Innate and acquired immunity in myocardial adaptation to ischemia - possible therapeutic gains?

Atherosclerosis is our major cause of morbidity and mortality, causing cerebral stroke, myocardial infarction, lower extremity gangrene, renal infarctions etc. Atherosclerosis is a chronic process involving both innate and adaptive immunity in its develop ment, and is a subject for attempts of immunomodulation in several research centers throughout the world. In ischemic heart disease cardiomyocytes die by necrosis or apoptosis, or reversible symptoms such as arrhythmias or myocardial dysfunction are observed. To salvage ischemic myocardium revascularisation is essential, but may cause reperfusion injury. The pathophysiology of reperfusion injury involves an inflammatory process. Short episodes of ischemia and reperfusion prior to a sustained ischemic event, termed ischemic preconditioning, increases the tolerance to ischemia in all organs investigated. Preconditioning signals its protection through activation of innate immunity. In depth analysis of the role of innate and acquired immunity in this co ntext may lead to development of immunomodulatory therapies. Innate immunity is a non-spesific line of defence responsible for containing microrganisms at the site of entrance, mediated by a host of cells producing cytokines and activating proteolytic cascade systems in response to pathogen associated molecular patterns. Pattern-recognition receptors such as toll-like receptors are bridges between innate and acquired immunity, as their binding to microbial ligands mature dendritic cells and trigger a ntigen-specific adaptive immune responses. Toll-like receptors signal to the transcription factor nuclear factor kappa B, which we know is important for evoking preconditioning. This program explores a possible role for toll-like receptors, pattern recogn ition receptor ligands, and activation of myeloid and lymphoid cells in evoking myocardial protection. The target is to establish an immunomodulatory therapy to evoke protection against acute myocardial ischemia.