Fundamental Papers

The UVICF has published several theoretical articles laying out a rationale for why GSH augmentation in CF patients would have positive effects on the pathophysiology of that disease. The following two links are the two most elaborated versions of that thesis. However, they are written in "scientific-ese," and may be difficult to understand. So, underneath the links, you will find a short description of the CF-GSH hypothesis, in which a mighty effort to write in colloquial English has been made (whether successfully is for you to judge).

The Fundamental Papers


Layman's Explanation of the CF-GSH Hypothesis

GSH is the abbreviation for reduced L-glutathione. GSH is a very important substance in your body's defenses. It is produced inside of cells, where it plays a role in neutralizing harmful substances. GSH is also exported from cells, and once outside of the cells in the extracellular environment, it plays several important roles as well. We will talk more about exactly what GSH does in a moment.

Normally, the cells make enough GSH for themselves, and also export GSH to outside of the cells. Some areas of the body need more extracellular GSH than others. One such place is the lungs. Your lungs, in addition to releasing GSH from its own cells into the fluid lining the lungs, also imports GSH from the rest of the body in order to have enough GSH to meet its needs.

However, a strange situation exists in a CF person's body. To understand this situation, you must first understand that GSH is an anion, or a negatively charged substance. Cells have special anion transporters or channels that allow anions like GSH to be exported from the cells. The usual transporter in most epithelial (surface) cells, whether those be in the lung or the intestine, is the channel created by the CFTR protein. This channel is missing or defective in CF persons. There is also a channel created by the MRP protein. It does almost everything the CFTR channel does, but unfortunately for CF persons, most cells do not normally express this channel. Only a few types of cells normally express the MRP channel, and these include liver cells, red blood cells, and also immune system cells.

So here is the strange situation: because CF persons have a missing or defective CFTR channel, most of their epithelial cells-- the cells that do not express MRP-- will not be able to export GSH very efficiently if at all. This leads, over time, to a severe deficit of GSH in the extracellular environment of a CF person. However, in the cells which do express MRP, GSH levels will be depleted, because those cells will be trying very hard to make up that big deficit outside of the cells by exporting their GSH to the blood where it can be circulated to areas that need it more. (Either that, or by using up their glutathione stores through bactericidal activity, cells may be unable to efficiently replenish those stores because of the extracellular deficit.) Got that? Regular cells will have normal (or even slightly high) levels of GSH inside of them. MRP cells will have depressed levels of GSH inside of them. And the levels of GSH outside of the cells, such as in the fluid lining the lungs or the intestines, will be very low. This is the strange situation of a person with CF.

Let's look at the effects of this strange situation on a CF person's body:

1) Regular cells will have normal (or even slightly high) levels of GSH inside of them, but be relatively unable to efflux that GSH.

No one yet knows what the consequences of this are. Stay tuned.

2) MRP-expressing cells will have depressed levels of GSH inside of them.

The MRP-expressing cells that are important to look at here are the immune system cells. The immune system consists of many different types of cells. These cells control the body's defenses. The two main thrusts of body defenses (outside of the antibody system) are inflammation and neutralizing/killing harmful things, such as toxins or germs. Those two thrusts go hand in hand. When your body inflames, it is marshalling the killing forces and sending them to where the harmful things are. In the case of, say, a germ, the killing forces release oxidants and elastase, which pummel the germ in question. After pummeling it, the killing forces attempt to actually kill and clear away the germ from the body.

GSH is a very important part of all of this activity. The level of GSH (actually, the "redox ratio" of reduced to oxidized glutathione) inside of the immune system cells determines whether the cells go into inflammatory action or not. Low levels of GSH lead to inflammation. Normal levels of GSH switch off inflammation.

Furthermore, the level of GSH in the killer cells themselves determines whether the cells get the signal to "kill!" or not. Low levels of GSH in the killer cells lead to lack of killing action. Normal levels of GSH in the killing cells allow them to kill.

You can see the problem already, I'm sure. In CF, a person's immune cells will be in a constant state of depleted GSH. The consequences? First, chronic inflammation. Those immune cells will never switch off the inflammation mode, because (at least in CF adults) they never have normal levels of GSH inside of them. Chronic inflammation is a hallmark of CF.

Second, immunodeficiency. The killer cells will be very ineffective killers because they never get a clear signal to kill. Because they aren't effective killers, germs will remain and the body will recruit more and more killers because the germs aren't being killed. (A CF person has about 400 times the number of neutrophils (one type of killer cell) than normal persons.) But the greater number of killers doesn't do much good, because they can't kill very well. Furthermore, chronic stimulation of these killer cells because of chronic inflammation leads the killer cells to "poop out." This is another reason why the needed killing doesn't take place. The germs get a big break. Colonization of the lung with germs and other nasties is another hallmark of CF.

The end result? A CF person is in a chronic state of inflammation -- even over- inflammation -- but cannot get rid of germs and other nasty organisms because of immunodeficiency. While there are many other contributing factors to this end result, the GSH problem in CF is a large part of the situation.

3) Over time, a severe extracellular deficit of GSH develops.

A mentioned above, GSH not only plays an important part inside of cells, it plays an important part outside of cells as well, in the extracellular environment, sch as in the fluid lining the lungs or the intestines. However, CF adults have only about 10% of normal GSH levels in the extracellular environment of their lungs. So what happens if, like in CF, a person over time develops a severe shortage of GSH in the extracellular environment?

One important consequence is that your mucus becomes thicker. GSH in the extracellular environment is used by the body to break down mucus and make it thinner. A severe shortage of GSH outside the cells will prevent that desired thinning action from taking place.

Second, your lung surface will begin to lose its protective coating, called surfactant. Normal levels of GSH are needed for adequate surfactant in the lungs.

The third cluster of effects relate to the antioxidant capabilities of GSH. There are numerous antioxidants used by the body, but the main small molecule antioxidant is, in fact, GSH. In the case of CF, a deficit of GSH means a breakdown of antioxidant function. What does this mean?

Well, first, any oxidants you breathe in (like pollution) will be less likely to be neutralized.

But perhaps even more important than the oxidants you breathe in are the oxidants you produce yourself. Remember those immune system cells? One of the primary means of defense is polymorphonuclear neutrophils (PMN, or neutrophils for short). These neutrophils are killers, sent out to destroy bacteria and other nasties that get into your lungs. Now, the weapons the neutrophils use, and the debris left over from killing the nasties, are themselves harmful things. To simplify, the neutrophils cause the production of oxidants and the neutrophils also produce elastase. Oxidants can directly damage cells. Elastase eats elastin -- the connective tissue of the body. The task for the body is to keep these killers around, while simultaneously preventing the oxidants and the elastase produced by their activities from damaging the body itself.

So, the body has a couple of systems to prevent that from happening. One is called the antioxidant system. This system finds and neutralizes oxidants so that they cannot attack your own cells. The second system is called the antiprotease system. Antiproteases tackle elastase and prevent it from eating your own connective tissue.

So in the normal body, everything is fine. The neutrophils kill nasties, and the antioxidant system cleans up the oxidants produced, and the antiproteases tackle the elastase produced and so the body is protected from the killing activity of the neutrophils.

So what happens when one of the body's main antioxidants is in seriously short supply extracellularly? One effect of this is easy to see--oxidants produced by neutrophils will not be neutralized and these oxidants can then damage your cells directly. Ouch.

But there's more. Oxidants inactivate antiproteases. The increased amount of un-neutralized oxidants attack the antiproteases, causing them to be less effective. Less elastase is neutralized by the body. So this un-neutralized elastase attacks the connective tissues of the body. Double ouch.

But there's even more. Oxidants also damage the neutrophils themselves. For this reason, as well as the reasons outlined in the previous section, the neutrophils lose their killing ability to a significant degree. This results in two things: more nasties can stay in the lungs and not get killed, but also the body makes a lot more neutrophils to overcome their lack of killing power. In CF, your body will make almost 400 times the normal amount of neutrophils to compensate for this. Triple and quadruple ouch. And as all these over-recruited neutrophils die, they will spill their contents into your mucus, making it even thicker. Quintuple ouch.

Now, these almost 400 times more neutrophils are going to produce much more elastase and oxidants. Much more. And because of the messed up antioxidant system, this means that there will be even more killing of your body's cells and connective tissue. More and more and more. It is a cascade -- a vicious negative cycle that gets worse and worse. Ouch to the tenth power!

How do your lungs die in CF?  Yes, in part from the harm done by the bacteria and other nasties which can now take up residence in your lungs. But also because your body's attempt to kill these nasties is in fact killing your own body. We call that "auto-immune destruction." Indeed, scientists are beginning to think of CF as a disease with a strong autoimmune destruction component. Though CF is not like other "true" auto-immune diseases, such as lupus, in that the CF body is not mistaken about what is your body and what is the enemy, it is still primarily your own body's immune system that destroys your lungs and other affected organs. So even if you are not colonized by any bacteria, your lung function will degenerate every day that you live. Every single day.

What to Do?

The therapeutic approach described is actually pretty simple. If you can't get GSH out of the cells because of the genetic defect, why not just take more into your body, whether by inhalation, oral supplementation, or even IV? In other diseases, this has worked effectively to restore normal levels of GSH. Restoring that GSH will prevent the oxidant damage, prevent the elastase damage (by rescuing the antiproteases), and restore the killing capacity of the neutrophils -- which will in turn cause the body to produce less (that is, more normal levels of) neutrophils. The inflammation switch is turned to "off." Killer cells get the signal to "kill." Your mucus is thinner, as it should be. Lung protective coating is restored. Your body stops the bacteria and your body stops killing itself and starts effectively protecting itself. (It may also be desirable at the beginning of the treatment period to add something called a cysteine donor, such as NAC (N-acetyl cysteine), as well, in order to help the MRP-expressing cells to up their level of GSH inside of themselves quicker. But the backbone of the approach remains the addition of GSH to the body directly.)

The only study we could initially find of CF and GSH way back in the late 1990s when the UVICF was putting the CF-GSH hypothesis together, was an in vitro study (a study done in cell plates). When they added GSH to CF sputum, an indicator of oxidant presence dropped by over 90%. An indicator of amount of neutrophils dropped by almost 50%. An in vivo trial with several CF patients was reported by the same team in July 1999. They found similar decreases in oxidant stress. Since those early days, many more articles based on new research and trials on the role of GSH in CF pathophysiology have been authored, and links to many of these can be found in our empirics section.

An old, unglamorous, unpatentable therapy--the augmentation of GSH--may in fact be extremely effective. The scientific essays listed in the links above, as well as the Investigator's Brochure on GSH that we have put on this website, also provide evidence that it is safe. Sometimes old, unglamorous unpatentable therapies are overlooked by the scientific and pharmaceutical worlds. But they should not be overlooked. That was the purpose in writing the above-linked essasy on the scientific rationale of this approach. Give it to your doctor and have a serious discussion about it.

The other sections of our Glutathione Page on this website will provide an overview of selected clinical trials, observational studies, and case reports that your doctor might also find interesting. Dr. Clark Bishop's protocol for GSH augmentation therapy in CF is also provided, along with many other pertinent pieces of information. Click the green button below, and dive right in!