Commentary - Biomedical Research (2022) Advances in Health Science and Biotechnology Application: Edition: II
Membrane transport system in cystic fibrosis
Department of Physiology and Pharmacology, SUNY Downstate Medical Center, New York, USA
- Corresponding Author:
- Burton Altura
Department of Physiology and Pharmacology
SUNY Downstate Medical Center
Accepted date: April 27, 2022
Barriers that exhibit selective permeability properties surround cells. The cells establish the electrical potential between the interior and outside of the cell, as well as many other vital homeostatic activities, through the operation of these membranes. Solute transport through biological membranes is facilitated by four mechanisms or clusters of mechanisms. Diffusion, carrier mediated transport (including assisted diffusion and active transport), osmosis, and endocytosis–exocytosis are the mechanisms involved.
Barriers that exhibit selective permeability properties surround cells. The cells establish the electrical potential between the interior and outside of the cell, as well as many other vital homeostatic activities, through the operation of these membranes. Solute transport through biological membranes is facilitated by four mechanisms or clusters of mechanisms. Diffusion, carrier mediated transport (including assisted diffusion and active transport), osmosis, and endocytosis–exocytosis are the mechanisms involved. Cystic Fibrosis (CF) is a deadly hereditary disease caused by defects in exocrine epithelia's fluid and electrolyte transport. An underlying membrane deficiency in Na+ and Cl− permeability affects both absorptive and secretory activities. The effect of the impairment on transport function, on the other hand, appears tissue specific. The sweat duct decreases net electrolyte absorption, while the airway epithelium increases it. The intestine is unaffected. The deficiency manifests itself in secretion as a persistent failure to respond to -adrenergic stimulation and cAMP- mediated secretion in most, if not all, exocrine organs. The secretory response to cholinergic and Ca2+ mediated stimulation, on the other hand, is normal in the sweat gland, and appears to be normal in the airway, but missing in the intestine. The underlying deficiency is not lethal in and of itself, and heterozygotes may benefit from the imbalance between absorption and secretion processes in surviving complications of intestinal infections. The major physiological cause of the eventually fatal secondary infections in the lungs of CF homozygotes is most likely a transport deficiency.
In Cystic Fibrosis (CF), abnormal epithelial transport appears to give a unifying explanation to explain the disease's various clinical symptoms. The main issue is cell control of epithelial Cl− secretion; however, other electrolyte transport anomalies have been discovered. Cystic Fibrosis (CF) is caused by over 1300 distinct mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a condition marked by decreased epithelium Cl− production and increased Na+ absorption. The progressive lung disease determines the disease's clinical course. As a result, innovative pharmacological techniques are predominantly focused on correcting the ion transport deficit in the airways. Current therapy techniques aim to compensate for a lack of Cl− secretion as well as increased Na+ absorption. A number of substances, such as genistein and xanthine derivatives, have been discovered to directly activate mutant CFTR. Alternative Ca2+ activated Cl− channels or basolateral K+ channels, which supply the driving power for Cl− secretion, may be activated by other substances. Apart from that, Na+ channel blockers such as phenamil and benzamil, which prevent NaCl hyperabsorption in CF airways, are being investigated. Purinergic drugs, such as the P2Y2 receptor agonist INS365, are being tested in clinical trials. It has been discovered that activating P2Y2 receptors simultaneously activates Cl− secretion and inhibits Na+ absorption. The ultimate goal is to restore mutant CFTR channel activity Cl− by either increasing protein synthesis and expression or activating silent CFTR Cl− channels. Combining these medications with chemicals that facilitate Cl− secretion while reducing Na+ absorption in vivo may be the most effective way to treat cystic fibrosis' ion transport problem.
Apart from that, the cotranslational insertion of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) into the Endoplasmic Reticulum (ER) membrane and core glycosylation would be the first steps in its biogenesis. Following these initial events, a complex series of actions is performed with the purpose of determining the overall quality of CFTR conformation in order to encourage its escape from the ER via the secretory pathway. Failure to pass the ER quality control checkpoints causes the most common disease-causing mutant protein (F508del-CFTR) to be degraded prematurely. Although nonconventional trafficking paths have been discovered for wild-type CFTR that exits the ER, trafficking through the Golgi is the primary location for glycan processing. Multiple protein interactors, including as Rab proteins, Rho small GTPase, and PDZ proteins, influence CFTR stability once it reaches the cell surface. These control not just anterograde trafficking to the cell surface, but also endocytosis and recycling, allowing for fine and precise CFTR plasma membrane level modulation. Recent research has linked autophagy and epithelial differentiation to CFTR transport regulation.