In Utero Mapping and Development Role of CFTR in Lung and Gastrointestinal Tract of Cystic Fibrosis Patients

Abstract

In cystic fibrosis (CF) the ability of the CF transmembrane conductance regulator (CFTR) protein to mediate chloride and water transport is disrupted. While much progress has been made in CF research leading to effective treatments to improve CFTR function, including small molecule modulators, patients present with varying disease manifestations and responses to therapy. For many CF-affected organs, disease onset is known to occur during in utero development before treatments can be administered and progresses over time leading to irreversible damage to these organs. Thus, the role of functional CFTR protein, in particular, during early development needs to be further elucidated. Studies have detected CFTR proteins at very early gestational stages and revealed temporally and spatially variable CFTR expression patterns in fetuses, suggesting a potential role of CFTR in fetal development. However, the actual mechanisms of how defective CFTR in CF results in fetal morphogenetic abnormalities are yet to be established. This review aims to summarize fetal CFTR expression patterns specifically in the lung, pancreas, and gastrointestinal tract (GIT), as compared to adult patterns. Case studies of structural abnormalities in CF fetuses and newborns and the role of CFTR in fetal development will also be discussed.

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

“…The CFTR protein is located predominantly on the epithelial cells of organs such as the pancreas, liver, salivary glands, gastrointestinal tract, lungs, and the male and female reproductive systems . Not restricted to these organs, CFTR is also detected to have regulatory functions in immunity; for instance, CFTR normal expression was found to impact various immune cell cytokine production and their normal functions. ,− Hence, CF patients not only exhibit abnormalities in organ functions but also experience immune dysregulation, such as chronic airway inflammation. , Besides, defective CFTR is often associated with a wide spectrum of comorbidities since it affects the viscosity and pH of mucus on the surface of multiple organs; the lung, pancreas, and GIT are the most frequently affected among CF patients. ,− …”

“…48−50 Among CF children, there was an elevation of the pathogenic bacteria such as Escherichia coli and a reduction in beneficial bacteria such as bifidobacteria, which contribute to CF-related intestinal dysbiosis and inflammation. 41,48,50,51 CFTR in Lung. CFTR on the epithelial cell membrane in the airway plays an essential role in maintaining proper lung function.…”

“…Schematic of cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is composed of five functional domains including two membrane spanning domains (MSDs), each composed of six transmembrane domain (TMDs) and forming an ion transport pathway; two cytosolic nucleotide-binding domains (NBD) which ATP binds to, and a cystolic regulatory domain (R-domain) that needs to be phosphorylated by protein kinase A for CFTR normal function. Reproduced from ref . Copyright 2023 American Chemical Society.…”

“…Moreover, studies indicate CF patients have an abnormal gut microbiome composition. − Among CF children, there was an elevation of the pathogenic bacteria such as Escherichia coli and a reduction in beneficial bacteria such as bifidobacteria, which contribute to CF-related intestinal dysbiosis and inflammation. ,,, …”

“…Consequently, the accumulated mucus forms a “mucous protective screen” for foreign pathogens, such as bacteria. Moreover, the lung environment is further conducive to bacterial infections, since they are neither physically removed by the mucus clearance mechanism nor directly killed by immune cells, as pwCF are usually accompanied by immune dysregulation. , The bacteria colonization lasts longer, and eventually leads to chronic infection and inflammation …”