Progenitor cell pretreatment against acute surgical I/R

描述(由申请人提供)： 心肌缺血再灌注损伤(I/R)是我国男性和女性的主要死亡原因。炎症细胞因子(肿瘤坏死因子、白介素1和白介素18)参与了心肌I/R的发病过程。心肌梗死后将祖细胞注入坏死区，可使存活心肌发生阳性重构和再生。外科手术诱发的缺血是一种独特的情况，在这种情况下，存在着侮辱前的治疗选择。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都会遇到严重的外科缺血，这可能会导致灾难性的后果。大量研究已经证明，如果在损伤后使用祖细胞可以带来潜在的临床益处，然而，细胞治疗预处理的效果是全新的。尽管目前还不可能急切地将这些细胞用于立即分化，但祖细胞是生长因子的丰富来源，并且能够在I/R期间持续释放它们。这一特性可能允许持久地产生保护性物质，无论是它们自己还是通过未来设计的细胞编程来释放保护性物质。事实上，某些生长因子已被证明可以减少炎性细胞因子介导的心肌I/R。因此，祖细胞的预处理不仅可以使损伤后存活的组织最终复苏，而且在I/R期间它们还可以作为稳定/保护的“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从心肌I/R延伸到多器官和不同损伤保护的治疗意义。我们的初步数据使我们假设，在心肌I/R之前给予祖细胞具有保护作用，这种保护作用似乎至少部分是通过减弱缺血诱导的促炎信号来介导的。由于保护的时间性质太短暂，不能用细胞分化来解释，我们假设祖细胞分泌保护物质(S)。祖细胞是生长因子的丰富来源，其中一些已被证明通过减少肿瘤坏死因子的产生来保护心肌。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)来限制心肌I/R诱导的细胞因子介导的损伤(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).