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Page: Pathophysiology
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Cystic fibrosis occurs when there is a mutation in the CFTR gene. The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lung, pancreas, and other affected organs. The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel is primarily responsible for controlling the movement of chloride from outside the cell into the cell. When the CFTR protein does not work, chloride is trapped outside the cell. Because chloride is negatively charged, positively charged ions also cannot cross into the cell because they are affected by the electrical attraction of the chloride ions. Sodium is the most common ion in the extracellular space and the combination of sodium and chloride creates the salt which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.
How this malfunction of cells in cystic fibrosis causes the clinical manifestations of CF is not well understood. One theory suggests that the lack of chloride absorption through the CFTR protein leads to the accumulation of nutrient–rich mucus in the lungs which allows bacteria to hide from the body's immune system. Another theory proposes that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory focuses on abnormal chloride movement out of the cell, which also leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc. These theories all support the observation that the majority of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick feces, etc.
The role of chronic infection in lung disease
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread amongst individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus encourages the development of bacterial microenvironments (biofilms) that are difficult for immune cells (and antibiotics) to penetrate. The lungs respond to repeated damage by thick secretions and chronic infections by gradually remodeling the lower airways (bronchiectasis), making infection even more difficult to eradicate.
Over time, both the types of bacteria and their individual characteristics change in individuals with CF. Initially, common bacteria such as Staphylococcus aureus and Hemophilus influenzae colonize and infect the lungs. Eventually, however, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics which allows the formation of large colonies — these strains are known as "mucoid" Pseudomonas and are rarely seen in people who do not have CF.
One way in which infection has spread is by passage between different individuals with CF.[27] In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers) was not sterilized between individual patients. This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are routinely isolated from one another in the health care setting and health care providers are encouraged to wear gowns and gloves when examining patients with CF in order to limit the spread of virulent bacterial strains. Often, patients with particularly damaging bacteria will attend clinics on different days and in different buildings than those without these infections.
Molecular biology
The CFTR gene is found at the q31.2 locus of chromosome 7, is 180,000 base pairs long, and creates a protein which is 1,480 amino acids long. The most common mutation, ?F508 is a deletion (?) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein. This mutation accounts for seventy percent of CF worldwide and ninety percent of cases in the United States. There are over 1,400 other mutations which can produce CF, however. In Caucasian populations, the frequency of mutations is as follows:
There are several mechanisms by which these mutations cause problems with the CFTR protein. ?F508, for instance, creates a protein which does not fold normally and is degraded by the cell. Several mutations which are common in the Ashkenazi Jewish population result in proteins that are too short because production is ended prematurely. Less common mutations produce proteins that do not use energy normally, do not allow chloride to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.
The location of the CFTR gene on chromosome 7
The location of the CFTR gene on chromosome 7
Structurally, CFTR is a type of gene known as an ABC gene. Its protein possesses two ATP-hydrolyzing domains which allows the protein to use energy in the form of ATP. It also contains two domains comprised of 6 alpha helices apiece which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.
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Important notice:
The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other
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