Progenitor cell pretreatment against acute surgical I/R

描述（由申请人提供）： 心肌缺血和再灌注损伤（I/R）是美国男性和女性死亡的主要原因。 炎性细胞因子（TNF、IL-1和IL-18）参与了心肌I/R的发病机制。梗死后将祖细胞注射到坏死心肌区域中导致了正性重构和存活心肌的再生。手术诱导的缺血代表了存在损伤前治疗选择的独特情况。普通外科、心脏外科、移植外科、神经外科、血管外科、泌尿外科和整形外科遇到可能导致毁灭性后果的专性手术缺血。许多研究已经证明了祖细胞在损伤后使用时的潜在临床益处，然而，细胞治疗预处理的效果是完全新颖的。虽然这些细胞用于立即分化的急性使用尚不可能，但祖细胞是生长因子的丰富来源，并且可能能够在I/R期间持续释放它们。这种性质可以允许保护性物质的持久生产，无论是靠它们自己还是通过编程用于保护性物质释放的细胞的未来设计。事实上，某些生长因子已被证明可减少炎性细胞因子介导的心肌I/R。因此，用祖细胞预处理不仅可以允许损伤后活组织的最终复活，而且它们还可以在I/R期间充当稳定/保护性“辅助细胞”。如果是这样的话，细胞治疗作为一种预处理策略可能具有治疗意义，其延伸到心肌I/R以外的多器官和各种损伤保护。我们的初步数据使我们假设祖细胞在心肌I/R前给药时具有保护作用。保护作用似乎是介导的，至少部分地，由缺血诱导的促炎信号的衰减。由于保护的时间性太短暂，不能用细胞分化来解释，我们假设祖细胞分泌保护物质。祖细胞是生长因子的丰富来源，其中一些已被证明可以通过减少TNF的产生来保护心肌。因此，我们的总体假设是祖细胞预处理通过原位产生生长因子（VEGF、IGF、EGF和HGF）限制心肌I/R诱导的、精氨酸介导的损伤（坏死、凋亡、功能障碍）。

DESCRIPTION (provided by applicant): 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).