NSAIDs and Cox-1 vs. Cox-2

While there are many forms of anti-inflammatories (steroids, herbs, certain foods, etc.), the most common type are NSAIDs, Non-Steroidal Anti-Inflammatory Drugs. Their main purpose is to not only reduce inflammation but to also decrease fevers and pain.

The type most people have heard of and taken are the form you can buy over the counter. Aspirin, ibuprofen (such as Advil or Motrin), and naproxen (Aleve) are all familiar household names. They block or inhibit enzymes and proteins in the body, specifically prostaglandins (PGs).  PGs promote inflammation, pain, and blood clotting, which are good for the body but can cause us ache after injury. Thus NSAIDs are also used to treat pain in disorders such as rheumatoid arthritis or kidney stones. For such disorders or for post-operational patients, doctors generally prescribe such drugs or variants (depending on the disease or recent surgery) in much high quantities.

Aspirin is an unusual NSAID. While most NSAIDs can increase your chance of cardiovascular disease, an aspirin a day has been shown to reduce risk of CVD. In addition, aspirin is a cox-1 inhibitor, while most NSAIDs partially inhibit both cox-1 and cox-2.

Cox-2 is the cox isoform that deals with inflammation, directly being affected by such cytokines as TNF and IL-1. Cox-1 is the isoform found on almost every type of cell in the body and involved in homeostasis of things such as GI tract, kidneys, and blood content. It is also the isoform that promotes PG proliferation. Ibuprofen and naproxen are nonselective, meaning that they partially inhibit both isoforms, meaning that they promote a decrease of PG as well as stopping the body’s overall message to become inflamed. At minor over-the-counter doses, cox-1 is not affected much and swelling decreases. Overdoses of such medications result due to inhibition of natural homeostasis. Gastrointestinal complications, ranging from indigestion to stomach ulcers, are 3 times higher in frequent NSAID users. Renal complications are also common side effects.

Because of these side effects, research has gone into creating an inhibitor of cox-2 only. While many versions are on the market and a couple of them are FDA approved (Celecoxib, aka Celebrex or Celebra), most are either still in trial phases or have been pulled from the market due to statistically higher rates of cardiac issues. Research is still being performed to find a healthier balance of cox-inhibitions by the NSAIDs available.

Gotlieb, David, MBChB. “Non Steroidal Anti-Inflammatory Drugs: NSAIDs.” August 2011. http://www.arthritis.co.za/nsaids.html

“NSAIDs for Arthritis Pain.” AstraZeneca, 2012. http://www.vimovo.com/nsaid-therapy.aspx

 “Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).” Pain Management Health Center, WebMD, 4 August 2011. http://www.webmd.com/pain-management/nonsteroidal-anti-inflammatory-drugs-nsaids

Good news for lactose TOLERANT Scandanavians!

Good news for lactose TOLERANT Scandanavians!

During our AIDS lecture, we learned that there is a population of people who are relatively resistant to HIV infection. These people are either heterozygous or homozygous for a mutant CCR5 allele (called Delta32). Remember: CCR5 is a chemokine receptor that serves as a co-receptor in the process by which T cells are infected with HIV particles. Without this receptor, T cell infection is greatly inhibited, and these people will have virus within their bodies but may remain “healthy” for a long period of time before they do eventually progress to AIDS (I assume that T cells are eventually infected through some other manner?).  Anyway, I began to wonder who are these lucky people with this mutant allele, and HOW did this allele evolve?

These people are Caucasians, and mostly Scandanavian (Norway, Finland, Sweden, see top picture below). It had been proposed, and is still the dominant theory out there, that this allele evolved from selective pressure from the Bubonic plague. However, a new(ish) article published in the Oxford Journal of Medicine (1) performed an extensive analysis of this hypothesis. It turns out that the places hit the hardest by the Bubonic plague were northern Africa, Asia, the Middle east, ETC. but NOT northern Europe (see bottom picture below). Plague did reach Norway and Sweden and eventually Finland, although it returned there only a few times compared with dozens of times to the hardest hit areas. So, could the bubonic plague have realistically been the evolutionary pressure by which the CCR5 mutant allele expanded? According to this article, this is highly unlikely. SO then, what WAS the evolutionary pressure?

Figure 1: Population frequencies of the CCR5-Δ32 allele (upper section: black >10%, dark grey 6–10%, pale grey <6%) and Black Death mortalities 1346–53 (lower section: black >50%, dark grey 25–50%, pale grey <25%) in Europe. Based on data from Stephens et al.¹ For computer-simulated maps, see Novembre et al.² (Taken from Cohen and Weaver, 2006)

This may seem out there, crazy, etc. (especially because it remains untested) but I think it is very interesting.   Upon trying to understand what could be different between these populations (people with the mutant allele versus without) they stumbled upon the fact that most scandanavians are lactose TOLERANT. Whereas, many of the other countries listed above (Africa, Asia, Middle East) have higher incidences of lactose INTOLERANCE (1).  Could the ingestion of dairy placed positive evolutionary pressure upon the mutant CCR5 allele? What do you think?? How would you test this hypothesis?? (I am asking because I have no idea).

 

(1) S.K. Cohn Jr andL.T. Weaver. The Black Death and Aids: CCR5-Δ32 in genetics and history.QJM: An International Journal of Medicine Volume 99, Issue 8, p. 497-503.

IgG Food Allergy Testing

 
It seems like everyone has a gluten intolerance these days, and I am no exception. I stopped eating gluten in 2007 because my doctor thought that gluten intolerance could be the cause of some skin issues I was having. I took it out of my diet, and it didn’t help the skin issues, but when I tried to put it back into my diet, I started having stomach pain. I had never had stomach issues before that. For the next couple of years, I oscillated between a gluten-free diet and periods of trying to reintroduce gluten. It never worked, and eventually I resigned myself to the gluten-free diet.
I asked my doctor about being tested for gluten intolerance, and she said that I had already done the most effective method of diagnosis – an elimination diet. She mentioned IgG blood tests of food intolerance, but she said that she considered them extremely unreliable. The other option involved me putting gluten back into my diet. At that point, I knew how I felt when eating gluten, so we agreed that it wasn’t worth the discomfort.
When I moved to Colorado and got a new doctor, she thought that I should be tested for food allergies. She wanted me to do the IgG blood test. I told her that my previous doctor was skeptical of the results, but this doctor insisted that the results from her lab are quite reliable. The test was covered by my insurance, so I did it. My results had a few foods that I should avoid completely and a few foods that I could eat no more than every 4 days, including gluten. Most of the other foods on the list were things that I eat regularly and had eaten within the 24 hours before the test. I tried the diet for a few weeks, but it was really challenging, and I didn’t notice any difference in how I felt, so I went back to my gluten-free diet.
After learning a bit more about allergies and immunoglobulin in class, I thought it would be interesting to look into the IgG blood testing more. The tests use ELISA method to evaluate IgG-mediated immune responses to various foods.
I found this blog post by a pharmacist who comes out pretty strongly against the tests. He evaluates the tests based on analytic validity, clinical validity, clinical utility and ethical / legal/ social implications, and concludes that the tests are a waste of money at best. He emphasizes that IgG antibodies signify exposure to foods not intolerance. Some research actually suggests that IgG might be a marker for food tolerance or resolution of food intolerance. He lists the recommendations against IgG blood testing by numerous US and European allergy associations.
Sheryl Miller, the clinical director at Bastyr University in Seattle, a school of Naturopathic medicine, wrote a review back in 1998 about the reliability of IgG blood testing. At their clinic, they sent the same blood sample to 3 labs for the tests under 6 different names – 3 of the samples were sent immediately after the blood draw and the rest were sent a week later, frozen according to guidelines. The results were not consistent. Bastyr concluded that the variability in results was unacceptable at two of the three labs. Miller also questioned the theory behind IgG food allergy testing. This paper was written many years ago, and perhaps the tests are more consistent now, but I did find more recent, similar anecdotes online.
Is there any evidence for the reliability or utility of these tests? It seems like most of the proponents are the labs themselves. I did see one clinical trial in which IBS patients who followed a diet based on IgG test results had significantly fewer symptoms than control patients. However, the study has been criticized for numerous shortcomings, including the fact that most patients on the IgG diet removed dairy or wheat, and regardless of IgG status, most IBS benefit from removing these foods.
After reading through all this information, though, I am still a little confused about whether IgG antibodies to commonly eaten foods are normal among people with no issues with leaky gut. It seems to me that food should stay in the digestive system and not be floating around stimulating an immune response, right? Are positive results on an IgG food intolerance test indicative of intestinal permeability rather than intolerance to specific foods?
References

Atkinson, W., Sheldon, T. A., Shaath, N. & Whorwell, P. J. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 53, 1459–1464 (2004).

Gavura, S. “IgG Food Intolerance Tests: What does the science say?” (2012).

Hunter, J. O. Food elimination in IBS: the case for IgG testing remains doubtful. Gut 54, 1203–1203 (2005).

Jones, S. M. et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. Journal of Allergy and Clinical Immunology 124, 292–300 (2009).

Miller, S. IgG Food Allergy Testing by ELISA/EIA: What Do They Really Tell Us? Townsend Letter January, 62-65 (1998).

Tomičić, S. et al. High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life. Pediatric Allergy and Immunology 5(1), 35-41 (2008).

Ancient Herbs: Boswellia

Originating from India and Egypt, Boswellia (or Frankincense) was used as one of the main components in the medical “Balsam of Jerusalem” and was also used in the treatment of skin wounds, mummification, and cremation. Today we recognize it for its anti-inflammatory properties. Seen both in vitro and in vivo, the type of molecule (triterpenes) that is found in Boswellia inhibits 5-lipoxygenase, which will limit the synthesis of leukotrienes. We know leukotrienes are an important inflammatory marker in major diseases because we see increased levels in inflammatory states such as bronchial asthma and colitis. Leukotrienes contribute by enhancing chemotaxis, superoxide radical formation, breakdown of lysosomes by phagocytes, (and in asthma) bronchoconstriction, increased mucus secretion, and increased edema just to name a few. So as you can see, they can have a powerful effect on the body, and regulating leukotriene levels may be beneficial to many people.

Boswellia help by shifting the immune response to TH2, while inhibiting TH1. It also has been shown to stabilize mast cells and regulate vascular responses to inflammation. Boswellia has also been known to have some anti-cancer properties by enhancing antiproliferation, differentiation, and apoptosis in leukemia cell lines. By inhibiting the renin-angiotensin system and stimulating the kinin system, Boswellia is able to improve sodium-water balance (by indirectly decreasing vasoconstriction and increasing vasodilation). Clinical studies have been done assessing the effectiveness of Boswellia extracts on certain inflammation-related diseases. Positive outcomes (decreased pain, swelling, side effects) were correlated with the intake of Boswellia seen in diseases such as cancer, arthritis, and IBD. However, it should be noted that some of these studies were done in addition to other treatments. Patients also experienced some side effects such as abdominal discomfort, epigastric pain, hyperacidity, and diarrhea. Interesting studies will continue to be done, but in my opinion, centuries of use indicate something positive about this herb. 

Sources: http://csuvets.colostate.edu/pain/articlespdf/benefits%20of%20boswellia.pdf

Should Everyone Undergo Aspirin Therapy for Cardiovascular Protection?

After recently learning from Dr. Cohen’s Cardiovascular Physiology class that some people take small daily doses of aspirin as a protective mechanism in preventing myocardial ischemia from a blockage in the coronary vessels, I wanted to research the side effects associated with daily aspirin intake.

Aspirin is a Non-selective NSAID (Nonsteroidal Anti-inflammatory Drug).  Non-selective means this particular drug inhibits both the COX-1 and COX-2 enzyme.  It is common for aspirin to be taken daily by patients wanting to reduce their risks of cardiovascular disease that includes conditions such as a myocardial infarction caused by an arterial thrombosis or stroke.  Aspirin prevents platelet aggregation in the coronary vessels by inhibiting the COX-1 enzyme that causes platelet activation and production by the eicosanoid, Thromboxane A₂ (TXA₂). 

However, aspirin therapy is not for everyone wanting to reduce their risks of a cardiovascular event because there is a balance of risks and benefits that must be considered.  Aspirin is associated with an increased risk of bleeding in the gastrointestinal tract as well as in the brain, which can lead to gastric ulceration with irritation to the protective lining of the stomach and a hemorrhagic stroke, respectively.  Thus, the American Heart Association (AHA) does not recommend aspirin therapy for people with an allergy to aspirin, people at risk for gastrointestinal bleeding or hemorrhagic stroke, regular alcohol drinkers, and users undergoing any simple medical or dental procedures because of aspirin’s blood thinning properties which would lead to excessive bleeding. 

Benefits against risks must be weighed out for people considering low dosage long-term aspirin use.  People should always consult with their doctor before beginning their own aspirin therapy.  Patients who are recommended for aspirin treatment have a history of a cardiovascular related event, have high risk for cardiovascular disease, have had coronary bypass surgery with a stent placed in a coronary artery, or are a diabetic male over the age of 50 or a diabetic woman over the age of 60.  Individuals who do not fit under these high risk categories should not start their own daily aspirin therapy as a cardioprotective mechanism because the side effects of internal bleeding far outweigh the benefits. 

Sources:

http://www.heart.org/HEARTORG/Conditions/HeartAttack/PreventionTreatmentofHeartAttack/Aspirin-and-Heart-Disease_UCM_321714_Article.jsp

http://www.mayoclinic.com/health/daily-aspirin-therapy/HB00073

Anti-inflammatories- a new cure for Type II Diabetes?

Type II Diabetes, a disease which has been increasing in prevalence throughout the modern world, is generally linked to obesity and an unhealthy diet. People with type II diabetes are able to produce insulin, unlike those who have type I diabetes, however, the insulin secreted by those with type II diabetes is either not enough to work properly, or their body is unable to recognize the insulin produced.  According to the review article assigned to this weeks class, type II diabetes is an autoinflammatory disease, in which the body is in a chronic state of inflammation in which interleukin-1 beta is produced and kills the beta islet cells in the pancreas (Dinarello). High levels of glucose can stimulate interleukin-1 beta production by the beta islet itself, and it can also be produced by fat cells (Dinarello). Therefore, anti-inflammatories such as interleukin-1 beta receptor antagonists can be beneficial in the treatment of type II diabetes by reducing interleukin-1 beta mediated inflammation. This is emphasized in the article "Anakinra Provides Sustainable Benefits for Diabetes," in which a study done by Dr. Thomas Mandrup-Poulsen from the Hagedorn Research Institute and Steno Diabetes Center in Gentofte, Denmark, is highlighted. Anakinra is an interleukin-1 receptor antagonist.

In Dr. Mandrup-Poulsen's study, over 70 patients were randomized to obtain Anikinra or placebo treatment for 13 weeks, adding on to their current diabetic therapy. He states that those who received 13 weeks of Anikinra treatment showed improvements in beta cell function, hemoglobin A1c levels (reflects blood glucose level), and systemic inflammation. Out of the 70 randomized patients, over 64 remained in the study to participate in the 39 week follow-up period. However, the author does not state what the criteria was to remain involved in the study, nor the reason as to why not all 70 of the patients were included in the follow up period. The authors state that at the end of the 13 week lead in period, there had not been a difference between anakinra treated patients and placebo treatment patients in A1c reduction, insulin sensitivity, or increase in insulin or metformin dose. However, during the 39 week follow up period of which none of the patients were administered Anakinra, the proinsulin/insulin ration remained significantly lower in the former Anakinra treated patients as opposed to then former placebo-treated patients. Similar results were expressed of the C-reactive protein and IL-6 levels, another cytokine which is involved in inflammation. Also, "previous responders had maintained their improved beta cell function and had achieved their target hemoglobic A1c levels with significantly lower increases in thier insulin doses, compared to the anakinra-unresponsive patients" (Diabetes Care).

Dr. Mandrup-Poulsen believes that the results of this study prove that type II diabetes is due to interluekin-1 beta mediated inflammation, and  that a  "short course of IL-1 blockade could be envisaged as add on to existing antidiabetic therapy to break the vicous cycle of glucose unduced IL-1 and IL-1 autoinduction in beta-cells" (Mandrup-Poulsen). 

However, there is another anti-inflammatory that is believed to have a positive effect on type II diabetes. Salsalate is an anti-inflammatory drug derived from salicylate and is primarily used to treat arthritis.  In the article, "Salsalate May Help Treat Type II Diabetes," it is stated that salsalate helps reduce blood sugar levels and helped with glycemic control within a variety of doses in people with type II diabetes. "In a study, published in the Annals of Internal Medicine, researchers randomly assigned 108 people with type 2 diabetes to receive 3, 3.5, or 4 grams per day of salsalate or a placebo in addition to their current diabetes therapy for 14 weeks" (Warner). The results showed that those who underwent salsalate therapy showed improvements of their blood sugar A1c levels, as well as other markers of glycemic control and heart disease risk (Warner). However, there were elevated levels of protein in the urine of some patients, which may indicate negative effects on the kidney. The author states that due to these negative effects and the small study sample, salsalate cannot yet be recommended as a treatment for type II diabetes.

In both articles, it is claimed that the pathogenesis of inflammation is involved in the onset of type II diabetes. Therefore, it is positively suggested by both studies that anti-inflammatories can potentially be used as treatment of type II diabetes once further research is enacted. What I disliked about the first article about the interleukin-1 beta blocker is that not a single negative side effect of the study was mentioned, nor was an explanation given as to why only 64 out of the 70 patients were allowed to continue to the follow up period. However, the fact that the study has moved onto a phase II trial is promising. 

What do you guys think about the pathogenesis of inflammation in type II diabetes and anti-inflammatory treatment for the disease?

Sources:

"Diabetes Care." Diabetes Care. 32. (2009): 1663-1668. Web. 25 Nov. 2012. <http://www.diabetesincontrol.com/studies/8400-&action=1>.

Dinarello, Charles A. "Leading Edge Review." Leading Edge Review. (2010): 939. Web. 25 Nov. 2012.

Warner, Jennifer. "WebMD HealthNews." WebMD HealthNews. (2010): n. page. Web. 25 Nov. 2012. <http://diabetes.webmd.com/news/20100315/salsalate-may-help-treat-type-2-diabetes>.

Caffeine may cure Parkinson Disease

       To tie coffee to health benefits, a recent study showed that caffeine might control the symptoms of Parkinson Disease. Sixty-one people in their mid-60s, with daytime sleepiness (one of the symptoms of Parkinson disease) were tracked for the study in which participants were randomly assigned to six weeks of caffeine pills or placebo pills. Caffeine pill groups received 100 milligram-caffeine pills twice per day. After 3 weeks, caffeine dose was increased to 200-milligram, which is equivalent to 2-4 cups of coffee.

            Into the six-week study, people taking caffeine didn’t show any improvement in sleepiness. Their results showed that caffeine group has averaged a five-point improvement on a ratings scale of Parkinson's symptom severity than the group who took placebos. Even though it was just modest improvement, small improvements can provide benefits to these people with the disease. But caffeine pills group did improve on an overall scale of Parkinson's symptoms, including on measures of muscle rigidity and other movement problems.

            They mention that long-term study needs to be done to determine weather the effect of caffeine wears off over time or not. Their result didn’t suggest that caffeine could be used as a treatment, so their study is not yet conclusive. But according to Dr. Michael, “caffeine seems to block a malfunctioning brain signal in Parkinson's disease that may explain these benefits in patients, but still cant be use as a treatment for Parkinson. “

            What I think of this study is, first of all their sample is too small so it’s not reliable. They also casually dismiss the difference between caffeine and coffee; they are not the same thing because there are additional chemicals, in varying amounts, in coffee.

           

http://www.cbsnews.com/8301-504763_162-57484791-10391704/caffeine-from-two-to-four-daily-cups-of-coffee-may-reduce-parkinsons-disease-symptoms/#postComments

Can Physical Therapy Improve cognitive decline in HD?

Huntington ’s Disease (HD) is a neurodegenerative disease that is cause by genetic defect. Normally the DNA sequences cytosine-adenine-guanine (CAG) is repeated 10-28 times in a healthy person but HD patients has 36-120 repetitions. Since, it is passed through families, the number seems to increase. The more the CAG repetitions occurred the higher the chance of getting the HD.

The symptoms of HD are usually noticeable around age 30s to 40s. In the early stage, patients might see some changes in mood, movement and behavior but they are still able to do daily activity like driving. In the mid to late stages, patients could experience involuntary movement (Tremors), aggression, difficulty swallowing, depression, speech impairment, memory lose and many other symptoms. 

Currently, HD is not yet curable but patients are given medications to help reduce the symptoms and make them comfortable as possible. One of the article I read online says that Huntington diseases patients who are doing physical therapy has maintained a reasonably good level of motor performance and cognitive level than it would have been without therapy. However, the article didn’t mention how long/often the patients received therapy and what stage of the disease they were on. In your opinion would the effect of physical therapy be differ in the early and later stage of HD? How often would you recommend the therapy to the patients?

https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/physical-therapy-and-huntingtons-disease-treatment-and-management/

http://www.hdsa.org/living-with-huntingtons/family-care/stages-of-hd.html

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001775/

http://physicaltherapyjournal.com/content/88/7/820.full

http://en.wikipedia.org/wiki/Huntington%27s_disease

Anti inflammatory diet

There are people that claim that dieting correctly can help decrease inflammation and even prevent it. "Learning how specific foods influence the inflammatory process is the best strategy for containing it and reducing long-term disease risks"[1]. Dr. Weil explains in his webpage the caloric intake, carbohydrates, fats, proteins, fiber, phytonutrients, vitamins and minerals, dietary supplements and water that we are supposed to intake daily to decrease inflammation. It seems to me just as a healthy diet and that the results turn out more into a placebo effect, due to a better life style, reducing diseases, such as diabetes and cardiovascular disease. 
The diet is based on a pyramid giving you options for you to create your own personalized diet.[2]

Other places claim that certain products help specific diseases. Erythritol is a "safe" sweetener which doesn't affect your blood sugar, and it is really low in calories and in fact it is "used" to help fight cancer and diabetes. Coconut milk is "used" by many people to treat neurodegenerative diseases, diabetes and cancer.[3] There are many products that people used to treat diseases but to be certain which ones works are hard to say, because there is no scientific evidence to proof such thing, mostly it can be a placebo, that happens in response to the change in life style.

To conclude many people agree with eating certain foods and avoiding another ones. Most of the websites that talk about anti-inflammatories foods, agree to eat fats and oils such as omega-3-fatty acids, flax seeds, canola oil, etc. Fruits and vegetables and good protein sources. As well as avoiding junk food, high-fat meats, sugar, and processed foods.[4] 


[1] http://www.drweil.com/drw/u/ART02012/anti-inflammatory-diet
[2] http://www.drweil.com/drw/u/ART02995/Dr-Weil-Anti-Inflammatory-Food-Pyramid.html
[3] http://www.theholistickitchen.com/tag/anti-inflammatory-foods/
[4] http://nutrition.about.com/od/dietsformedicaldisorders/a/antiinflamfood.htm

Inflammation During Heart Attacks

The group I work for has been studying heart attacks and myocardial ischemia-reperfusion injury. When I first joined this lab I thought it would be a lot of focus on therapies targeting good vs. bad cholesterol or blood pressure- however during the past few years I’ve come to realize there is more to a heart attack.

Of course it’s good to focus on a healthy diet and your blood pressure among other things to limit your chances of a heart attack, but the American lifestyle hasn’t really been the best influence. Poor diet, smoking, lack of exercise and family history are only some of the factors that increase the risk of a heart attack. Obviously it’s hard to predict when someone is going to have a heart attack and normally a patient is seen following a heart attack so this is the most likely point in treating someone suffering from a heart attack. In all reality, heart attacks are going to occur and for now the best therapy is early reperfusion (restoration of blood flow). However reperfusion is an evil all to itself…

This is where the immune system kicks in. During ischemia, which is the restriction of blood flow and is what occurs during a heart attack, there is a limited availability of oxygen to the tissue which leads to necrosis. Necrotic tissue releases damage associated molecular patterns or DAMPs, which eventually begin the cascade of an immune response (1). This can be good and bad. On one hand you will have the clearance and clean up of dead cells and tissue but on the other hand you have infiltrating cells that can cause more damage. During reperfusion, you have the up-regulation of intercellular adhesion molecules and the prominent infiltrating cells being neutrophils. These neutrophils use up oxygen, release more cytokines and free radicals inevitably damaging more tissue and increasing the infarct size and affecting the contractility (2). This idea is known as ischemia-reperfusion injury and it’s not only limited to heart attacks but also strokes and transplantations.

So when a patient is presented at the hospital with a heart attack the first step is to remove the occlusion and restore blood flow/oxygen to that portion of the heart in hopes of limiting the infarct size, but limiting the damage during reperfusion is still up for grabs. There are many current clinical trials looking into immunosuppresion during reperfusion. There is one looking into a drug Myfortic which is a known immunosupressor in hopes of limiting kidney damage during reperfusion (3). Another clinical trial used dipyridamole which inevitably allows for more extracellular adenosine (4). The increase in adenosine is thought to act on the adenosine receptors and limit inflammation (5). This idea has been around for a while but has yet to be entirely evaluated. These are just a few of the many clinical trials looking into limiting inflammation during reperfusion.

I was surprised to learn that the immune system, even though it is just doing its’ job, can have such an effect on surviving a heart attack. I know a lot of research has been targeting neutrophils either by dampening its’ cytokine release or migration into the tissue but not a lot is known on how this is regulated and at what point does the immune system decide to stop. If Tregs are thought to limit the amount of inflammation during a pathogen invasion, which is not self, what limits the inflammation in this case, since it is self and you’re probably not going to have self-reactive Tregs? I guess maybe the healthy/necrotic tissue balance starts to lean more towards healthy and therefore signals from the healthy tissue start outweighing the necrotic signaling ultimately affecting neutrophil activity and telling them that their work is done… just a thought but maybe this could be a potential target in therapies.

References

1)      Fatih Arslan, Dominique P. de Kleijn,  Gerard Pasterkamp. Innate immune signaling in cardiac ischemia. Nature Reviews Cardiology 8, 292-300 (May 2011) | doi:10.1038/nrcardio.2011.38

2)      James E. Jordan, Zhi-Qing Zhao, and Jakob Vinten-Johansen. The role of neutrophils in myocardial ischemia–reperfusion injury Cardiovasc Res (1999) 43(4): 860-878 doi:10.1016/S0008-6363(99)00187X

3)      http://www.clinicaltrials.gov/ct2/show/NCT01149993?term=ischemia+reperfusion+injury&rank=1

4)      http://www.clinicaltrials.gov/ct2/show/NCT00457405?term=ischemia+reperfusion+injury&rank=12

5)      Joel Linden. New insights into the regulation of inflammation by adenosine. J. Clin. Invest. 116:1835–1837 (2006). doi:10.1172/JCI29125