Fw: Cytokines

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From: " ilena rose " <ilena@...>

Sent: Monday, September 24, 2001 2:13 AM

Subject: Cytokines

CYTOKINES: CAUSE OF CHRONIC FATIGUE

Novel chronic fatigue syndrome (CFS) theory finally produces

detailed explanations for many CFS observations:

(email - pall@...; phone 509-335-1246)

(SMB WEBSTE http://molecular.biosciences.wsu.edu/)

A novel theory of the cause of CFS has been published which is

supported by diverse biochemical and physiological observations of CFS,

while providing explanations for five of most difficult puzzles about this

medical condition. The theory has been published by Dr. L. Pall

(Professor of Biochemistry and Basic Medical Sciences, Washington State

University) in several publications (1-4,9). The theory starts with the

observation that infections that precede and may therefore induce CFS and

related conditions act to induce excessive production of inflammatory

cytokines that induce, in turn, the inducible nitric oxide synthase (iNOS).

This enzyme, in turn, synthesizes excessive amounts of nitric oxide which

reacts with another compound (superoxide) to produce the potent oxidant

peroxynitrite (see Fig. 1). Peroxynitrite acts via six known biochemical

mechanisms to increase the levels of both nitric oxide and superoxide which

react to produce more peroxynitrite (Fig. 1). In this way, once

peroxynitrite levels are elevated, they may act to continue the elevation,

thus producing a self-sustaining vicious cycle (ref.1). It is this cycle,

according to the theory, that maintains the chronic symptoms of CFS and it

is this cycle, therefore, that must be interrupted to effectively treat this

condition.

Twelve different observations on chronic fatigue syndrome and

its symptoms provide support for this theory:

1. The levels of neopterin, a marker for the induction of the

inducible nitric oxide synthase are reported to be elevated in CFS (1).

2. Mitochondria are reported to be dysfunctional in CFS and

mitochondria are known to be attacked by peroxynitrite and also by nitric

oxide (1).

3. Both cis-aconitate and succinate levels are reported to be

elevated in CFS and the enzymes that metabolize these two compounds are

known to be inactivated by peroxynitrite (1).

4. The four inflammatory cytokines implicated have been reported

to been reported to be elevated in 10 different studies of CFS (1,2).

5. These same inflammatory cytokines have been reported to

induce fatigue when injected into humans (1).

6. An animal (mouse) model of CFS has " fatigue " induced by a

bacterial extract that can induce both the inflammatory cytokines and also

the inducible nitric oxide synthase.

7. Polyunsaturated fatty acid pools are reported to be depleted

in CFS and such polyunsaturated fatty acids are known to be oxidized by

oxidants such as peroxynitrite.

8. Anecdotal evidence has suggested that antioxidants such as

coenzyme Q-10, flavonoids and glutathione precursors may be useful in CFS

treatment, consistent with a role for an oxidant such as peroxynitrite.

9. Women are reported to produce more nitric oxide than men,

possibly explaining the gender bias seen in CFS. A similar gender bias is

seen in autoimmune diseases characterized by excessive peroxynitrite (i.e.

lupus, rheumatoid arthritis).

10. Cases of CFS are associated with high levels of deleted

mitochondria DNA, suggesting but not proving that mitochondrial dysfunction

can produce the symptoms of CFS (1).

11. Biochemical similarities - depletion of glutamine and

cystine pools - have been reported in CFS and several diseases characterized

by elevated peroxynitrite levels, suggesting a similar biochemical basis for

all of these conditions (1).

12. Because peroxynitrite is a potent oxidant, this theory

predicts that oxidative stress will be elevated in CFS. There was no direct

evidence for this when the theory was published but three subsequent papers

have reported substantial evidence for such oxidative stress in CFS (5-7).

These results, may therefore, be considered to confirm important predictions

of the theory, although the authors were unaware of this theory when they

initiated these studies.

CFS puzzles explained by the elevated nitric oxide/peroxynitrite

theory:

There are five different puzzles of CFS that are explained by

this theory. The first of these, the chronic nature of CFS, is explained by

the self-sustaining vicious cycle that is central to this theory. The second

is how infection and other stress which often precede CFS may produce CFS.

This theory predicts that each of these can lead into this mechanism by

inducing excessive nitric oxide. Infection is not the only stress that may

be involved in this way - both physical trauma and severe psychological

trauma can produce excessive nitric oxide synthesis (2). In addition, tissue

hypoxia may induce this cycle by increasing levels of superoxide (the other

precursor of peroxynitrite) (2).

A third puzzle about CFS is how it leads to the many

biochemical/physiological correlates reported to occur in CFS. This is

discussed with the list of 12 such correlates described above.

A fourth puzzle about CFS is how the diverse symptoms of this

condition may be generated. It turns out that a variety of factors,

including nitric oxide, superoxide, oxidative stress and

mitochondrial/energy metabolism dysfunction may have important roles (2).

For example, nitric oxide is known to stimulate the nociceptors that

initiate the perception of pain, and therefore excessive nitric oxide may

cause the multi-organ pain associated with CFS (2). Nitric oxide has a

central role in learning and memory and so its elevation may also provide a

partial explanation for the cognitive dysfunction characteristic of CFS (2).

Other symptoms explained by this theory include orthostatic intolerance,

immune dysfunction, fatigue and post-exertional malaise (2). The immune

dysfunction reported in CFS, may allow for opportunistic infections to

develop, such as mycoplasma or HHV6 infections, which may exacerbate the

basic CFS mechanism by increasing inflammatory cytokine synthesis.

What about multiple chemical sensitivity, posttraumatic stress

disorder and fibromylagia?

A fifth puzzle regarding CFS is its variable symptoms and, most

importantly, its association with three other conditions of equally puzzling

etiology, multiple chemical sensitivity (MCS), posttraumatic stress disorder

(PTSD) and fibromylagia (FM). The theory explains the variable symptoms,

>from one case to another, in part, by a somewhat variable tissue

distribution of the elevated nitric oxide/peroxynitrite.

A common etiology (cause) for CFS with MCS, PTSD and FM has been

suggested by others (discussed in refs 4,9). A common causal mechanism for

these four conditions is suggested not only by the association among these

different conditions (many people are afflicted by more than one) but also

by the overlapping symptoms typically found in these four conditions (see

refs. 4 and 9 for discussion). These overlaps raise the question about

whether MCS, FM and PTSD may be caused by excessive nitric oxide and

peroxynitrite. Each of these four conditions is reported to be often

preceded by and possibly induced by exposure to a relatively short-term

stress that can induce excessive nitric oxide synthesis.

Pall and Satterlee (4) present a substantial case for an

excessive nitric oxide/peroxynitrite cause for multiple chemical sensitivity

(MCS), including the following:

a.. Organic solvents and pesticides whose exposure is reported

to precede and presumably induce multiple chemical sensitivity, are also

reported to induce excessive nitric oxide synthesis. Such chemicals are also

reported to induce increased synthesis of inflammatory cytokines which

induce, in turn, the inducible nitric oxide synthase (leading to increased

synthesis of nitric oxide).

b.. Neopterin, a marker of induction of the inducible nitric

oxide synthase, is reported to be elevated in MCS.

c.. Markers of oxidative stress are reported to be elevated in

MCS, as predicted if excessive peroxynitrite is involved.

d.. In animal models of MCS, there is convincing evidence for

an essential role for both excessive NMDA activity (where such activity is

known to induce excessive nitric oxide) and for excessive nitric oxide

synthesis itself. If one blocks the excessive nitric oxide synthesis in

these animal models, the characteristic biological response is also blocked.

This and other evidence shows the nitric oxide has an essential role (4).

Somewhat similar evidence is available suggesting an elevated

nitric oxide/peroxynitrite mechanism for both PTSD and FM (9). PTSD is

thought to be induced by excessive NMDA stimulation, which, as discussed

above, is known to produce excessive nitric oxide and peroxynitrite (9). Two

inflammatory cytokines known to induce increased synthesis of nitric oxide

have been reported to be elevated in PTSD. PTSD animal model studies have

reported an essential role for both excessive NMDA stimulation and nitric

oxide synthesis in producing the characteristic biological response.

Interestingly, a recent study of FM implicates elevated nitric

oxide and also elevated NMDA stimulation (8), and such NMDA stimulation is

known to increase nitric oxide synthesis. As in the other conditions

discussed here, there is a pattern of evidence from studies of FM patients,

consistent with the proposed nitric oxide/peroxynitrite mechanism (9). The

theory that elevated nitric oxide/peroxynitrite is responsible for the

etiology of CFS, MCS, PTSD and FM appears to be the only mechanism to be

proposed that explains the multiple overlaps among these four conditions.

While the pattern of evidence supporting it cannot be considered definitive,

the many types of evidence providing support for this view must be

considered highly suggestive.

What does this proposed mechanism suggest about CFS treatment?

As discussed in ref 1, there are a number of agents that may be useful in

the treatment of CFS, based primarily on anecdotal evidence, that are

expected to lower the consequences of the proposed nitric

oxide/peroxynitrite mechanism. Possibly the most intriguing such mechanism

relates to the widespread use of vitamin B12 injections in treatment of CFS

(3). Two forms of vitamin B12 are being used here, hydroxocobalamin, which

is a nitric oxide scavenger and cyanocobalamin, which is converted to

hydroxocobalamin by Pall human cells (3). These observations suggest that

the nitric oxide/peroxynitrite proposed mechanism for CFS makes useful

predictions for effective treatment. It is hoped that this proposed

mechanism may allow us to optimize the use of these and other agents for

treatment of CFS and related conditions.

Other Sites with Thoughtful Presentations linked to this site

that you may wish to access are as follows:

http://www.users.skynet.be/nvdeynde/cfs/index.htm

http://www.square-sun.co.uk/cfs-nim/

http://www3.sympatico.ca/me-fm.action/

References:

1. Pall ML. Elevated, sustained peroxynitrite levels as the

cause of chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125.

http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10790736 & form=6 &

db=m & Dopt=b

2. Pall ML. Elevated peroxynitrite as the cause of chronic

fatigue syndrome: Other inducers and mechanisms of symptom generation.

Journal of Chronic Fatigue Syndrome, in press.

3. Pall ML. Cobalamin used in chronic fatigue syndrome therapy

is a nitric oxide scavenger. Journal of Chronic Fatigue Syndrome, in press.

4. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite

mechanism for the common etiology of multiple chemical sensitivity, chronic

fatigue syndrome and posttraumatic stress disorder. ls of the New York

Academy of Science, in press.

5. s RS, TK, Mathers MB, RH, McGregor NR,

Butt HL. Investigation of erythrocyte oxidative damage in rheumatoid

arthritis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome

2000;6:37-46.

6. s RS, TK, McGregor NR, RH, Butt HL.

Blood parameters indicative of oxidative stress are associated with symptom

expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.

http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10905542 & form=6 &

db=m & Dopt=

7. Fulle S, Mecocci P, Fano G, Vecchiet I, Vecchini A, Racciotti

D, Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. Specific

oxidative alterations in vastus lateralis muscle of patients with the

diagnosis of chronic fatigue syndrome. Free Radicals in Biology and Medicine

2000;15:1252-1259.

http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10924813'>http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10924813 & form=6 &

db=m & Dopt=b

8. Larson AA, Giovengo SL, IJ, Michalek JE. Changes in

the concentrations of amino acids in the cerebrospinal fluid that correlate

with pain in patients with fibromyalgia: implications for nitric oxide

pathways. Pain 2000;87:201-211.

(http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10924813'>http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10924813 & form=6

& db=m & Dopt=b

9. Pall ML. Common etiology of posttraumatic stress disorder,

fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via

elevated nitric oxide/peroxynitrite, Medical Hypotheses, in press.