Discussion

Abstract

Dr Randall B. Griepp (New York, NY). I was mostly impressed by the extensive in vivo work elucidating one of the pathways for injury after DHCA, but I feel somewhat unqualified to comment on that, so I am going to confine my remarks to the rat model. I have several questions. In the pig model and in clinical series, 30 minutes of DHCA usually don't result in significant cerebral damage or at least irreversible cerebral damage. What is the situation in this rat model, that is, if these rats were allowed to awaken, are they behaviorally normal or are they damaged, and if they are damaged, are the CIRP knockout mice protected? Dr Mingyue Liu (Beijing, China). With the advantage of genome editing and low price, we chose rats to perform DHCA in the present setting. In this rat model, the left femoral rat artery was cannulated for blood pressure monitoring. CPB was performed via the rat tail artery, rat external jugular vein and rat atrium. Cerebral perfusion was not performed. This is also one of the limitations of this rat model. Our previous published study showed that hippocampus neurologic injury was observed after 30 minutes DHCA duration, which persisted for at least 14 days and recovered after 30 days and severe histologic injury without evident neurologic dysfunction was also observed at 14 days after DHCA. A postoperative functional experiment may better reveal the relationship between CIRP and postoperative cognitive dysfunction. Previous studies showed that controlling microglia activation was a potential therapeutic intervention to limit neurologic dysfunction after DHCA. In the present study, we mainly focused on the molecular factors involved in microglia activation during DHCA, that is the effect of CIRP on microglia activation and related signaling pathway in acute stage. Further functional studies will be performed with regard to the long-term effect of CIRP after DHCA in the future. We are exploring it in another experiment. We think that the methods that are used in the experiment may not be the best, but it could be sufficient to get to our central contribution. Dr Griepp. The rats were exposed to both hypothermia and to 30 minutes of anoxic arrest. Do you have any indication which of those really is responsible for activating the CIRP activation? Dr Liu. Both factors contribute to CIRP activation. CIRP is a kind of stress protein. It increased under certain stressful conditions, including hypoxia, hypothermia, oxidative stress. For example, it was reported that CIRP expression increased in the animal model of stroke and mild hypothermia on traumatic brain injury respectively. Dr Griepp. Finally, do you have any suggestions for any inhibitors of CIRP activation that might be possibly useful in vivo? Dr Liu. This is a new kind of discovered protein. Neutralizing antisera to CIRP and C23, an oligopeptide derived from CIRP that binds with high affinity to TLR4-MD2 complex were reported in 2015 and 2018 respectively. But these drugs were only synthesized in the laboratory and were only used in cell lines or animal models to reduce inflammation. So further study is needed to prove the effectiveness and the stability of these drugs before proceeding with clinical trials.