Aspirin As A Cure For Sepsis

[tyw]

All the studies mentioned are observational studies, specific only to Staphylococcus aureus, and do not elucidate the mechanism behind why such observations are shown.

First, there is direct evidence that Aspirin did nothing for many other types of bacterial infection. We should assume this to be the case until proven otherwise. Commentary will be made with reference to Staph specifically.

Also, studies like this one -- http://aac.asm.org/content/39/8/1748.full.pdf , are talking about preventing the side effects of Staph infection, specifically with reference to endocarditis (inflammation of endocardium in the heart), and specifically when a Staph infection is forced upon the subject (rabbits in this case).

In other words:

(1) Any study on aspirin wrt Staph infections already assumes that the infection has taken place. They say nothing about how aspirin could affect the susceptibility to infection (which in the study I cited previously, shows actual iron-dependent mechanics by which aspirin can potentially lead to increased likelihood of infection -- The Active Component of Aspirin, Salicylic Acid, Promotes Staphylococcus aureus Biofilm Formation in a PIA-dependent Manner)

(2) The main benefits from aspirin cannot be assumed to be associated with modulation of infection virulence (as I will discuss below).

----

Then, at least 20% of people carry around Staph with them all the time, and have no symptoms of infection whatsoever. We have no clue what modulates virulence and infection -- Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design

All we can talk about is this vague notion that "those who are immune-compromised seem to suffer symptoms from colonisation of Staph", and that "The majority (>80%) of S. aureus nosocomial bacteremias are caused by invasion of the endogenous colonizing strain"

Note that this is often associated with reduced levels of inflammatory signalling molecules:

Interleukin-4 (IL-4), mannose-binding lectin, toll-like receptor 2 (TLR2), glucocorticoid receptor gene, and C-reactive protein polymorphisms have all been linked to carriage, as has HLA-DR3 (69, 95–97). The identified IL-4 polymorphism causes lower levels of IL-4, resulting in reduced mucin production and dampening of the Th2 response (98, 99).​

"Dampening of the Th2 response" => more risk of infection. Aspirin, of course, affects these signalling molecules as well. In what direction (more or less inflammatory signals), and to what consequence, is completely unknown.

Then, we have the whole bacterial quorum sensing and competition model:

This “first-come-first-served” approach is also observed in its interplay with other staphylococcal species. Staphylococcus epidermidis colonizes almost 100% of humans, often with multiple strains concurrently (113). S. aureus carriage is negatively associated with S. epidermidis and P. acnes in adults (107). Resident S. epidermidis reduces but does not prevent S. aureus colonization in animal models following elimination of their original nasopharyngeal flora.​

This becomes mind-boggling complex .... we have no clue what co-infections and other factors leads to Staph aureus specifically infecting one person vs another.

Even the case mentioned here -- Aspirin treatment is associated with a significantly decreased risk of Staphylococcus aureus bacteremia in hemodialysis patients with tunneled cath... - PubMed - NCBI . These were already unhealthy hemodialysis patients, whereby:

There was a lower rate of catheter-associated S aureus bacteremia in patients treated with aspirin versus those not treated with aspirin (0.17 versus 0.34 events/patient-catheter-year, P = 0.003), whereas no such difference was observed for other bacteria. This association was dose dependent, seen mostly with the 325-mg aspirin dose.​

Again, no difference for any other bacteria, and only a mild absolute difference in risk, with no clue how other medications these patients were taking interacted with aspirin, with no possibility of inference toward populations who are not already undergoing hemodialysis.


All these complications is why I hold to the fact that we have no clue by what mechanism aspirin works with Staph Aureus, in what patient context, much less wrt any other bacterial infection, much less to infections from other pathogen types. We do not have a plausible mechanism by which this works. The closest we have to a mechanism is the iron-associated mechanism described by Dotto et. al., and that mechanism proposes that aspirin increases Staph Aureus biofilm formation.

There are reasons to take aspirin, but any mechanisms toward using aspirin for management of infections are isolated to Staph Aureus, and are still shrouded in uncertainty.

....

 

[Amazoniac]

#include <iostream>
using namespace std;

int main ()
{

int obvious;
obvious=0;
cout<<" \n"; //silly greeting
cout<<" \n\n"; //exception to the greeting
cout<<"Both of these guys are software developers, there must be something about it that attracts people with a great deal of weight, brain weight.\n";
cout<<"What is burtlan's profession?";
cin>>obvious;
while (obvious!="Software developer")
{

cout<<"ARE YOU HIGH?\n";​

}
cout<<"Correct.";​

return 0;
}

Ok, I can already feel a slight skull expansion.

--
If the inflammation was induced mainly by the infection to protect yourself from it, then how can aspirin help? However if the infection flared because of a constant inflammed state, it's understandable if it worked. I know that it gets to a point where it's difficult to discern, but still..
If someone has a latent infection that's being kept under the best possible control, supressing inflammation will allow it to spread further, and as soon as you stop the anti-inflammatory drug that were not assisted by antibiotics, that's a recipe for shock, isn't it? What am I missing?

 

[PakPik]

If someone has a latent infection that's being kept under the best possible control, supressing inflammation will allow it to spread further, and as soon as you stop the anti-inflammatory drug that were not assisted by antibiotics, that's a recipe for shock, isn't it? What am I missing?

Hello Amazoniac,

It's my understanding that shock is more severe and more likely to happen in people who do not mount an effective antiinfectious, pro-inflammatory response early on the infectious process. That is, shock is more likely to happen and to be deadly in a person who was immunesuppressed beforehand. That doesn't align well with the explanations that shock is bad because of the inflammatory response, and that the inflammatory response is "the" culprit in shock. Therefore, to reduce the possibility of the shock state or make it less likely to be deadly/severe, a person would want to make sure that they are not immunesuppresssed and that they are perfectly capable of mounting a fast, acute (as in not delayed and lengthy), effective and strong pro-inflammatory response. You can check out my post here where I elaborate and share evidence on the subject: Sugar Slows Down Immune Function

Regarding aspirin, it is important to know that aspirin is like 4 or more different drugs depending on the dose or concentration of salicylate achieved in blood/tissue. This is a good classification for aspirin (see reference "***" at the end):

ASPIRIN I -> 0.1 mM - 0.5 mM of salicylate in blood, achieved by about 300 mg -2000 mg aspirin daily
ASPIRIN II -> 0.5 mM - 1 mM of salicylate blood, achieved by about 2000 mg - 4000 mg daily
ASPIRIN III -> 1 mM - 2 mM '', '' 4000 mg - 6000 mg daily
ASPIRIN IV -> 2 mM - 5 mM '', '' 6000 mg - 8000 mg daily

Immune effects (as per the previously mentioned reference, and many other papers I've seen):

ASPIRIN I -> Highly immunestimulatory, or pro-iflammatory, specially in doses above 500 mg (Note: very low doses of aspirin, such as the 80 mg aspirin might not exert this effect as powerfully since they only block Cyclooxygenase-1, not Cyclooxygenase-2). It enhances the inflammatory response to antigens (for example endotoxin, etc...). This might be a problem for people with chronically high antigen exposure, but at the same time this might be a great thing for a person who is immunesuppressed to fight infections and lower the chance of getting chronically infected, developing a bad case of -or even preventing- sepsis, cancer, etc. This pro-inflammatory effect is largely mediated by the blockage of Prostaglandin-E with subsequent decrease in cyclic-AMP (cAMP) <- two of the more important directors of immunesuppression.
ASPIRIN II -> This is a blurry area; may have either or both anti-inflammatory and pro-inflammatory effects.
ASPIRIN III-> I haven't come across much info on this one (but I suspect it enters immunosuppressive terrain).
ASPIRIN IV -> Immunesuppressive a.k.a anti-inflammatory, and very powerful at that. Mainly due to powerfully increasing extracellular adenosine.

This article/letter echoes what I'm trying to point out (everything he is referring to falls in the terrain of "ASPIRIN I" as I defined before):
Aspirin may improve outcome in sepsis by augmentation of the inflammatory response. - PubMed - NCBI

"for aspirin treatment we would like to argue that it is more likely that this is related to an augmented pro-inflammatory response rather than to anti-inflammatory effects.

Perhaps counter-intuitively, aspirin increases the pro- inflammatory cytokine response after whole blood stimulation with endotoxin in healthy volunteers [2]. Other non-steroidal anti-inflammatory drugs, such as ibuprofen, have also been shown to significantly augment levels of the pro-inflammatory cytokines TNFα, IL-6, and IL-8 following intravenous administration of endotoxin in healthy volunteers, by 3.9-, 3.1-, and 2.9-fold, respectively [3]. As prostaglandins are known to attenuate (innate) pro-inflammatory cytokine production at the transcriptional level [4], it appears plausible that the pro-inflamatory effects of these COX inhibitors are mediated by attenuation of prostaglandin production. Therefore, patients on chronic low dose aspirin may exhibit an augmented pro-inflammatory cytokine response to invading pathogens. This enhanced initial cytokine response likely results in more effective clearance of bacteria [5], whereas an initially less pronounced pro-inflammatory cytokine response may result in ineffective microbial killing, leading to an increase of the bacterial load, ultimately causing more pronounced activation of the immune response, septic shock, organ failure, and increased risk of death"​

So, ASPIRIN I is a great pro-inflammatory, inmmune enhancing agent -though it has certain anti-inflammatory effects by reducing something like certain platelet factors, etc-. Other than that, ASPIRIN I is not an anti-inflammatory and it is protective against sepsis, infections, cancers because it fights immunesuppression and primes the immune system to respond strongly and more effectively against insults. The real anti-inflammatory/immunesuppressive aspirin would be around over 4 grams daily (ASPIRIN III, ASPIRIN IV).

In short, if aspirin is beneficial to prevent or protect from sepsis, which I'm convinced it is in many of cases, it is not due to it being an antii-inflammatory, but due to it being a pro-inflammatory, anti-immunesuppressive agent at doses taken as in ASPIRIN I. Conversely, taking ASPIRIN III or IV doses for sepsis would probably be very detrimental (well, unless it is sepsis caused by fungus. Aspirin can be a great antifungal agent, but I'm not sure how immunesuppressive doses of aspirin would play out in the context of fungal sepsis).


*** This is the paper where I originally started to think about aspirin in classes. The classification I made is slightly different, but in general terms I was inspired by their classification: Modes of action of aspirin-like drugs: Salicylates inhibit Erk activation and integrin-dependent neutrophil adhesion

@Koveras, this might be of your interest

 

[Amazoniac]

Aspirin may improve outcome in sepsis by augmentation of the inflammatory response. - PubMed - NCBI

ASPIRIN I is not an anti-inflammatory and it is protective against sepsis, infections, cancers because it fights immunesuppression and primes the immune system to respond strongly and more effectively against insults. The real anti-inflammatory aspirin would be around over 4 grams daily (ASPIRIN III, ASPIRIN IV).

Interesting! Thanks.
@DaveFoster

 

[Koveras]

Hello Amazoniac,

It's my understanding that shock is more severe and more likely to happen in people who do not mount an effective antiinfectious, pro-inflammatory response early on the infectious process. That is, shock is more likely to happen and to be deadly in a person who was immunesuppressed beforehand. That doesn't align well with the explanations that shock is bad because of the inflammatory response, and that the inflammatory response is "the" culprit in shock. Therefore, to reduce the possibility of the shock state or make it less likely to be deadly/severe, a person would want to make sure that they are not immunesuppresssed and that they are perfectly capable of mounting a fast, acute (as in not delayed and lengthy), effective and strong pro-inflammatory response. You can check out my post here where I elaborate and share evidence on the subject: Sugar Slows Down Immune Function

Regarding aspirin, it is important to know that aspirin is like 4 or more different drugs depending on the dose or concentration of salicylate achieved in blood/tissue. This is a good classification for aspirin:

ASPIRIN I -> 0.1 mM - 0.5 mM of salicylate in blood, achieved by about 80 mg -2000 mg aspirin daily
ASPIRIN II -> 0.5 mM - 1 mM of salicylate blood, achieved by about 2000 mg - 4000 mg daily
ASPIRIN III -> 1 mM - 2 mM '', '' 4000 mg - 6000 mg daily
ASPIRIN IV -> 2 mM - 5 mM '', '' 6000 mg - 8000 mg daily

Immune effects:

ASPIRIN I -> Highly immunestimulatory, or pro-iflammatory, specially in doses above 500 mg. It enhances the inflammatory response to antigens (for example endotoxin, etc...). This might be a problem for people with chronically high antigen exposure, but at the same time this might be a great thing for a person who is immunesuppressed to fight infections and lower the chance of getting chronically infected, developing a bad case of -or even preventing- sepsis, cancer, etc. This pro-inflammatory effect is largely mediated by the blockage of Prostaglandin-E with subsequent decrease in cyclic-AMP (cAMP) <- two of the more important directors of immunesuppression.
ASPIRIN II -> This is a blurry area; may have either or both anti-inflammatory and pro-inflammatory effects.
ASPIRIN III-> I haven't come across much info on this one.
ASPIRIN IV -> Immunesuppressive a.k.a anti-inflammatory, and very powerful at that. Mainly due to powerfully increasing extracellular adenosine.

This article/letter echoes what I'm trying to point out (everything he is referring to falls in the terrain of "ASPIRIN I" as I defined before):
Aspirin may improve outcome in sepsis by augmentation of the inflammatory response. - PubMed - NCBI

"for aspirin treatment we would like to argue that it is more likely that this is related to an augmented pro-inflammatory response rather than to anti-inflammatory effects.

Perhaps counter-intuitively, aspirin increases the pro- inflammatory cytokine response after whole blood stimulation with endotoxin in healthy volunteers [2]. Other non-steroidal anti-inflammatory drugs, such as ibuprofen, have also been shown to significantly augment levels of the pro-inflammatory cytokines TNFα, IL-6, and IL-8 following intravenous administration of endotoxin in healthy volunteers, by 3.9-, 3.1-, and 2.9-fold, respectively [3]. As prostaglandins are known to attenuate (innate) pro-inflammatory cytokine production at the transcriptional level [4], it appears plausible that the pro-inflamatory effects of these COX inhibitors are mediated by attenuation of prostaglandin production. Therefore, patients on chronic low dose aspirin may exhibit an augmented pro-inflammatory cytokine response to invading pathogens. This enhanced initial cytokine response likely results in more effective clearance of bacteria [5], whereas an initially less pronounced pro-inflammatory cytokine response may result in ineffective microbial killing, leading to an increase of the bacterial load, ultimately causing more pronounced activation of the immune response, septic shock, organ failure, and increased risk of death"​

So, ASPIRIN I is a great pro-inflammatory, inmmune enhancing agent -though it has certain anti-inflammatory effects by reducing something like certain platelet factors, etc-. Other than that, ASPIRIN I is not an anti-inflammatory and it is protective against sepsis, infections, cancers because it fights immunesuppression and primes the immune system to respond strongly and more effectively against insults. The real anti-inflammatory/immunesuppressive aspirin would be around over 4 grams daily (ASPIRIN III, ASPIRIN IV).

This is the paper where I originally started to think about aspirin in classes. The classification I made is slightly different, but in general terms I was inspired by their classification: Modes of action of aspirin-like drugs: Salicylates inhibit Erk activation and integrin-dependent neutrophil adhesion

In short, if aspirin is beneficial to prevent or protect from sepsis, which I'm convinced it is in many of cases, it is not due to it being an antii-inflammatory, but due to it being a pro-inflammatory, anti-immunesuppressive agent at doses taken as in ASPIRIN I. Conversely, taking ASPIRIN III or IV doses for sepsis would probably be very detrimental (well, unless it is sepsis caused by fungus. Aspirin can be a great antifungal agent, but I'm not sure how immunesuppressive doses of aspirin would play out in the context of fungal sepsis).

@Koveras, this might be of your interest

Thanks PakPik

 

[Sheila]

Dear Contributors All,
What a fascinating post denoting "the dose makes the poison", or aspirin's usefulness depends upon what one is trying to achieve and for how long/short etc.
Could it be that many medicinally active agents have this dose/response curve? I am thinking of many anti-microbial herbs that may indeed actually be immune stimulatory and are often only suggested low dose and if they work in a similarly contextual manner, high dose might be hugely contraindicated - depending, of course on what you want to do and their activity as currently understood! I have seen so much trouble in the Alt Health industry with more is better....
Thank you, thank you, this has given me much to consider and I appreciate your time to get your thoughts down here.
Sincerely
Sheila

 

[Constatine]

Thats what separates this forum from many others: the ability to engage in objective discussion (most of the time) without getting overly emotional. These discussions are helpful to all of us, so thanks for that.

Just avoid the political discussions

 

[Constatine]

#include <iostream>
using namespace std;

int main ()
{

int obvious;
obvious=0;
cout<<" \n"; //silly greeting
cout<<" \n\n"; //exception to the greeting
cout<<"Both of these guys are software developers, there must be something about it that attracts people with a great deal of weight, brain weight.\n";
cout<<"What is burtlan's profession?";
cin>>obvious;
while (obvious!="Software developer")
{

cout<<"ARE YOU HIGH?\n";​

}
cout<<"Correct.";​

return 0;
}

Ok, I can already feel a slight skull expansion.

--
If the inflammation was induced mainly by the infection to protect yourself from it, then how can aspirin help? However if the infection flared because of a constant inflammed state, it's understandable if it worked. I know that it gets to a point where it's difficult to discern, but still..
If someone has a latent infection that's being kept under the best possible control, supressing inflammation will allow it to spread further, and as soon as you stop the anti-inflammatory drug that were not assisted by antibiotics, that's a recipe for shock, isn't it? What am I missing?

Lol I'm a software developer as well. A whole lot of us on this forum.

 

[Giraffe]

When talking about the immune system, Ray Peat sometimes cites Jamie Cunliffe. I only recently started to study Cunliffe's work. Here is what I read so far:

According to the general accepted view the purpose of the immune system "is to locate, chase, attack and eliminate invading foreign organisms (‘pathogens’) – hence, intentional pathogen killing." Cunliffe however thinks that this assumption is "potentially flawed". In his view, the core function of the immune system is to dispose of tissue debris and restore order." The immune system discriminates between mess and non-mess and responds accordingly.

Cells survey their own health, and if they sense that they are damaged beyond the capacity to repair it, they commit suicide (apoptosis). This is a controlled shutdown, and normally it's not a big deal to clean up behind those cells. If this has failed, and cells die by necrosis, we have a mess: "their [the cells'] membranes rupture, their contents are spilled and this promotes inflammation. Inflammation provokes aggressive T-cell responses."

In his article Intentional Pathogen Killing – or Denial of Substrate? he suggests that debris of degenerating cells would provide a rich source of nutrients for micro-organisms, while a rapid disposal of debris would starve 'pathogens' by denial of nutrient substrate. In consequence this would suppress infection.

On his website Cunliffe mentioned that "aspirin lowers the threshold at which individual cells opt for apoptosis", and he links to this article. I don't know what the mechanism is. Peat thinks that "things [can] interfere with that whole process of either repairing or letting the cells die quickly to be replaced." (interview). -- Does maybe aspirin offset this interference?

-----

You will say now, "Wait a minute! Haidut's original post states that NSAIDs delayed cell death, presumably by blocking caspase activity, and caspase is involved in apoptosis."

So I tried to look up the study. I think it's this one.

Aspirin is not a caspase inhibitor.

To explore NSAID specificity, we assayed the catalytic activity of caspases-1, -3, -4, -5, and -9 (Figure 1).These caspases were selected to represent inflammatory, initiator, and executioner caspases with diverse tetrapeptide substrates. Inhibition was not specific to caspase-4, as NSAIDs reduced catalysis of multiple caspases (Table2). Aspirin is a notable exception, with no inhibitory properties. However, aspirin has a unique acetylation mechanism that will not affect caspase catalysis (Lecomte et al., 1994).

Possible detriments of caspase inhibition should not be discounted.

We propose that caspase contributions are relevant to the NSAID anti-inflammatory mechanism of action by reducing cell death and the generation of pro-inflammatory cytokines. However, despite the beneficial anti-inflammatory results of caspase inhibition, the possible detriments should not be discounted. Reducing healthy caspase signaling increases the incidence of viral and bacterial infection, and deregulates inflammation and cell proliferation (Guo et al., 2015; McIlwain et al., 2013).

-----

Aspirin is discussed as treatment for sepsis, and I think that there are multiple mechanisms by which aspirin can help. It's mostly its antiinflammatory effect and its effect on platelet aggregation that are discussed. Some articles mention that several clinical trials are currently exploring aspirin both as a preventative agent and as a treatment in sepsis and acute respiratory distress syndrome (ARDS).

 

[Giraffe]

This article/letter echoes what I'm trying to point out (everything he is referring to falls in the terrain of "ASPIRIN I" as I defined before):
Aspirin may improve outcome in sepsis by augmentation of the inflammatory response. - PubMed - NCBI

"for aspirin treatment we would like to argue that it is more likely that this is related to an augmented pro-inflammatory response rather than to anti-inflammatory effects.

So, ASPIRIN I is a great pro-inflammatory, inmmune enhancing agent -though it has certain anti-inflammatory effects by reducing something like certain platelet factors, etc-. Other than that, ASPIRIN I is not an anti-inflammatory and it is protective against sepsis, infections, cancers because it fights immunesuppression and primes the immune system to respond strongly and more effectively against insults. The real anti-inflammatory/immunesuppressive aspirin would be around over 4 grams daily (ASPIRIN III, ASPIRIN IV).

The letter mentioned by PakPik points to this study.

Let's consult Wikipedia first:

[ Interleukin-18-binding protein (IL18BP)] is an inhibitor of the proinflammatory cytokine IL18. This protein binds to IL18, prevents the binding of IL18 to its receptor, and thus inhibits IL18-induced IFN-gamma production. This protein is constitutively expressed and secreted in mononuclear cells. The expression of this protein can be enhanced by IFN-gamma.

So when an antiinflammatory drug is used, what will happen to IL18BP? It will go down, right?

And what did they do in the study?

They took blood samples before aspirin treatment and several times afterwards. Each time they mixed one blood sample with LPS (lipopolysaccharide) to measure aspirin's effect on TNF-alpha, and they mixed another blood sample with LPS and IL18 to measure its effect on IFN-gamma.

• I think that IL-18 and thus IFN-gamma measurements were taken out of context: IL18 was added without its counterpart IL18BP.
  
• TNF-alpha and aspirin work in so many ways, it's difficult to tell from tests in whole blood cultures what would happen in vivo. Aspirin seems to inhibit some of the actions of TNF-alpha.

Effects of Low-Dose Aspirin on Acute Inflammatory Responses in Humans | The Journal of Immunology
This study says low dose aspirin (75 mg) in vivo is protective and antiinflammatory.

 

[lollipop]

The letter mentioned by PakPik points to this study.

Let's consult Wikipedia first:

So when an antiinflammatory drug is used, what will happen to IL18BP? It will go down, right?

And what did they do in the study?

They took blood samples before aspirin treatment and several times afterwards. Each time they mixed one blood sample with LPS (lipopolysaccharide) to measure aspirin's effect on TNF-alpha, and they mixed another blood sample with LPS and IL18 to measure its effect on IFN-gamma. No control blood samples.

• I think that IL-18 and thus TNF-alpha measurements were taken out of context: IL18 was added without its counterpart IL18BP.
  
• TNF-alpha and aspirin work in so many ways, it's difficult to tell from tests in whole blood cultures what would happen in vivo. Aspirin seems to inhibit some of the actions of TNF-alpha.

Effects of Low-Dose Aspirin on Acute Inflammatory Responses in Humans | The Journal of Immunology
This study says low dose aspirin (75 mg) in vivo is protective and antiinflammatory.

Thank you @Giraffe for your posts. I learn so much from your thorough, sound, well supported posts. Not sure you are often recognized and after this post, I felt the urge to express my appreciation.

 

[PakPik]

So when an antiinflammatory drug is used, what will happen to IL18BP? It will go down, right?

Hi @Giraffe

1st of all, every single drug has a different Mode of Action. So, we can not jump to the conclusion that "will happen to IL18BP? It will go down, right?". We can't say neither yes or no, this is because every drug has its own specifics, and we can not make such a huge assertion, that something will go down or up, on any drug, before studying its specific mechanisms.

2nd) IL18BP is antiinflammatory while IL18 is PRO-inflammatory. Aspirin, at specific dosages, as you rightly shared, increases IL-18-induced IFN-gamma production, but to my knowledge aspirin does not increase IL18BP, so the results are perfectly valid and the experiment is not lacking because they didn't include IL18BP as you assume (if you have evidence that aspirin increases IL18BP, I'd appreciate if you share with me through a Private Message. Also Note: I'm talking about aspirin/salicylate concentrations 0.1 mM-0-5 mM- to be consistent with the study)

Since the cytokine IL-18 is normally readily produced in the body when there's a Lypopolysaccharide (LPS) challenge, then adding IL-18 to the blood can be of great value to mimic the "in vivo" response. The Liver's Kupffer cells are one great source of IL-18 under LPS challenge, therefore a significant portion of IL-18 that appears in the blood after a LPS challenge comes from the liver. That's why they wisely designed this experiment with added IL-18: to mimic the cytokine profile -in this case specifically using IL-18- that would appear in the blood in vivo.

Also, there's a similar human study but this time it's in vivo and using Ibuprofen (another cyclooxygenase inhibitor). This time the human subjects themselves were injected with an Endotoxin load, so obviously there was no need to add IL-18 or other Co-stimulator. Results: significant increases in TNF-alpha. (Of course, it would be of interest to find similar "in vivo" studies done on aspirin and compare, but a huge body of evidence leads me to suspect the results would be quite similar to this ibuprofen study, at least regarding TNF-alpha increase, a very important TH1 cytokine.)
Pretreatment with ibuprofen augments circulating tumor necrosis factor-alpha, interleukin-6, and elastase during acute endotoxinemia. - PubMed - NCBI

"In vitro prostaglandin E2 (PGE2) was found to exert a negative feedback on the release of IL-1 and TNFa [18, 19], while inhibition of prostaglandin synthesis by indomethacin augmented lipopolysaccharide (LPS)-induced TNFa release [20]. It is likely that in vivo pharmacologic manipulation of arachidonic acid metabolism interferes with cytokine regulation."

"Plasma levelsof tumor necrosis factor-a (TNFa), interleukin-1 (IL-1),and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers."​

"Pretreatment with ibuprofen caused significant increase and temporal shift in plasma levels of both TNFa (P = .003 vs. endotoxin alone) and IL-6"

"The present study demonstrated for the first time that also in humans inhibition of the cyclooxygenase pathway of arachidonic acid metabolism results in increased levels of circulating cytokines in endotoxinemic subjects. "
​

3rd) The study you mention was done with the live blood (an "ex vivo" study), yes it's not an ideal in vivo study, but the blood is useful to study what the effects of taking 650 mg of aspirin for a period of time are on immune function, specifically white blood cells. Ex vivo studies can be useful when an in vivo study is not possible -for ethical reasons, etc...-. And they are relatively trustworthy as they mimic natural conditions closely.

Ex vivo
"In science, ex vivo refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal alteration of natural conditions." (Wikipedia)​

4th) Prostaglandin-E inhibition, as a pro-inflammatory and anti-immunosuppressant approach, is a very, very well studied concept. They study it all the time in cancer immunology research, with different scientific techniques: in vivo, ex vivo, in vitro, etc... It's common knowledge to these researchers that Prostaglandin-E inhibition is key to increase cell-mediated and Th1 effector immunity, which is a highly inflammatory branch of the immune system, the one the body employs to mop up cancer cells and also key against most viral and bacterial infections presentations. There are different Cyclooxygenase/Prostaglandin receptors inhibitors effectively used in the labs, and interestingly they have studied low-to-moderate doses aspirin as well. They have shown over an over low-to-moderate-dose aspirin to be a useful Pro-inflammatory agent against different types of cancer (i.e found to be an effective activator of anti-tumor immunity) for example:
https://www.sciencedaily.com/releases/2015/09/150903131416.htm
, consistent with the many other studies showing the pro-inflammatory, anti-immunosuppressive profile of low-to-moderate dose aspirin.

In conclusion, the previous discussion and papers I've shared show aspirin at certain doses where it is able to block both Cox-1 AND Cox-2 (specifically those that achieve around 0.1-0.5 mM salicylate concentration) is a powerful enhancer of pro-inflammatory, Th-1 immunity; that is not a mystery, and there are tons of papers on that. Such immune-enhancement has important applications for pathologies where immunosuppression, in particular of of the Cell-meadiated and Th1 kind (e.g sepsis, cancer, etc...). This doesn't negate it has some antiinflammatory actions (it calms down certain platelets activities, for example), but the pro-inflammatory effects when the immune system is under specific stimuli are more prominent. A true anti-inflammatory profile of aspirin -i.e that dampens the pro-inflammatory immune responses- is reached practically only with high doses of aspirin -multiple grams daily, reaching over 1 mM of salicylate concentration in blood-, as it was pointed out in my previous post (you might be interested in this paper as well, which focuses mainly on high-dose, millimolar, the true "anti-inflammatory" concentrations of Aspirin https://www.researchgate.net/publication/51882648_Aspirin_and_immune_system).

P.S: Immunosuppressive/antiinflammatory agents have been a total failure in the clinical use for sepsis. They not only don't improve outcomes, but also have increased mortality in trials. This shouldn't be surprising, since the old theory of sepsis has been shown to be wrong. They are calling now for the use of immuno-stimulant (i.e specific Pro-inflammatory agents in sepsis such as TLR4 agonists/activators, etc..., also calling for inhibitors or agents that reverse the immunosuppression that is rampant in people who develop sepsis, so that antibacterial and antiviral inflammatory responses can *hopefully* act.) Therefore, potent anti-inflammatories and/or immunosuppressants as a main line of treatment is something outdated and counterproductive, according to the findings from recent years. There's plenty of information on those findings on science databases that I suggest to check out if you're interested, because, if I am not wrong, you're holding on to the old and incorrect explanation and description of sepsis.

Note: As always, I'm merely sharing my conclusions to the best of my understanding and info from many scientific materials studied -none of this is medical advice or guidance-. You can check out all these subjects and verify yourself.

 

[Giraffe]

@lisaferraro, thanks. :)

..........

1st of all, every single drug has a different Mode of Action. So, we can not jump to the conclusion that "will happen to IL18BP? It will go down, right?". We can't say neither yes or no, this is because every drug has it's own specifics, and we can not make such a huge assertion, that something will go down or up, on any drug, before studying its specific mechanisms.

2nd, IL18BP is antiinflammatory while IL18 is PRO-inflammatory. Aspirin, at specific dosages, as you rightly shared, increases IL-18-induced IFN-gamma production, but to my knowledge aspirin does not increase IL18BP, so the results are perfectly valid and the experiment is not lacking because they didn't include IL18BP as you assume (if you have evidence that aspirin increases IL18BP, I'd appreciate if you share with me through a Private Message. Also Note: I'm talking about aspirin/salicylate concentrations 0.1 mM-0-5 mM- to be consistent with the study)

What I wrote is not a "huge assertion", but how the regulation of these substances is understood today: IFN-gamma increases the binding protein IL18BP, and IL18BP in turn blocks the production of IFN-gamma triggered by IL18. This is a self-limiting feedback circle. If inflammation is low, IL18 and IFN-gamma are low, hence no need for IL18BP. In inflammation all three will be elevated. As far as I know, this is not controversial at all.

Since the cytokine IL-18 is normally readily produced in the body when there's a Lypopolysaccharide (LPS) challenge, then adding IL-18 to the blood can be of great value to mimic the "in vivo" response. The Liver's Kupffer cells are one great source of IL-18 under LPS challenge, therefore a significant portion of IL-18 that appears in the blood after a LPS challenge comes from the liver. That's why they wisely designed this experiment with added IL-18: to mimic the cytokine profile -in this case specifically using IL-18- that would appear in the blood in vivo.

IL18 is a requirement for the induction of IFN-gamma. They tested the IFN-gamma response in blood samples stimulated with LPS and IL18, and found that it was stronger in the blood samples pretreated with aspirin.

@PakPik, induction of IL18BP occurs after some delay (source). You argue, that cells in the liver are an important source of IL18, and therefore adding IL18 to the blood sample mimics the in vivo condition.
(1) Don't you think that a similar argument (liver/spleen important) could be urged for IL18BP?
(2) Are you claiming that the pre-existing level of IL18BP does not matter?

That said, based on the in vivo study on ibuprofen you posted, I agree that reduced IL18BP probably is not the main factor. It's likely that other mechanisms (among others presumably prostaglandin inhibition) were involved. :)

They did a similar study but this time it's in vivo and using Ibuprofen (another cyclooxygenase inhibitor). This time the human subjects themselves were injected with an Endotoxin load, so obviously there was no need to add IL-18 or other Co-stimulator. Results: significant increases in TNF-alpha and IL-6. (Of course, it would be of interest to find similar studies done on aspirin and compare, but evidence leads me to suspect the results would be quite similar to this ibuprofen study.)

Pretreatment with ibuprofen augments circulating tumor necrosis factor-alpha, interleukin-6, and elastase during acute endotoxinemia. - PubMed - NCBI

"In vitro prostaglandin E2 (PGE2) was found to exert a negative feedback on the release of IL-1 and TNFa [18, 19], while inhibition of prostaglandin synthesis by indomethacin augmented lipopolysaccharide (LPS)-induced TNFa release [20]. It is likely that in vivo pharmacologic manipulation of arachidonic acid metabolism interferes with cytokine regulation."

"Plasma levelsof tumor necrosis factor-a (TNFa), interleukin-1 (IL-1),and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers."

"Pretreatment with ibuprofen caused significant increase and temporal shift in plasma levels of both TNFa (P = .003 vs. endotoxin alone) and IL-6"

"The present study demonstrated for the first time that also in humans inhibition of the cyclooxygenase pathway of arachidonic acid metabolism results in increased levels of circulating cytokines in endotoxinemic subjects. "

Both IL-6 and TNF-alpha seem to have central roles in the regulation of the immune response. They are both seen as mainly inflammatory, but both have been described to possess antiinflammatory actions as well. -- Homeostasis can't be described with just a few markers. It's the net effect what matters.

If TNF-alpha and IL-6 were sufficient markers for an inflammatory immune response, how do you explain that the fever was lower in the ibuprofen treated group?

Side note: I am not disputing that permanently elevated levels indicate that something is out of whack. I think that levels after an acute insult may be difficult to interpret.

IL-6 Is an Antiinflammatory Cytokine Required for Controlling Local or Systemic Acute Inflammatory Responses

While IL-10 has been shown to play an antiinflammatory role during endotoxemia or acute lung inflammation (27, 30, 31), our findings suggest that IL-6 is also an antiinflammatory molecule whose function cannot be compensated for by other antiinflammatory molecules such as IL-10.

3rd The study you mention was done with the live blood (an "ex vivo" study), yes it's not a perfect in vivo study, but the blood is useful to study what the effects of taking 650 mg of aspirin for a period of time are on immune function, specifically white blood cells. Ex vivo studies can be useful when an in vivo study is not possible -for ethical reasons, etc...-. And they are relatively trustworthy.

Ex vivo

"means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal alteration of natural conditions." (Wikipedia)

I do agree that in vitro studies have their place. I think they are the means of choice when researchers want to find out more about mechanisms, but to say, "This marker was elevated, this proves that aspirin is inflammatory in vivo", is quite a stretch.

 

[goodandevil]

All the studies mentioned are observational studies, specific only to Staphylococcus aureus, and do not elucidate the mechanism behind why such observations are shown.

First, there is direct evidence that Aspirin did nothing for many other types of bacterial infection. We should assume this to be the case until proven otherwise. Commentary will be made with reference to Staph specifically.

Also, studies like this one -- http://aac.asm.org/content/39/8/1748.full.pdf , are talking about preventing the side effects of Staph infection, specifically with reference to endocarditis (inflammation of endocardium in the heart), and specifically when a Staph infection is forced upon the subject (rabbits in this case).

In other words:

(1) Any study on aspirin wrt Staph infections already assumes that the infection has taken place. They say nothing about how aspirin could affect the susceptibility to infection (which in the study I cited previously, shows actual iron-dependent mechanics by which aspirin can potentially lead to increased likelihood of infection -- The Active Component of Aspirin, Salicylic Acid, Promotes Staphylococcus aureus Biofilm Formation in a PIA-dependent Manner)

(2) The main benefits from aspirin cannot be assumed to be associated with modulation of infection virulence (as I will discuss below).

----

Then, at least 20% of people carry around Staph with them all the time, and have no symptoms of infection whatsoever. We have no clue what modulates virulence and infection -- Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design

All we can talk about is this vague notion that "those who are immune-compromised seem to suffer symptoms from colonisation of Staph", and that "The majority (>80%) of S. aureus nosocomial bacteremias are caused by invasion of the endogenous colonizing strain"

Note that this is often associated with reduced levels of inflammatory signalling molecules:

Interleukin-4 (IL-4), mannose-binding lectin, toll-like receptor 2 (TLR2), glucocorticoid receptor gene, and C-reactive protein polymorphisms have all been linked to carriage, as has HLA-DR3 (69, 95–97). The identified IL-4 polymorphism causes lower levels of IL-4, resulting in reduced mucin production and dampening of the Th2 response (98, 99).​

"Dampening of the Th2 response" => more risk of infection. Aspirin, of course, affects these signalling molecules as well. In what direction (more or less inflammatory signals), and to what consequence, is completely unknown.

Then, we have the whole bacterial quorum sensing and competition model:

This “first-come-first-served” approach is also observed in its interplay with other staphylococcal species. Staphylococcus epidermidis colonizes almost 100% of humans, often with multiple strains concurrently (113). S. aureus carriage is negatively associated with S. epidermidis and P. acnes in adults (107). Resident S. epidermidis reduces but does not prevent S. aureus colonization in animal models following elimination of their original nasopharyngeal flora.​

This becomes mind-boggling complex .... we have no clue what co-infections and other factors leads to Staph aureus specifically infecting one person vs another.

Even the case mentioned here -- Aspirin treatment is associated with a significantly decreased risk of Staphylococcus aureus bacteremia in hemodialysis patients with tunneled cath... - PubMed - NCBI . These were already unhealthy hemodialysis patients, whereby:

There was a lower rate of catheter-associated S aureus bacteremia in patients treated with aspirin versus those not treated with aspirin (0.17 versus 0.34 events/patient-catheter-year, P = 0.003), whereas no such difference was observed for other bacteria. This association was dose dependent, seen mostly with the 325-mg aspirin dose.​

Again, no difference for any other bacteria, and only a mild absolute difference in risk, with no clue how other medications these patients were taking interacted with aspirin, with no possibility of inference toward populations who are not already undergoing hemodialysis.


All these complications is why I hold to the fact that we have no clue by what mechanism aspirin works with Staph Aureus, in what patient context, much less wrt any other bacterial infection, much less to infections from other pathogen types. We do not have a plausible mechanism by which this works. The closest we have to a mechanism is the iron-associated mechanism described by Dotto et. al., and that mechanism proposes that aspirin increases Staph Aureus biofilm formation.

There are reasons to take aspirin, but any mechanisms toward using aspirin for management of infections are isolated to Staph Aureus, and are still shrouded in uncertainty.

....

Blah blah blah blah blah

 

[goodandevil]

The letter mentioned by PakPik points to this study.

Let's consult Wikipedia first:

So when an antiinflammatory drug is used, what will happen to IL18BP? It will go down, right?

And what did they do in the study?

They took blood samples before aspirin treatment and several times afterwards. Each time they mixed one blood sample with LPS (lipopolysaccharide) to measure aspirin's effect on TNF-alpha, and they mixed another blood sample with LPS and IL18 to measure its effect on IFN-gamma.

• I think that IL-18 and thus IFN-gamma measurements were taken out of context: IL18 was added without its counterpart IL18BP.
  
• TNF-alpha and aspirin work in so many ways, it's difficult to tell from tests in whole blood cultures what would happen in vivo. Aspirin seems to inhibit some of the actions of TNF-alpha.

Effects of Low-Dose Aspirin on Acute Inflammatory Responses in Humans | The Journal of Immunology
This study says low dose aspirin (75 mg) in vivo is protective and antiinflammatory.

Interesting and excellent.

 

[Texon]

@haidut The first two studies did not use cell culture. The second two studies used yeast cells (of fungi kingdom, not animal).

The two studies I quoted were done on animal tissue, with some in vivo treatment, and yielded minor to no result.

I should qualify my statement then: We don't know if aspirin works as an anti-pathogenic aid in animals, nor on what types of pathogens it is effective against, nor in what ways it works synergistically (or not) with other treatment protocols.

....

@tyw @lisaferraro @haidut
The title is a bit misleading, as it is actually a combo of IV vitamin c, thiamine and low dose hydrocortisone. Hope this finds an audience as it appears to be so effective. Turns out about 50 hospitals including UT Houston are using this right now. Thank God Dr. Marik wasn't afraid to try something different.

Could Vitamin C Be the Cure for Deadly Infections? | Science | Smithsonian

 

[haidut]

@tyw @lisaferraro @haidut
The title is a bit misleading, as it is actually a combo of IV vitamin c, thiamine and low dose hydrocortisone. Hope this finds an audience as it appears to be so effective. Turns out about 50 hospitals including UT Houston are using this right now. Thank God Dr. Marik wasn't afraid to try something different.

Could Vitamin C Be the Cure for Deadly Infections? | Science | Smithsonian

Excellent, thanks for this link! Finally some real progress in medicine.

 

[lollipop]

@tyw @lisaferraro @haidut
The title is a bit misleading, as it is actually a combo of IV vitamin c, thiamine and low dose hydrocortisone. Hope this finds an audience as it appears to be so effective. Turns out about 50 hospitals including UT Houston are using this right now. Thank God Dr. Marik wasn't afraid to try something different.

Could Vitamin C Be the Cure for Deadly Infections? | Science | Smithsonian

Thank you for the tag @Texon. Very interesting. I know @yerrag and @Janelle525 have explored Vitamin C with great success. I have started a low daily dose and like it. Interesting that Thiamine is involved. Haidut has posted some great studies on Thiamine recently.

 

[lollipop]

Excellent, thanks for this link! Finally some real progress in medicine.

+1

 

[CarbAppreciator]

On his website Cunliffe mentioned that "aspirin lowers the threshold at which individual cells opt for apoptosis", and he links to this article. I don't know what the mechanism is.

I suspect aspirin's promotion of AMPK expression is involved, working similarly to fasting, as these pathways selectively stress the most cluttered/damaged cells/mitochondria.
http://molpharm.aspetjournals.org/content/molpharm/88/4/708.full.pdf
Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling

Thanks for those links, very interesting and elegant view of the immune system.