Progenitor cell pretreatment against acute surgical I/R

针对急性手术 I/R 的祖细胞预处理

• 批准号: 6759062
• 负责人: DANIEL R MELDRUM
• 金额: $ 30.1万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6759062
• 关键词: adipose tissue; apoptosis; cardiac myocytes; cell cell interaction; cytoprotection; endotoxins; epidermal growth factor; growth factor; hepatocyte growth factor; inflammation; insulinlike growth factor; interleukin 1; interleukin 18; laboratory rat; macrophage; mitogen activated protein kinase; myocardial ischemia /hypoxia; necrosis; nuclear factor kappa beta; phosphorylation; regeneration; reperfusion; stem cell transplantation; tissue /cell culture; tumor necrosis factor alpha; vascular endothelial growth factors

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).

描述（由申请人提供）： 心肌缺血和再灌注损伤（I/R）是该国男性和女性死亡的主要原因。 炎症细胞因子（TNF、IL-1 和 IL-18）与心肌 I/R 的发病机制有关。梗死后将祖细胞注射到坏死心肌区域导致了积极的重塑和存活心肌的再生。手术引起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、泌尿科和整形外科都会遇到必然的手术缺血，这可能会导致毁灭性的后果。大量研究已经证明，祖细胞在损伤后使用时具有潜在的临床益处，然而，细胞疗法预处理的效果是全新的。尽管急性使用这些细胞进行立即分化尚不可能，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。这种特性可能允许保护性物质的持久产生，无论是它们本身还是通过未来设计的用于保护性物质释放的编程细胞。事实上，某些生长因子已被证明可以减少炎症细胞因子介导的心肌缺血再灌注。因此，用祖细胞进行预处理不仅可以使受伤后的活组织最终复活，而且还可以在 I/R 过程中充当稳定/保护性“辅助细胞”。如果是这样，细胞疗法作为预处理策略的治疗意义可能会超出心肌缺血再灌注，扩展到多器官和多种损伤保护。我们的初步数据使我们推测，在心肌缺血再灌注之前施用祖细胞具有保护作用。保护作用似乎至少部分是通过缺血诱导的促炎信号传导的减弱来介导的。由于保护的时间性质太短而无法通过细胞分化来解释，因此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）来限制心肌 I/R 诱导的细胞因子介导的损伤（坏死、细胞凋亡、功能障碍）。