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Increased levels of alginate biosynthesis cause mucoidy in Pseudomonas aeruginosa, a virulence factor of particular importance in cystic fibrosis. The algR gene product, which controls transcription of a key alginate biosynthetic gene, algD, is homologous to the activator members of the two-component, environmentally responsive systems (NtrC, OmpR, PhoB, ArcA, etc). In this report, we show that mutations in the muc loci, (muc-2, muc-22, and muc-23, in the standard genetic P. aeruginosa strain PAO, as well as a mapped muc allele in an isolate from a cystic fibrosis patient) affect transcription of algD and algR. This influence was strongly dependent on environmental factors. Regulation by nitrogen was observed in all strains examined, but the absolute transcriptional levels, determining the mucoid or nonmucoid status, were strain (muc allele)-dependent. Increased concentrations of NaCl in the medium, an osmolyte which is elevated in cystic fibrosis lung secretions, resulted in an increased algD transcription and mucoid phenotype in a muc-2 strain; the same conditions, however, produced a nonmucoid phenotype in the muc-23 background and abolished algD transcription. Mutations in the muc loci may cause mucoidy by deregulating the normal response of the alginate system to environmental stimuli.
Mol Microbiol 1990 Feb
PMID:Mucoid Pseudomonas aeruginosa in cystic fibrosis: mutations in the muc loci affect transcription of the algR and algD genes in response to environmental stimuli. 214 Jan 47

The somatic cell hybrid C121, with chromosome 7 as its sole human component, arose when mouse macrophages SV40 genomes are integrated at 7q31-7q35. We show that hybrids with a reduced chromosome 7 component, but which retain markers linked to the cystic fibrosis locus, can be generated by direct in vivo tumor selection or following chromosome-mediated gene transfer and SV40-mediated cellular transformation. Our methods for chromosome fragmentation and fine-structure mapping can now be applied to the substantial number of SV40-transformed human cell lines, with independent chromosomal integration sites, already available. Our results also suggest that expression of human epidermal growth factor receptor augments the tumorigenic potential of the SV40-transformed C121 hybrid.
Somat Cell Mol Genet 1990 Jan
PMID:SV40-mediated tumor selection and chromosome transfer to enrich for cystic fibrosis region. 215 77

Mortality among cystic fibrosis (CF) patients is most commonly attributed to pulmonary infection by mucoid, alginate-producing Pseudomonas aeruginosa. The initial infecting P. aeruginosa are typically non-mucoid; however, upon continued exposure to the CF lung environment, they become highly mucoid. The CF lung is an osmotically high environment because of the presence of substantial concentrations of electrolytes and dehydrated mucus. In this report we demonstrate that ethanol (a commonly used dehydrating agent) activates transcription from a critical alginate promoter, algD, and show that prolonged exposure to ethanol allows switching to the mucoid form. This activation appears to be dependent on DNA gyrase. Analysis of alginate gene activation, and the subsequent reversal of the activation process by bacterial DNA gyrase inhibitors, should aid the development of treatment strategies for CF patients infected with this organism.
Mol Microbiol 1990 May
PMID:Pulmonary dehydration and infection in cystic fibrosis: evidence that ethanol activates alginate gene expression and induction of mucoidy in Pseudomonas aeruginosa. 216 23

Point mutations in genes can be etiologic of pulmonary diseases, as in the case of the inherited disorders alpha-1-antitrypsin deficiency and cystic fibrosis or in the context of dominant and recessive oncogenes in lung cancer. Various methodologies have been developed to screen for single-base mutations. These techniques include direct DNA sequencing, RNase protection, denaturing gradient gel electrophoresis, and chemical mismatch cleavage. The latter method offers the advantages of rapid and efficient analysis of genomic or cDNA and is thus ideally suited to screening applications. Furthermore, all possible single-base changes can theoretically be detected. In the present work, chemical mismatch cleavage was utilized to detect mutations in the p53 gene in small cell and non-small cell lung cancer. This technique was modified by using a two-step, hemi-nested PCR procedure for preparation of target genomic DNAs permitting an expanded target size for analysis. Evaluation by chemical mismatch cleavage of eight p53 cDNAs derived from lung tumors shown to have different mutations by DNA sequencing correctly detected the presence of a point mutation in all instances. Analysis of six additional tumor genomic DNAs with defined mutations in the corresponding p53 cDNAs accurately confirmed the mutation at the level of the genome. The technique also identified codon 72 and intron 6 polymorphisms. Using the intron 6 polymorphism, loss of heterozygosity at the p53 locus in tumor DNA was readily detected by chemical mismatch cleavage. Finally, utilizing this technique for scanning analysis of the p53 gene of uncharacterized lung tumor DNAs, additional mutations were identified in a prospective manner which were confirmed by sequence analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Nov
PMID:A chemical mismatch cleavage method useful for the detection of point mutations in the p53 gene in lung cancer. 222 98

Cellular mechanisms regulating airway secretion, secretory products of individual airway cell types, and control of airway cell growth and differentiation are poorly understood. In order to aid studies of these questions, we have established a system for culturing human tracheobronchial submucosal gland cells. Gland acini were isolated by enzymatic disaggregation from submucosal tissue obtained postmortem from patients without pulmonary diseases and from patients with cystic fibrosis. In culture, acini attached to a collagen substratum, and gland cells proliferated and formed confluent monolayers which were homogeneous by phase microscopy. In contrast to cells of freshly disaggregated acini which expressed either serous or mucous gland cell secretory antigens, in culture virtually all cells (greater than or equal to 95%) concurrently expressed both antigens as assessed by immunocytochemical staining with serous and mucous cell-specific antibodies. Similarly, electron microscopy revealed cells with serous- or mucous-type secretory granules, and cells containing both types of granules. Cultures incorporated 35S into high (greater than 10(6) D) and lower (greater than 700 kD; 150 kD) molecular weight molecules. Cholinergic and adrenergic agonists increased release of radio-labeled secretions. These findings demonstrate that human tracheal gland cells in culture retain immunocytochemical, ultrastructural, and functional features of both differentiated serous and mucous gland cells. This culture system will be useful for studying the biology and pathology of human tracheobronchial submucosal gland cells.
Am J Respir Cell Mol Biol 1990 Jan
PMID:Human tracheobronchial submucosal gland cells in culture. 230 68

Using monoclonal antibody 19-9, elevated levels of the sialyl Lea antigen (NeuAc alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNac beta 1-3R) are detected in serum from most cystic fibrosis patients. We now report further characterization of the serum antigen and evidence that it is on a mucin glycoprotein and not on glycolipids. The antigen has an apparent molecular weight greater than 2 X 10(6) by gel filtration on Sephacryl S-400. On density gradient centrifugation, the antigen has a density of 1.54 g/ml in cesium chloride and 1.42 g/ml in cesium chloride/4 M guanidine HCl. Immunostaining with monoclonal antibody 19-9 of lipid extracts from cystic fibrosis patient serum and erythrocytes does not detect any antigen on glycolipids. The antigen was purified by gel filtration and density gradient centrifugation. After tritium labeling of the sialic acid residues, sodium dodecyl sulfate gel electrophoresis separates two subunits with apparent molecular weights of 200,000 and 400,000. All of the labeled sialic acid is released as low molecular weight oligosaccharides after mild alkaline borohydride degradation. The purified antigen contains fucose, galactosamine, glucosamine, and galactose but no mannose and is enriched in the amino acids threonine, serine, glycine, proline, and alanine. The purified antigen binds several antibodies recognizing epitopes common to many mucins. Thus, the physical, biochemical, and immunochemical properties of the purified antigen indicate that the sialyl Lea antigen is present on mucins in the serum of cystic fibrosis patients.
Am J Respir Cell Mol Biol 1990 Apr
PMID:Isolation and characterization of mucin from the serum of cystic fibrosis patients. 232 69

The human INT1L1 gene, which exhibits homology to the protooncogene INT1 is very closely linked to the MET gene and cystic fibrosis locus on human chromosome 7. In the present study we have isolated overlapping genomic clones that correspond to the mouse homolog of the INT1L1 gene and have used the cloned DNA as probes to examine the distribution of the mouse INT1L1 gene within a series of 35 mouse-hamster somatic cell hybrids. These analyses have localized the INT1L1 gene to mouse chromosome 6. In addition, we demonstrate that the mouse INT1L1 and MET genes are coamplified in lines of spontaneously transformed mouse NIH3T3 cells, indicating that these genes may remain closely linked within the mouse genome.
Somat Cell Mol Genet 1989 Nov
PMID:Molecular cloning and localization to chromosome 6 of mouse INT1L1 gene. 253 31

We here report a method for the characterization of carcinoma cells in cryosections of human breast tissue. Cryosections from 37 biopsies including carcinomas, fibrocystic disease specimens and reduction mammoplasties were incubated in an atmosphere of either pure nitrogen or 99.5% oxygen. The incubation medium contained neotetrazolium, phenazine methosulphate and the colloid stabilizer Polypep 5115. A marked overlap in formation of reaction product was found between carcinomas, benign tissue and normal breast tissue when sections were incubated in pure nitrogen. However, following 5 min of oxygen incubation no reaction was seen in normal breast tissue, whereas carcinoma cells consistently showed reaction. Moreover, a statistically significant difference was seen between the level of reaction in carcinoma cells and that of ductal epithelial cells in fibrocystic disease not containing apocrine metaplasia. Apocrine metaplasia, on the other hand, showed the highest activity recorded at all.
Virchows Arch B Cell Pathol Incl Mol Pathol 1985
PMID:Effect of oxygen on the tetrazolium reaction for glucose 6-phosphate dehydrogenase in cryosections of human breast carcinoma, fibrocystic disease and normal breast tissue. 286 40

It has been suggested that a defective chloride transport is the primary cellular basis for the disease cystic fibrosis (CF). Therefore, the effects of chronic furosemide treatment on the structure and function of rat exocrine glands were investigated. X-ray microanalysis of the submandibular gland showed an increase in the cellular Ca and Mg concentrations, and a decrease in the cellular Cl concentration. Transmission electron microscopy showed intracellular accumulation of mucus and the presence of mucus in acinar and ductal lumina. The volume of saliva secreted by the submandibular gland after pilocarpine stimulation was markedly reduced in furosemide-treated animals; the salivary concentrations of Na and Ca were higher, and that of K was lower, than in control animals. The protein concentration in submandibular saliva was not significantly affected. The response of the submandibular gland to isoproterenol stimulation was reduced in furosemide-treated animals. In the parotid gland, chronic furosemide treatment caused an accumulation of immature zymogen granules in the acinar cells and a decrease in the cellular Cl concentration. In the pancreas, the acinar lumen was dilated and completely filled with secretory material, and the acinar cells contained less Na and somewhat less Cl than in control animals. The chronically furosemide-treated rat shows a number of parallels with other animal models for CF, in particular the chronically reserpinized rat. There is also agreement with the human disease itself.
Exp Mol Pathol 1988 Apr
PMID:Effects of chronic furosemide treatment on rat exocrine glands. 335 Jan 42

The present investigation was undertaken to determine whether or not there are histochemical and morphological changes in the intestine of the chronically reserpine-treated rat, an animal model of cystic fibrosis. Male Sprague-Dawley rats were given seven daily intraperitoneal injections of reserpine at dosages of 0.5 (n = 6) or 1.0 mg/kg body weight (n = 6). Control groups consisted of parfed solvent-injected (n = 6), solvent-injected (n = 4), and saline-injected animals (n = 4). Light microscopic histochemical procedures and morphological assessments were performed on sections of "Swiss rolls" of small and large intestine. Chronic reserpine treatment caused an increase in the sulfation of goblet cell mucin in the small intestine without accompanying morphological change; these findings resemble those reported in cystic fibrosis. No qualitative differences in mucin were found in the large intestine but there was an increased number of goblet cells in the surface epithelium and retention of mucus within these cells. Similar although less marked changes were noted in the parfed controls suggesting that those observed in the treated groups may be due, in part, to the reserpine-induced anorexia. The resemblance between the changes in the small intestine of the reserpine-treated rat and those observed in CF patients supports the contention that the chronically reserpine-treated rat is suitable as a model of cystic fibrosis.
Exp Mol Pathol 1987 Aug
PMID:Morphological and histochemical changes in intestinal mucosa in the reserpine-treated rat model of cystic fibrosis. 360 43


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