Submucosal glands are the predominant site of CFTR expression in the human bronchus

Engelhardt, John F.; Yankaskas, James R.; Ernst, Stephen A.; Yang, Yiping; Marino, Christopher R.; Boucher, Richard C.; Cohn, Jonathan; Wilson, James M.

doi:10.1038/ng1192-240

Cited by 613 publications

(424 citation statements)

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“…Furthermore, CFTR regulates sodium transport across epithelial membranes through interactions with the epithelial sodium channel ENaC [9], and facilitates the trans-membrane export of the small organic anionic peptide glutathione [10]. The expression of CFTR is located in the apical membrane of epithelial cells that line mucous membranes and submucosal glands [11,12]. The tissues most affected by CFTR deficiency include the vas deferens, exocrine pancreas, liver, large intestine, sinuses, and the lower airways.…”

Section: Introductionmentioning

confidence: 99%

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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Although great strides are being made in the care of individuals with cystic fibrosis (CF), this condition remains the most common fatal hereditary disease in North America. Numerous links exist between progression of CF lung disease and oxidative stress. The defect in CF is the loss of function of the transmembrane conductance regulator (CFTR) protein; recent evidence that CFTR expression and function are modulated by oxidative stress suggests that the loss may result in a poor adaptive response to oxidants. Pancreatic insufficiency in CF also increases susceptibility to deficiencies in lipophilic antioxidants. Finally the airway infection and inflammatory processes in the CF lung are potential sources of oxidants that can affect normal airway physiology and contribute to the mechanisms causing characteristic changes associated with bronchiectasis and loss of lung function. These multiple abnormalities in the oxidant/antioxidant balance raise several possibilities for therapeutic interventions that must be carefully assessed. IntroductionCystic fibrosis (CF) is the most common fatal disease caused by a single gene defect in Europe and North America [1,2]. The defective gene was identified in 1989 [3][4][5] and shown to encode the cystic fibrosis trans-membrane conductance regulator protein (CFTR). CFTR is a cyclic AMP-regulated anion channel with greatest selectivity for chloride, and bicarbonate [6][7][8]. Furthermore, CFTR regulates sodium transport across epithelial membranes through interactions with the epithelial sodium channel ENaC [9], and facilitates the trans-membrane export of the small organic anionic peptide glutathione [10]. The expression of CFTR is located in the apical membrane of epithelial cells that line mucous membranes and submucosal glands ☆ A list of participants may be found in the Acknowledgments.

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Section: Introductionmentioning

confidence: 99%

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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“…Submucosal glands are well developed in human airways and comprise a system of mucous (mucin-secreting) and serous (fluid-secreting) acinar tubules and conducting ducts that secrete a mixture of mucins and liquid into the lumen of large airways (Burkitt et al, 1996). An important study (Engelhardt et al, 1992) reported that CFTR expression in human lungs was highest in submucosal gland acini, suggesting that decreased gland output of fluid and antimicrobial factors might cause CF lung disease (Jiang and Engelhardt, 1998). However, compelling physiological evidence has recently accumulated suggesting that the superficial epithelium controls the volume of liquid on airway surfaces.…”

Section: Introductionmentioning

confidence: 99%

“…However, the relative contribution of the superficial epithelium and submucosal glands to ASL volume homeostasis and thus to CF airway pathogenesis remains controversial (Verkman et al, 2003). Historically, submucosal glands, not the superficial epithelia, have been considered as the main site of CFTR expression in the lungs (Engelhardt et al, 1992). Submucosal glands are well developed in human airways and comprise a system of mucous (mucin-secreting) and serous (fluid-secreting) acinar tubules and conducting ducts that secrete a mixture of mucins and liquid into the lumen of large airways (Burkitt et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Kreda

Mall

Mengos

et al. 2005

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Previous studies in native tissues have produced conflicting data on the localization and metabolic fate of WT and ⌬F508 cystic fibrosis transmembrane regulator (CFTR) in the lung. Combining immunocytochemical and biochemical studies utilizing new high-affinity CFTR mAbs with ion transport assays, we examined both 1) the cell type and region specific expression of CFTR in normal airways and 2) the metabolic fate of ⌬F508 CFTR and associated ERM proteins in the cystic fibrosis lung. Studies of lungs from a large number of normal subjects revealed that WT CFTR protein localized to the apical membrane of ciliated cells within the superficial epithelium and gland ducts. In contrast, other cell types in the superficial, gland acinar, and alveolar epithelia expressed little WT CFTR protein. No ⌬F508 CFTR mature protein or function could be detected in airway specimens freshly excised from a large number of ⌬F508 homozygous subjects, despite an intact ERM complex. In sum, our data demonstrate that WT CFTR is predominantly expressed in ciliated cells, and ⌬F508 CFTR pathogenesis in native tissues, like heterologous cells, reflects loss of normal protein processing.

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“…10,11 Using various glycosylated polylysines as vectors, we have shown that some sugars enhanced the vector capability of polylysine and yielded high expression of the reporter gene lucifer- …”

Section: Figure 2 Gene Transfer With Nonviral Vectors Into Immortalizmentioning

confidence: 99%

Targeting of cell receptors and gene transfer efficiency: a balancing act

et al. 2002

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Cationic polymers are synthetic molecules that have been developed to introduce exogenous genes into cells to produce new proteins. For instance, poly-L-lysine which interacts with nucleic acids, is widely used to compact plasmid DNA containing a gene of interest and transfect cells with the resulting DNA/cationic polymer complexes. However, the main goal is to obtain cell-specific transfer which might be achieved by taking advantage of cell-surface receptors that mediate DNA uptake. Hence, bifunctional conjugates have been constructed in which the polylysine allows DNA binding and the ligand domain allows receptor-mediated delivery of the nucleic acid. Using this model, polylysine has been substituted with protein ligands, such as transferrin, to target airway cells through the transferrin receptor. 1 Sugar moieties commonly expressed on glycoproteins have also been used as ligands specific to receptors, called lectins. A large variety of cells express membrane lectins that selectively recognize glycoconjugates containing complex oligosaccharide structures. [2][3][4] Wu and coworkers achieved one of the first successes of in vitro and in vivo glycoconjugate-based transfection through the galactose-specific membrane lectin of hepatocytes by using DNA complexed with polylysine coupled to the asialoorosomucoid glycoprotein (for a review, see Ref. 5). The drawbacks with these strategies using proteins or glycoproteins are that the preparation and purification of such polypeptidic structures coupled to polylysine are difficult, their solubility may be very low and they may induce immune

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Submucosal glands are the predominant site of CFTR expression in the human bronchus

Cited by 613 publications

References 39 publications

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Targeting of cell receptors and gene transfer efficiency: a balancing act

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