Reduced reperfusion injury from decreased expression of P-selectin

Hello All,
   After the discussion of the stroke articles this week I started to think that there are a lot of studies being done to reduce reperfusion injury after a stroke by manipulating inflammation. However, inflammation is our bodies way of healing itself and it wouldn't activate if there wasn't a good reason, so why would we want to interfere with something that's designed to help us? Then after thinking over some of the articles it seemed to me that it's not inflammation that causes reperfusion injury, rather it's over activation that causes damage due to inflammation. Thus, thinking that there had to be a better method of reducing reperfusion injury, other than manipulating inflammation, I searched the internet and found an awesome research article in the Journal of Immunology that did just that.
   The article "Complement-Dependent P-selectin Expression and Injury Following Ischemic Stroke" Looks at the affects of reperfusion injury on three groups of mice 1) wild type normal, 2)C3-deficient (complement deficient), and 3) CR2-Crry induced mice. CR2-Crry is a complement inhibitor that inhibits complement at the C3 stage and targets to sites of complement activation. Furthermore, by reducing complement the researchers were also looking to see a reduction in P-selectin expression, as P-selectin has been linked to promoting leukocyte adhesion, platelet aggregation and coagulation, and may also increase complement activation. In reducing these factors, the researchers were hoping to see a significant reduction in reperfusion injury in C3-deficient mice and the CR2-Crry induced mice.
   According to the experiment the mice were subjected to 60min MCAO (Middle Cerebral Arterial Occlusion) induced ischemia and 24hrs of reperfusion. With the results showing 62% survival rate of the normal group, 100% survival rate of the C3-deficient group, and an 80% survival rate for the CR2-Crry induced mice. Furthermore, both the C3-deficient and the CR2-Crry group mice were shown to have statistically significant protection from tissue and neuronal damage, as well as improved neurological function compared to the control group.
   Moreover, when looking at the presence of P-selectin, it was found that there was great expression in the control group, no expression in the C3-deficient group, and very little or no expression in the CR2-Crry group. Furthermore, expression of P-selectin mRNA levels in the cerebro-vasculature were high in the control group but were significantly reduced in the the other two groups. The results further go on to reveal that the presence of micro-thrombi and residual thrombus were less present in the C3-deficient and CR2-Crry mice than in the control.
   Of all the results however, the discussion focused on the CR2-Crry group as this was the group of interest through out the experiment. The results from this group for all tests performed showed similar results to the C3-deficient group. More importantly, according to the researchers the CR2-Crry complement inhibitor was shown to "provide appropriate bioavailabity in cerebral injury to enable complement inhibition, at a dose that will not significantly affect systemic levels of serum complement activity or host immunity to infection.
   Overall, I thought this article was really cool, especially with what the researchers did with the CR2-Crry group. According to the article they administered .25mg of the complement inhibitor via an I.V. tube 90min post ischemia and 30min post repurfusion. I didn't find anything in the article that explained why they chose that specific dosage or time to administer the inhibitor though. Regardless though, I truly liked how the researchers aimed to find a method that could reduce the activation of complement without shutting it down completely and putting the host at risk for infection. Moreover, the colored scans and graphs this paper contains really helps put the data into perspective. More experiments definitely need to be done regarding this procedure, but I could see this as a feasible method for use on human stroke sufferers to help the recovery process. Well I think I've talked enough, you've heard me hit the high points of this paper and give my thoughts, so why don't you follow the link, read the paper yourself and give me your thoughts on it?

http://www.jimmunol.org/content/177/10/7266.full.pdf