Myocardial ischemia and reperfusion injury (I/R) is the leading cause of death of both men and women in this country. Inflammatory cytokines (TNF, IL-1, and IL-18) have been implicated in the pathogenesis of myocardial I/R. Post-infarct injection of progenitor cells into regions of necrotic myocardium has resulted in positive remodeling and the regeneration of viable myocardium. Surgically-induced ischemia represents the unique situation where pre-insult treatment options exist. General surgery, cardiac surgery, transplant surgery, neurosurgery, vascular surgery, urology, and plastic surgery encounter obligate surgical ischemia which may result in devastating consequences. Numerous studies have demonstrated the potential clinical benefit of progenitor cells when used in a post-injury fashion, however, the effect of cell therapy pretreatment is completely novel. Although the acute use of these cells for immediate differentiation is not yet possible, progenitor cells are a rich source of growth factors and may be capable of their continuous release during I/R. This property may allow for the enduring production of protective substances, either on their own or by the future design of a cell programmed for protective substance release. Indeed, certain growth factors have been demonstrated to reduce inflammatory cytokine mediated myocardial I/R. Thus, pretreatment with progenitor cells may not only allow the ultimate resurrection of viable tissue following injury, but they may also act as a stabilizing/protective """"""""helper cell"""""""" during I/R. If so, cellular therapy as a pretreatment strategy may have therapeutic implications which extend beyond myocardial I/R to multi-organ and varied-insult protection. Our preliminary data lead us to hypothesize that progenitor cells have a protective effect when administered prior to myocardial I/R. The protective effect appears to be mediated, at least in part, by an attenuation of ischemia-induced pro-inflammatory signaling. Since the temporal nature of protection is too brief to be explained by cellular differentiation, we hypothesize that progenitor cells secrete protective substance(s). Progenitor cells are a rich source of growth factors, some of which have been shown to protect myocardium by decreasing TNF production. Thus, our global hypothesis is that progenitor cell pretreatment limits myocardial I/R-induced, cytokine-mediated injury (necrosis, apoptosis, dysfunction) via the in situ of production of growth factors (VEGF, IGF, EGF and HGF).
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