the Influence of Remote Ischemic Preconditioning on Inflammation During Human Endotoxemia, a Pilot Proof-of-principle Study

Although the immune system is essential to survival, a variety of diseases originate from inappropriate or excessive activation of the immune response. Examples include a wide range of auto-inflammatory disease, infectious diseases such as sepsis, but also after major surgery like cardiac artery bypass grafting, after radiation therapy in the treatment of cancer, or following organ transplantation. In these instances, attenuation of the immune response could be beneficial.

The concept of ischemic preconditioning (IPC) was first described in the 1980's. Murry and colleagues showed a protective effect of preconditioning the heart with 4 cycles of 5-minute long ischemia on the extent of myocardial infarction in dog hearts. Follow-up animal studies showed the same protective effects on the heart by introducing the cycles of ischemia to distant, or 'remote', organs like the kidney or the gut. Furthermore, this principle of 'remote ischemic preconditioning' (RIPC) was also shown to be effective in humans when using a tourniquet to temporary cut off blood supply to one of the limbs, either an arm or a leg. As such, RIPC has been identified as a cheap and easy method of protecting patients undergoing elective CABG surgery from perioperative myocardial ischemic damage. In recent studies, two different timeframes in which RIPC exerts its protective effects have been identified. The classical or 'early window of protection' protects in the 1-2 hour after the RIPC stimulus while a 'second window of protection' is evident 12-24 hours after RIPC and lasts for 48-72 hours. Multiple-dose RIPC may be of additional value, as 7 daily doses of RIPC in humans resulted in protection of endothelial dysfunction, with both the local and remote beneficial effects lasting for up to 8 days after the last RIPC dose. This could be due to additive or synergistic effects of combining the first and second windows of protection.

The mechanisms behind the observed protective effects are however still subject of investigation. Several have been put forward, of which attenuation of the inflammatory response is a major candidate.

For instance, recent animal work has shown that RIPC results in downregulation of pro-inflammatory cytokines such as TNF-α and IL-6 and upregulation of anti-inflammatory cytokines such as IL-10. In support of the latter, the cardioprotective effects of RIPC were absent in IL-10 knockout mice or in wild-type mice treated with a monoclonal antibody against the IL-10 receptor. Hypoxia-inducible factor (HIF) has been shown to be a major contributor to this RIPC-induced IL-10 response.

Adenosine appears to be a major determinant of the anti-inflammatory and tissue-protective effects of RIPC. In a in vivo forearm model, adenosine and ischemic preconditioning both resulted in the same reduction in ischemia-reperfusion injury. Also, administration of exogenous adenosine can mimic the protective effects of IPC, and antagonizing the adenosine receptor with caffeine blocks the protective effects of RIPC and augments the anti-inflammatory IL-10 response to lipopolysaccharide (LPS). Interestingly, one of the pathways in which ischemia-reperfusion can increase adenosine levels is through upregulation of CD73, which is dependent on the aforementioned HIF.