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Toward Correction of the Genetic Defect in Cystic Fibrosis
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Larry G. Johnson, Richard C. Boucher
More than 500 mutations have been reported since the cloning of the CF gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, in 1989 (19,20). The most common mutation in CFTR is a 3-bp deletion leading to a deletion of phenylalanine (F) at position 508 (ΔF508) of the protein product which is present on ∼70% of CF chromosomes (1,21,22). This mutation leads to abnormal intracellular processing and trafficking of mutant CFTRs such that CFTR is degraded prior to reaching the cell membrane. Failure of mutant CFTR to reach the membrane causes defective apical membrane chloride (Cl-) conductance in epithelial cells affected by this disorder (23). Alleles G551D, G542X, 621+1G-VT, R117H, W1282X, N1303K, and Δ3849+10 kb C->T account for another 10% to 20% of mutations (1,21,22). Four different classes of CFTR mutations have been proposed (21), including defective protein production (class I), defective processing (class II), defective regulation (class III), and defective conduction (class IV). AF508 falls within class II, G551D into class III, R117H into class IV, and G542X into class I. Interestingly, class IV mutations tend to be associated with pancreatic sufficiency, a milder disease course, and, frequently, congenital bilateral absence of the vas deferens (CBAVD), especially R117H (21,22).
Immune function of epithelial cells
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Richard S. Blumberg, Wayne Lencer, Arthur Kaser, Jerrold R. Turner
Simple columnar and cuboidal epithelial cells are structurally and functionally polarized, with a specialized apical membrane facing the mucosal surface that abuts the outside environment and a basolateral membrane facing the lamina propria and the internal environment of the host. The two membranes are composed of different protein and lipid compositions and structural features; the visually distinct microvilli present in the apical membrane of intestinal epithelial cells exemplify this dramatically. This polarity of structure and function is required for vectorial, i.e., directional, transport of solutes and water. Although apical and basolateral membrane domains are contiguous, they are separated by a functional “fence” that is presumed to prevent mixing of apical and basolateral lipids and proteins. Transport of membranes and cargo between the two surfaces occurs by vesicular traffic in a process termed “transcytosis.”
Cholangiocyte Ion Channels:
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Cholangiocytes in situ form a polarized epithelium with apical microvilli and tight junctions between cells.8,10 At the basolateral membrane, there is continuous uptake of Cl− as a result of Na+/K+/2Cl− cotransport; and channel-mediated K+ efflux serves to recycle K+ back out of the cell and maintain the interior-negative membrane potential.35 Under basal conditions, the Cl− permeability of the apical membrane is low. However, following development of methods for cell isolation, it became apparent that: increases in cAMP stimulate membrane Cl− permeability 20- to 40-fold;this response is mediated by opening of Cl− channels encoded by CFTR, the protein product of the cystic fibrosis gene; andin human liver, CFTR is localized to the apical membrane of cholangiocytes but not hepatocytes.1,4,9,20
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
The CFTR protein is expressed at the apical membrane of many epithelial cells with direct relationships between abnormal expression or function, and CF pathology. When open or activated, the CFTR channel allows passive diffusion of chloride and bicarbonate ions down their electrochemical gradient. It has also many other roles such as inhibition of sodium transport through the epithelial sodium channel and regulation of other chloride channels [8]. CFTR mutations lead to a loss of CFTR activity due to either reduced quantity or impaired function of the protein. In the airways, a defective CFTR protein leads to impaired mucociliary clearance, infection and inflammation, bronchiectasis, and respiratory failure. To date, around 2,000 CFTR mutations have been described and around 250 variants have evidence supporting a disease-causing effect [9]. In the last decade, very innovative drugs called CFTR modulators that improve the defective CFTR protein function have been approved for marketing in patients with CF.
The blood–brain and gut–vascular barriers: from the perspective of claudins
Published in Tissue Barriers, 2021
Anna Agata Scalise, Nikolaos Kakogiannos, Federica Zanardi, Fabio Iannelli, Monica Giannotta
The GVB allows the diffusion from lumen to blood of molecules as large 4 kDa, which is eightfold the maximal size reported for the BBB. This will be because these barriers need to fulfill distinct, and diverse, functions. Indeed, the main role of the BBB is to avoid uncontrolled movement of any substances from the blood into the brain parenchyma, to protect the CNS from the constantly changing milieu of the blood stream.18 To accomplish these functions, brain endothelial cells have low pinocytotic activity, lack fenestration, and are interconnected with the complex and continuous tight junctions, thus controlling junction permeability. The tight junctions closest to the apical membrane maintain the BBB integrity by preventing diffusion of proteins between the luminal and abluminal membrane compartments and restricting the paracellular pathway. This effectively prevents the passage of polar, hydrophilic drugs through the endothelial cell layer. Conversely, the intestinal endothelium is located underneath the epithelial layer, and it needs to be permeable to nutrients, due to the absorptive function of the gut (Figure 1(d)). Thus, the endothelium in the GVB collaborates with enteroglial cells and pericytes to form tight and adherens junctions according to the needs of the overlying epithelial tissue. On the other hand, the GVB acts as the last and potentially most important line of defense to prevent pathogens from invading the bloodstream, and the subsequent systemic consequences.
Targeting central nervous system pathologies with nanomedicines
Published in Journal of Drug Targeting, 2019
Shoshy Mizrahy, Anna Gutkin, Paolo Decuzzi, Dan Peer
The non-invasive approach can be achieved by systemic delivery of the therapeutic agents capable of crossing the BBB or by alternative pathways, which directly bypass the BBB such as intranasal administration. It is known that the olfactory and trigeminal nerves create a pathway connecting the nasal cavity and the brain, thus providing potential routes for non-invasive administration of therapeutics to the CNS [34,35]. This pathway enables a quick delivery of drugs to the CNS within minutes, especially drugs with lower molecular weight and higher lipophilicity. However, the disadvantage of the use of this method is the concentration that can be achieved in different regions of the brain and spinal cord. High-molecular weight drugs tend to be less efficient in this drug delivery method. Finally, the systemic administration can be achieved by intravenous (IV) administration. By IV injection, the therapeutic agents encounter the BBB and in order to penetrate the brain should be able to either diffuse passively or use the active pathways discussed earlier such as the transport proteins, RMT or AMT. The existence of abundant transporters and receptors on the apical membrane of the BBB and their unique characteristics offer substantial potential for drug development and will be discussed further on.