General Health

Cystic Fibrosis Transmembrane Conductance Regulator

Pathophysiology

There are several mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that induce different CFTR protein abnormalities, resulting in milder or more severe disease. Medicines that can probably restore the function of these protein abnormalities are also targeted. The F508-CFTR gene mutation results in a protein that does not fold properly and is not delivered to the cell membrane properly, resulting in its breakdown.

Other mutations induce early termination of protein creation, resulting in proteins that are too short (truncated). Other mutations result in proteins that do not utilise energy (ATP) correctly and do not enable chloride, iodide, or thiocyanate to enter the membrane properly and degrade at a quick rate than anticipated. Mutations may also result in the production of fewer copies of the CFTR protein.

The sweat glands, lungs, pancreas, and the rest of the body’s exocrine glands all generate a protein that binds to the outer membranes of cells. The protein crosses this membrane, acting as a channel between the cell’s inside (cytoplasm) and the surrounding fluid. This channel is largely important for managing the transit of halide anions from the inside to the outside of the cell; however, it also enables the transfer of chloride from the sweat duct into the cytoplasm in the sweat ducts. Chloride and thiocyanate released from sweat glands are retained inside sweat ducts and pumped to the skin when the CFTR protein fails to resorb ions.

Furthermore, the immune system is unable to synthesise hypothiocyanite. Because chloride is negatively charged, it alters the electrical potential within and outside the cell, preventing cations from entering. In the extracellular area, sodium is the most frequent cation. Excess chloride in sweat ducts limits sodium resorption through epithelial sodium channels, and the salt formed by the interaction of sodium and chloride is lost in large amounts in the sweat of individuals with CF. The sweat test is based on the salt that has been lost.

The majority of the damage in Cystic Fibrosis (CF) is caused by thicker secretions blocking the tiny channels of the afflicted organs. These obstructions cause lung infection, pancreatic damage from stored digestion enzymes, and gut blockage from thick faeces, among other things. Several theories have been proposed to explain how clinical consequences are caused by abnormalities in protein and cellular function.

According to modern theories, faulty ion transport causes dehydration in the airway epithelia and thickens mucus. Cilia exist between the cell’s apical surface and mucus in a layer known as airway surface liquid in airway epithelial cells (ASL). Ion channels such as CFTR control the flow of ions from the cell into this layer. CFTR not only regulates the ENac channel, which allows sodium ions to leave the ASL and enter the respiratory epithelium, but it also permits chloride ions to be pulled from the cell and into the ASL. Normally, the CFTR blocks this channel; however, if the CFTR is faulty, sodium flows freely from the ASL into the cell.

The depth of ASL will be depleted when water follows sodium, leaving the cilia in the mucous layer. Mucociliary clearance is hampered by the inability of cilia to move effectively in a thick, viscous environment, resulting in a mucus buildup that clogs tiny airways. Bacteria can hide from the body’s immune system by accumulating more viscous, nutrient-rich mucus in the lungs, resulting in recurrent respiratory infections. The presence of the same CFTR proteins in the pancreatic duct and sweat glands in the skin causes symptoms in these systems.

Chronic infections

Pathogens can enter and infect the lungs of people with CF from an early age. These bacteria grow in the altered mucus that gathers in the lungs’ tiny airways, which is common among people with CF. This mucus causes the production of biofilms, which are bacterial microenvironments that are resistant to penetration by immune cells and drugs. The lungs are continually damaged by viscous secretions and persistent respiratory infections, which eventually remodel the airways, making infection even more difficult to eradicate.

Once inside the lungs, these bacteria adapt to their surroundings and acquire resistance to antibiotics regularly administered. Pseudomonas can develop specific traits that allow enormous colonies to form, known as “mucoid” colonies. Pseudomonas aeruginosa, is uncommon in individuals who do not have CF. Scientific evidence suggests that the interleukin 17 pathway is important for resistance and control of the inflammatory response in CF patients infected with P. aeruginosa. Interleukin 17-mediated immunity, in the example, has a double-edged role during chronic airway infection: on the one hand, it helps limit P. aeruginosa burden, but on the other, it promotes pulmonary neutrophilia and tissue remodelling.

Infection can spread between people who have CF. Patients with CF were grouped in common spaces, and routine equipment (such as nebulizers) was not sterilised between patients. This resulted in the spread of more hazardous bacteria strains among patient groups.

Author

 Yash Batra

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