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)
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
5) Joel
Linden. New insights into the regulation of inflammation by adenosine. J. Clin. Invest. 116:1835–1837 (2006). doi:10.1172/JCI29125
I think this follows the same pattern for the immune system that is emphasized in almost all of the immunopathologies. The necessity of the immune system weighed against overactivity and resulting pathogenecity. Alternatively, I like to think of it as: The immune system going bad. However in this case, I really like the conflict of interest or almost something like an oxymoron. On the one hand you have to restore blood flow (reperfusion)to prevent further cardiomyocyte damage, but doing so also causes further damage. So your pretty much stuck between a rock and a hard place.
ReplyDeleteThis was interesting. I didn't think there were Tregs against self antigens, either, but the recent evidence is that a self-reactive T cell in the thymus has a choice of dying by apoptosis (negative selection) or turning into a Treg. I love this idea! A cool way to turn a potentially dangerous autoimmune cell into something that can actually prevent autoimmunity.
ReplyDeleteIf you remember we talked about sequestered antigens and autoimmunity and the heart. I wonder if some of the DAMPS released are sequestered antigens and upregulate the immune response. Another thing is I would be interested in the Treg level before and after a heart attack.
ReplyDelete