Cystic fibrosis is the result of reduced Cl- conductance in epithelial tissue. An autosomal recessive disease that is a result of a mutation on chromosome 7, affecting the cystic fibrosis transmembrance conductance regulator (CFTR), patients with cystic fibrosis die young, usually of lung failure. (There are also problems with sweat, pancreatic function, and infertility.) There is currently no cure; gene therapy is probably the best hope for the future. (I will post about gene therapy in the future.)
There are several classes of mutations in the CF gene that can be responsible for the malfunction in chloride conductance. These mutations disrupt CFTR function in the following ways: preventing expression of the transcript, reducing cell-surface expression of CFTR, impairing channel regulation, or by altering the channel properties. However in 70% of cases, the mutation is a three-nucleotide deletion which eliminates the amino acid phenylalanine from the protein CFTR, and because of the location of the absence, CFTR does not fold properly and cannot leave the endoplasmic reticulum/Golgi system.
As a consequence of these changes, chloride ions (negatively charged) that usually move passively through the CFTR and maintain equilibrium between the intracellular and extracellular space, now become trapped inside the cell. This in turn disrupts the electrical gradient, so that sodium ions (with their positive charges) also do not have their usual concentrations inside and outside the cell (sodium now stays inside the cell). Since NaCl becomes trapped inside the cell, water also moves from the extracellular space into the cell by osmosis, resulting in the accumulation of a higher than normal concentration of salt outside of the cell - the basis for the sweat test for cystic fibrosis (patients have higher than normal concentrations of salt in their sweat).
Due to this accumulation and the lack of normal water transport, the fluid layer in the lungs becomes more viscous and contains a higher concentration of mucous than in normal patients. The mucous plugs impair breathing and trap bacteria, making infection more likely. Additionally, the high NaCl concentration of the surface fluid in the lungs inactivates the antibacterial agents secreted by the lung epithelial cells. The bacteria therefore multiply, and most CF patients have established chronic pulmonary infection within the first few months of life. The resulting inflammatory response contributes to the mucous and leads to chronic lung damage.
So see how much trouble a little thing like negatively charged chloride ions not being able to move out of your cells can cause?? I hated taking a course on ion channels my first-year in grad school (I'm a behavioral neuroscientist, and had had all the electrical engineering I wanted in college), but the darn things are actually very important.
Information taken from Ion Channels and Disease (2002) by Frances M. Ashcroft. Graphic and description can be found here.
3 comments:
(To be said in my best air-head, dumb-blonde impersonating voice):
Science is hard!
Very interesting and though jargon-detailed as it must be, I got alot out of it. First, one small note -- the word `epithelial' equates to outer lining, basically for external surfaces even when internal as indeed, a cell surface, and that might be worth remarking on. But thats not really here or there, lol. What I got out of it is that cystic fibrosis gets its name from an actual functioning regulator, a normal part of the body at the cellular level, and not a term for degenerative process per-se. I found that interesting.
Second, what it boils down to is that cystic fibrosis disables or interferes with cellular ion traffic between a cell membrane to the outside world (still inside of course, like in the lung lining) in such a way that water is absorbed excessively by cells and this in turn leaves much of the salt of water "marooned" outside the cell, and this gunks up the inside passages and alveoli of the lungs by accumulating as mucous, etc.
The one thing not entirely clear, is it sounds like the disease is not directly fatal, it just sets up the kind of `domino' failures of the immune system and breathing to interfere with body functions. For some reason, I had prior to this the erroneous idea it was associated with a failure of the breathing reflex itself. Medical stuff when synthesized is so interesting! Keep up such science posts at intervals in the future.
Very good, an excellent example of `boxed' overview like I try to do in history.
- Aurelian
Aurelian,
Sorry about about all the jargon. I am frequently unsure of how much lingo and biological "shop-talk" others know, having been in the ivory tower for these long years. I'll try to communicate it differently in the future.
Actually, the regulator gets its name from the disease. Cystic fibrosis was named for the fibrosis that occurs in the pancreas and lungs, and the CFTR protein,when discovered, was named for its major role in the pathogenesis of the disease.
I'm glad you enjoyed it, and Saturday will always be Science day.
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