhere that acidification is an early event in apoptosis, preceding DNA cleavage. Cells expressing the most common mutation (delF508) of the cystic fibrosis transmembrane regulator (CFTR) exhibit a higher resting intracellular pH and are unable to secrete chloride and bicarbonate in response to cAMP. We hypothesized that defective acidification in cells expressing delF508 CFTR would interfere with the acidification that accompanies apoptosis, which in turn, would prevent endonuclease activation and cleavage of DNA. We therefore determined whether the function of the CFTR would affect the process of apoptosis in mouse mammary epithelial C127 cells stably transfected with the wild-type CFTR (C127/wt) or the delF508 mutation of the CFTR (C127/508). C127 cells possessed an acid endonuclease capable of DNA degradation at low pH. Sixteen hours after treatment with cycloheximide, C127/wt cells underwent cytoplasmic acidification. In contrast, C127/508 cells failed to demonstrate acidification. Furthermore, the C127/508 cells did not show nuclear condensation or DNA fragmentation detected by in situ nick-end labeling after treatment with cycloheximide or etoposide, in contrast to the characteristic features of apoptosis demonstrated by the C127/wt cells. Measurement of cell viability indicated a preservation of cell viability in C127/508 cells but not in C127/wt cells. That this resistance to the induction of apoptosis depended upon the loss of CFTR activity is shown by the finding that inhibition of the CFTR with diphenylamine carboxylate in C127/wt cells conferred similar protection. These findings suggest a role for the CFTR in acidification during the initiation of apoptosis in epithelial cells and imply that a failure to undergo programmed cell death could contribute to the pathogenesis of cystic fibrosis.

Animals↗
PubMed2005

Basal-like cells constitute the proliferating cell population in cystic fibrosis airways.

RATIONALE: Cystic fibrosis airways are recurrently exposed to noxious stimuli, leading to epithelial injury. Previous reports suggest that cystic fibrosis airway epithelia may respond to injury by increasing proliferation. OBJECTIVES: We sought to determine the characteristics of the proliferating cell population in cystic fibrosis airways. METHODS: Six cystic fibrosis and six normal lung sections from lung transplant recipients or lung surgery were obtained from the Duke Hospital pathology archives. Sections containing bronchi were evaluated for epithelial cell proliferation using immunohistochemistry for a nuclear proliferation antigen, Ki-67, and image analysis; immunohistochemistry for basal cells using a cytokeratin 5/14 antibody; and immunohistochemistry for the epidermal growth factor receptor and ErbB2, two receptor tyrosine kinases implicated in epithelial proliferation and differentiation. RESULTS: Overall, cystic fibrosis sections had a greater proliferation index than control sections with 25.1 +/- 2.1% positively staining nuclei/total nuclei compared with control sections, 4.6 +/- 0.9% (p = 0.002). In cystic fibrosis sections only, there were areas of hyperplastic cuboidal cells adjacent to normal pseudostratified columnar epithelial sections; in these areas of epithelial hyperplasia, there was uniform Ki-67 staining, indicating a zone of proliferating cells. The proliferating cell population also expressed the basal cell cytokeratins 5/14 and epidermal growth factor receptor. Expression of ErbB2 was diminished in the proliferating cells. CONCLUSIONS: Our results suggest that basal-like cells, expressing the epidermal growth factor receptor, constitute the proliferating cell population in cystic fibrosis airways.

Adolescent↗
PubMed1997

Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Cystic Fibrosis Study Group.

BACKGROUND: More data on the efficacy and safety of ciprofloxacin in pediatric cystic fibrosis patients are needed. METHODS: One hundred eight pediatric cystic fibrosis patients (ages 5 to 17 years) with acute bronchopulmonary exacerbations entered a randomized multicenter trial designed to compare the safety and efficacy of antipseudomonas therapy with oral ciprofloxacin (15 mg/kg twice daily; maximum dosage 750 mg twice daily) or intravenous ceftazidime plus tobramycin (CAZ/TM) for 14 days. RESULTS: Clinical improvement was observed in 93% of patients treated with oral ciprofloxacin and in 96% of those receiving parenteral therapy. Transient suppression of Pseudomonas aeruginosa was achieved in 63% of patients at the end of the course of iv CAZ/TM therapy and in 24% receiving ciprofloxacin. Ultrasound examination and nuclear magnetic resonance imaging scans showed no evidence of cartilage toxicity in any of the ciprofloxacin-treated patients. Musculoskeletal adverse events were reported with similar frequency in the two groups of patients (7% in the group receiving ciprofloxacin therapy and 11% in the IV CAZ/TM group). The only sustained musculoskeletal symptom was a case of synovitis in a patient receiving parenteral CAZ/TM. CONCLUSION: Ciprofloxacin thus appears to be safe and effective for use in young patients with bronchopulmonary exacerbation of cystic fibrosis.

Administration, Oral↗
PubMed1984

Diagnosis and treatment of cystic fibrosis. An update.

Cystic fibrosis is the most common fatal inherited disease of Caucasians. At present, cystic fibrosis accounts for most cases of chronic progressive pulmonary disease and for many other clinical features in the first three decades of life. Thus, it is a challenge to both pediatricians and internists, particularly chest physicians. The diagnosis is based on the triad of chronic obstructive pulmonary disease, pancreatic insufficiency, and increased levels of electrolytes in the sweat. The cardinal test for confirmation of the diagnosis is the "sweat test," which is an excellent discriminant for cystic fibrosis, even in adults. Ancillary features of cystic fibrosis may be of diagnostic assistance (eg, nasal polyposis, Pseudomonas aeruginosa in sputum, azoospermia, and others). Treatment of the pulmonary disease must be emphasized. Choice of antibiotics should be based on the results of sputum culture, but P aeruginosa is the most common pathogen. Removal of secretions by regular postural drainage and percussion is an integral part of the program. Pneumothorax, massive hemoptysis, cor pulmonale, and other complications may be encountered. Sinusitis is almost universal, and nasal polyposis is frequently present. Pancreatic insufficiency occurs in over 80 percent of the patients with cystic fibrosis and may result in intestinal malabsorption. Massive salt loss through the sweat in hot weather, a distinctive type of biliary cirrhosis without jaundice, gallbladder abnormalities, cholelithiasis, and diabetes mellitus also may be found. Of special importance are intestinal obstructive complications (meconium ileus in newborn infants with cystic fibrosis and intestinal obstruction due to fecal accumulation or intussusception in adults). Azoospermia is present in 95 percent of men and there is reduced fertility in women; however, pregnancy does occur in cystic fibrosis. This chronic and ultimately fatal disease produces a predictable set of psychosocial complications.

Adult↗
PubMed1983

Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis. A longitudinal study of immune complex activity and inflammatory response in sputum sol-phase of cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infections: influence of local steroid treatment.

A double blind controlled trial of Becotide (beclomethasone diproprionate) inhalations was carried out for treating cystic fibrosis patients with chronic P. aeruginosa lung infection to determine its efficacy and safety. The aim of the treatment was to diminish the inflammatory response in the lungs of these patients, a response which is initiated by an allergic type III reaction. Pulmonary inflammation was evaluated by measurements of proteolytic activity, albumin concentration and immune complex activity in the sputum sol-phase before, during, and after the 16 weeks the trial lasted. 26 cystic fibrosis patients participated (13 received Becotide and 13 placebo) and the results showed that local steroids have no effect on the inflammatory response in the lungs of cystic fibrosis patients with chronic P. aeruginosa lung infection. No adverse effects were demonstrated. There was, however, a significant increase in the inflammatory parameters for all 26 cystic fibrosis patients when the trial period was over, compared to the insidious pulmonary destruction which takes place in the lungs of these patients, and it corresponded to a significant decrease (p less than 0.05) in forced vital capacity which took place at the same time. Therefore, chronic P. aeruginosa lung infection in these patients should be treated as efficiently as possible.

Adolescent↗