DCS and the immune system redux

[boulderjohn]

A few months ago I started a thread on the issue of DCS as an immune response to bubble formation. Here it is:

http://www.scubaboard.com/forums/ask-dr-decompression/279200-dcs-immune-system.html

The concept was pretty well dismissed in that thread.

I recently encountered a situation where someone said that current thinking on DCS is that it is an immune response to bubble formation. Not only did it contradict the consensus of that thread, it suggested that this contradiction was actually the trend of thinking at this time.

I therefore asked for some documentation. I got this reply, which I am told is from a hyberbaric medicine physician.

There are many, many articles on the subject. The process is not yet well determined, but there are articles galore looking at various aspects of it. Look in the Rubicon Repository for older articles. Newer articles are still in the original journals only - SPUMS Journal; UHMS Journal; Aviation,Space and Environmental Medicine; Physiology; Applied Physiology: etc. There really isn't anybody who discounts the 'immune system' theory as being essential for the understanding of DCS. There are arguments as to how that works and what other process are involved, but immune-mediated mechanisms are definitely part of the picture. Any modern textbook of Diving Medicine will have at least one chapter on it: Bennett and Elliott, Bove and Davis, Neumann and Thom."

Can anyone help give me an explanation?

 

[Mr Carcharodon]

Is’nt reasonable to assume that there is more than one mechanism? Both hypoxia and immune reactions. Which occurs depends on the tissue involved, and the total volume and size of bubbles present.

That’s all hypothesis, and not validated.

 

[AzAtty]

An immunological component to DCS has been hypothesized for many years. The theory is that bubbles cause a response by the "complement system," and the response causes biochemical changes that may result in some of the symptoms commonly associated with DCS.

Having read the thread in which you originally posted, my sense is the more learned members of the forum believe that we do not know for certain the extent to which an immune response produces DCS symptoms (or even if it does). My own reading has indicated that the data offered in support of the theory are controversial and there is no consensus on the issue.

Indeed, in a 2006 article published by the UHMS, the authors of a study attempting to correlate DCS with complement levels stated: "The role of complement in DCS remains unclear. While some have reported its depletion in the high pressure environment, no one has demonstrated a conclusive relationship between complement activation and clinical DCS or risk of DCS. This is due to the paucity of observed DCS, and the lack of human dive trials large enough to yield sufficient statistical power to conclusively demonstrate an effect of DCS risk on complement formation."

However, the article also stated "...we were unable to obtain complete blood samples for a single case of DCS in our complement study. Because of this, it is difficult to comment on the role of complement in clinical DCS. This [sic] data however leaves open the possibility that complement activation may play a role in the development of clinical DCS."

Bottom line: We don't know. Hyperbaric medicine texts may certainly discuss the theory and provide the supporting information (e.g. increased levels of T and B leukocytes after decompression), but it appears that there is no broad consensus among the researchers concerning the validity of the theory just yet.

Do a search on "complement system" in the Rubicon Foundation's research repository and you'll find several articles on the subject.

 

[Dr Deco]

Hello readers:

Slow Bubble Growth In Tissues

[1] This question has been around since the late 1960’s. When I entered the field of hyperbaric physiology in 1970, there was the question of “lag time.” Specifically, why was there a duration of twenty to thirty minutes between decompression and the appearance and development of DCS? Red cell clumping, and immune response were proposed as the cause of the lag.

I used an ultrasound device to track the gas phase development in rat muscle, and found that this “lag time” was what was needed for the growth of the in vivo gas phase. There was a resistance to the diffusion of dissolved nitrogen molecules through muscle tissue. Biochemical intermediates were not necessary. I have listed the references to my work below.

Smaller Gas Volume for Limb DCS

[2] Considerable confusion was added because researchers used rats and other small mammals as the test subjects. These animals died following decompression, and this was used as the marker for DCS. All divers know that dive tables are not tested by determining how many test subjects [divers] did not die during the table trials.

A considerably greater volume of gas is needed to kill a rat as contrasted with the smaller volume causing limb pain [limping]. It is entirely possible that other events occur in the body when very large gas volumes are encountered – especially many bubbles in the venous system [vena cava].

Dr Deco :doctor:


References

MR Powell. Detection of gas-liquid phase separation in tissues by through-transmission ultrasound: 15th Annual Meeting, Biophysical Society, New Orleans, (1971).

Powell, M. R. 1971. Decompression from pressure: monitoring by ultrasound. Union Carbide Corporation Technical Memo, Tarrytown, New York

MR Powell. Biophysical studies of decompression bubbles and their effects. Fifth Symposium on Underwater Physiology, (1972).

MR Powell. Leg pain and gas bubbles in the rat following decompression from pressure: monitoring by ultrasound: Aerospace Med., 43, 168-172 (1972).

MR Powell. Gas phase separation following decompression in asymptomatic rats: visual and ultrasound monitoring: Aerospace Med., 43, 1240-1244 (1972).

GF Doebbler, MR Powell, RW Hamilton, Jr. Biochemical indicators of decompression sickness. In: Proceedings: International Symposium on Blood-Bubble Interactions In Decompression Sickness, Toronto, August (1974).

MR Powell, GF Doebbler, RW Hamilton, Jr. Serum enzyme level changes in pigs following decompression trauma. Aerospace Med., 45, 519-524 (1974).

MR Powell. In vivo bubble growth following decompression. The Physiologist, (August, 1975).

Powell, MR., and KJ Weydig. 1974. In vivo bubble growth studies following decompression. Technical Report CRL-T-798 under ONR contract N00014-74-C-0415. Tarrytown, N.Y.: Union Carbide Corp.

 

[Kevrumbo]

.....

Hello readers:

Slow Bubble Growth In Tissues

[1] This question has been around since the late 1960’s. When I entered the field of hyperbaric physiology in 1970, there was the question of “lag time.” Specifically, why was there a duration of twenty to thirty minutes between decompression and the appearance and development of DCS? Red cell clumping, and immune response were proposed as the cause of the lag.

I used an ultrasound device to track the gas phase development in rat muscle, and found that this “lag time” was what was needed for the growth of the in vivo gas phase. There was a resistance to the diffusion of dissolved nitrogen molecules through muscle tissue. Biochemical intermediates were not necessary. I have listed the references to my work below.

Smaller Gas Volume for Limb DCS

[2] Considerable confusion was added because researchers used rats and other small mammals as the test subjects. These animals died following decompression, and this was used as the marker for DCS. All divers know that dive tables are not tested by determining how many test subjects [divers] did not die during the table trials.

A considerably greater volume of gas is needed to kill a rat as contrasted with the smaller volume causing limb pain [limping]. It is entirely possible that other events occur in the body when very large gas volumes are encountered – especially many bubbles in the venous system [vena cava].

Dr Deco :doctor:


References

MR Powell. Detection of gas-liquid phase separation in tissues by through-transmission ultrasound: 15th Annual Meeting, Biophysical Society, New Orleans, (1971).

Powell, M. R. 1971. Decompression from pressure: monitoring by ultrasound. Union Carbide Corporation Technical Memo, Tarrytown, New York

MR Powell. Biophysical studies of decompression bubbles and their effects. Fifth Symposium on Underwater Physiology, (1972).

MR Powell. Leg pain and gas bubbles in the rat following decompression from pressure: monitoring by ultrasound: Aerospace Med., 43, 168-172 (1972).

MR Powell. Gas phase separation following decompression in asymptomatic rats: visual and ultrasound monitoring: Aerospace Med., 43, 1240-1244 (1972).

GF Doebbler, MR Powell, RW Hamilton, Jr. Biochemical indicators of decompression sickness. In: Proceedings: International Symposium on Blood-Bubble Interactions In Decompression Sickness, Toronto, August (1974).

MR Powell, GF Doebbler, RW Hamilton, Jr. Serum enzyme level changes in pigs following decompression trauma. Aerospace Med., 45, 519-524 (1974).

MR Powell. In vivo bubble growth following decompression. The Physiologist, (August, 1975).

Powell, MR., and KJ Weydig. 1974. In vivo bubble growth studies following decompression. Technical Report CRL-T-798 under ONR contract N00014-74-C-0415. Tarrytown, N.Y.: Union Carbide Corp.

Rebuttal (based on study done in July 2004):

In summary, our results show that DCS induces a stress response, as confirmed by the expression of heat-shock protein in lung, liver, and heart tissue. DCS preconditioning reduced the neurological impairment caused by subsequent rapid decompression from exposure to high pressure. We conclude that bubble formation in tissues after decompression can activate a stress response and that the protective effects derived from this stress response may be the mechanism responsible for the phenomenon of diving acclimatization. . .

The stress response is a self-repairing mechanism that protects living beings from repetitive insult (20). It has been shown that prior heat stress significantly attenuates tissue injuries induced by a variety of insults, such as cardiac surgery (4, 16), sepsis (9, 27), and ischemia-reperfusion (14). In a previous study, we demonstrated that prior heat shock induced a stress response in rats and protected the animals from acute lung injury caused by pulmonary air embolism (13). However, prior induction of the stress response did not reduce the occurrence of DCS in rats after exposure to high pressure. This insignificant protection against DCS may be due to the impossibility of grading the severity of DCS in small animals. In the previous study using a rat model, the protocol used to expose the rats to pressure induced symptoms of DCS, such as dyspnea, seizure, and death, which are too severe to be evaluated for the protective effects of stress preconditioning. Therefore, we used a rabbit model in the present study and a published neurological scoring system (25) to evaluate DCS severity. Our results show that 50% of rabbits developed signs of neurological DCS after experiencing the first course of compression-decompression. These rabbits survived severe DCS after treatment with hyperbaric oxygen and developed into animals with DCS preconditioning within 24 h. Although 50% of these 12 rabbits presented signs of DCS in the next cycle of high pressure, the severity of neurological impairment was significantly reduced (Fig. 3). This result indicates that DCS preconditioning reduces the neurological impairment caused by subsequent rapid decompression after exposure to high pressure. . .

Diving acclimatization has been described as an adaptive response to decompression stress after repetitive exposure to pressure (7). This adaptation reduces a diver's susceptibility to DCS or the severity of DCS. The mechanism contributing to diving acclimatization, however, remains obscure. We proposed an "induction hypothesis," speculating that repetitive compression-decompression is a form of preconditioning that generates protective factors and reduces the severity of acute tissue injury during subsequent bubble formation. In the present study, our results further demonstrate that DCS induces a stress response and that this DCS preconditioning significantly alleviates the neurological impairment induced by subsequent exposure to high pressure. These results strengthen our induction hypothesis by explaining the mechanism underlying diving acclimatization. . .

DCS is a disease caused by gas bubble formation in tissues. Air bubbles produce their effects by mechanical obstruction, by altering the biochemical environment, or both. Bubble formation interrupts blood flow and compresses or disrupts tissues (22). Air bubbles can also initiate an air-liquid interface reaction in tissues, which activates plasma proteins, including clotting factors, enzymes, and immunoglobulins (15). The complement system, polymorphonuclear leukocytes, and oxygen metabolites are proven factors that mediate air-bubble-induced tissue injury (22). Protection from air-bubble-induced tissue injury may result from a smaller number of bubbles or from less tissue reaction to air bubbles. Wisloff and Brubakk (31) reported that endurance exercise reduces bubble formation and increases survival in rats exposed to hyperbaric pressure. It is not known whether DCS preconditioning reduces bubble formation after the next episode of decompression from a hyperbaric environment. Nevertheless, endurance exercise is a stressor that increases the expression of HSP70 and may represent a powerful preventative agent against tissue injury in several models (8, 23). These reports suggest that stresses such as endurance exercise can activate bioprotective mechanisms. Compatible with these reports, our results show that prior DCS is also a stress inducer, which may activate a bioprotective mechanism similar to that induced by endurance exercise. This suggests that this protection involves mechanisms more complex than a reduction in bubble formation. . .

Acclimatization to neurological decompression sickness in rabbits -- Su et al. 287 (5): R1214 -- AJP - Regulatory, Integrative and Comparative Physiology

 

[nielsent]

I sat in on a lecture that was given by a diving physiologist one Dr. Bruce Cameron, who works for canadian navy. He works on the beginning portions of DCS, the venous gas emboli and how they effect immune response. In his talk he said that his research into the effects of venous gas emboli on the immune system showed that the bubbles cause an inflammation response by the immune system in all divers, but it is more pronounced in divers with little experience. It actually appears as if the immune system begins to recognize the venous emboli and does not react as pronounced with repeated exposure. I cite his most recent article in this post only as a reference to the scientist, as the research that I just spoke on is still in publication.

Cameron BA, CS Olstad, JM Clark, R Gelfand, EA Ochroch, RG Eckenhoff RG. 2007. Risk factors for venous gas emboli after decompression from prolonged hyperbaric exposures. AVIATION SPACE AND ENVIRONMENTAL MEDICINE . 78: 493-499.

 

[Kevrumbo]

Re-posting link, and a good overview of DCS and the Immune Response article here:

http://atlanticunderwater.com/index.php?option=com_docman&task=doc_download&gid=9&Itemid=91

 

[boulderjohn]

Re-posting link, and a good overview of DCS and the Immune Response article here:

http://atlanticunderwater.com/index.php?option=com_docman&task=doc_download&gid=9&Itemid=91

If you follow this discussion all the way through, you will see that this article is part of the question. It is very old. The information I received from many sources, including especially Rubicon and Gene Hobbes, is that the results of this have never been replicated and the idea is not currently accepted.

 

[Kevrumbo]

If you follow this discussion all the way through, you will see that this article is part of the question. It is very old. The information I received from many sources, including especially Rubicon and Gene Hobbes, is that the results of this have never been replicated and the idea is not currently accepted.

Use it as background and context in light of the July 2004 study cited above in rebuttal (post #5):

RE: ". . .The complement system, polymorphonuclear leukocytes, and oxygen metabolites are proven factors that mediate air-bubble-induced tissue injury (22). . ."

Boulderjohn --with all due respect to Dr Deco and others--"the idea" is plausible (using a revised test subject paradigm/model in study cited above) and not entirely dismissed by all. . . (see post#6 as well).

On the other hand, certain findings of other experimental or
human studies were reproduced by the authors in their rat
model. A reduction in the susceptibility to DCS was observed
in the rats after repeated hyperbaric exposure. In a recent study
using a rabbit model, Su and colleagues (12) have shown that
a DCS preconditioning reduced the neurological impairment
caused by subsequent rapid decompression from exposure to
high pressure. The protective effects could be derived from a
stress response with an expression of heat shock protein in
various tissues. This diving acclimatization has been suggested
to occur in humans; indeed, divers undergoing repeated compression-
decompression cycles have a reduced susceptibility to
acute DCS (9).

Invited editorial (Jan 2007): A rat model to study decompression sickness after a trimix dive.
http://jap.physiology.org/cgi/reprint/102/4/1301

 

[Dr Deco]

Hello Readers:

Immune Response and DCS

What are my views on this subject? The topic is large and extensive in time. Much is to be considered.

1. There is DCS and there is DCS. It takes many forms depending on the location of the free-gas phase and the volume of this phase. Joint-pain DCS [the “bends”] is very different in its etiology [cause and mechanism] than is arterial gas embolism of the spinal cord.

2. DCS in rats and rabbits is not exactly the same as DCS in humans both in terms of the gas volume and in DCS itself. In fact, Dr JS Haldane [in 1908] stated that he was not even certain that non-humans [e.g., goats and sheep, etc.] could get the same form(s) of DCS as human divers.

3. There is complete agreement amongst barophysiologists that DCS progresses from a “bubble disorder” [i.e., DCS that can be completely reversed by an application of pressure in a recompression chamber, say, within 3 to 4 hours] to some entity that cannot be altered by pressure [longer than 5 hours after the first appearance] but might respond to hyperbaric oxygen applied over an extended duration. In the former stage, immune responses probably play a small role, if any at all, while, in the latter case, immune responses could be very important.

4. In my research, I was most interested in the “early” cases, that is, those caused primarily by gas bubbles. Others were more interested in the “late” cases, since these were not caused by a few, simple bubbles but rather by many intricate [and more interesting!] biochemical processes. I worked with researchers from both sides and we all learned from each other.

5. While many interesting things can be learned from rats and rabbits, these do not elicit the same DCS response as humans. It is difficult to “push” the decompression with human test subjects to increase the DCS and find these immune responses. Many test subjects would actually die – as is true with rats and rabbits!

6. My research at NASA focused on DCS during EVA, commonly referred to as “space walks.” Here I found that the incidence of DCS depended on the amount of musculoskeletal activity [exercise] performed both before depress and while at lower pressure, in addition to the magnitude of the pressure change.

The premise of this “influence of exercise” was the formation of tissue micronuclei. This has yet to be proven [you cannot see the micronuclei], but it is consistent with the known physics of the situation. Virtually all barophysiologists today would agree that this exercise effect is correct but might not credit to it the importance that I do.

It is also possible that some additional process or processes are involved [immunological]. This would apply to the facilitation of nuclei formation or an increase in their ability to grow with a pressure reduction. Let us consider this aspect next.

Which End of the Bubble Process?

My work at NASA also revealed that the tendency to DCS varied from test subject to subject. This aspect is not novel. It has been known for decades that individuals vary with respect to their tendency to get “the bends.”

My particular version of this is that the biochemistry needs to be focused on what causes the difference in bubble formation. Thus far, work has been directed at what biochemical processes occur after depress. Thus far, few have been found – and the results are inconsistent – but this has not dampened enthusiasm amongst both professionals and amateurs alike. Unfortunate, nothing has been directed at the difference in bubble generation amongst individuals. I could not generate funding while at NASA, and I eventually retired.

Exercise is a big player, and I have mentioned it many times over the ten years of existence of “Ask Dr Deco.” [In addition, it is in the scientific literature.] Nevertheless, the vast majority of the postings have responders asking “Were you hydrated?” This is something that has been shown to not be of importance except in extreme cases. No one asks about exercise, “Did you push, pull, or strain?”

Thus, you see, I am not opposed to DCS and “immunological responses.” What I question is “where is the cart and where is the horse.” There might be a very strong role in bubble generation mechanisms. This is the “front end” so to speak, and the immunological part is the horse – not the cart.

Dr Deco :doctor: