Mechanisms of Marrow-Derived Stem Cell Remodeling of Aged Emphysematous Lungs

描述(申请人提供)：成人骨髓来源的细胞参与损伤后的肺重塑。这表明了一种令人兴奋的潜在治疗方法，用于治疗包括肺气肿在内的肺部疾病，肺气肿是一种毁灭性的、高度流行的肺部疾病，目前仍无治愈方法。然而，肺气肿主要是老年患者的一种疾病。评估肺上皮细胞再生的研究已经在幼鼠身上进行。目前尚不清楚老年肺，特别是老年病变肺中是否存在骨髓来源细胞的肺重塑。肺上皮细胞释放的可溶性介质在成人骨髓源性细胞向肺内募集中起着重要作用。然而，关于这一过程是否会随着年龄的增长而改变，我们知之甚少。我们假设上皮细胞释放介质和/或成人骨髓来源细胞对介质的反应随着年龄的增长而减少。如果要将成人骨髓来源的细胞用于肺气肿，这是一个关键的考虑因素。目前的建议将使用从年轻和老年小鼠获得的肺上皮细胞和骨髓来源细胞的原代培养在体外评估这一假说，并在体内评估成人骨髓来源细胞在肺气肿小鼠模型中的移植。评估将包括对骨髓来源的细胞肺重建的最先进的评估，包括对骨髓来源细胞的肺重建的潜在生理影响的复杂功能测量。我们的总体目标是为骨髓来源的细胞用于与衰老和肺气肿相关的肺部疾病的潜在治疗奠定科学基础。LAY声明-使用成人骨髓来源的细胞是包括肺气肿在内的许多肺部疾病的潜在治疗方法。这项拟议的研究将探讨成人骨髓来源细胞参与肺气肿修复的机制，并为设计未来的临床试验提供重要的基本科学信息和坚实的科学基础。

DESCRIPTION (provided by applicant): Adult marrow-derived cells participate in lung remodeling after injury. This suggests an exciting potential therapeutic approach for lung diseases including emphysema, a devastating and highly prevalent lung disease for which there remains no cure. However, emphysema is predominantly a disease of older patients. Studies evaluating repopulation of lung epithelium have been conducted in young mice. It is unknown whether lung remodeling with marrow-derived cells occurs in older lungs, particularly older diseased lungs. Soluble mediators released by lung epithelial cells play an important role in recruitment of adult marrow-derived cells to lung. However, little is known about whether this process is altered with aging. We hypothesize that release of mediators by epithelial cells and/or response to the mediators by the adult marrow-derived cells decreases with aging. This is a critical consideration if adult marrow-derived cells are to be utilized for emphysema. The current proposal will assess this hypothesis in vitro using primary cultures of lung epithelial cells and marrow-derived cells obtained from young and aged mice and in vivo assessing transplantation of adult marrow-derived cells in a mouse model of emphysema. Evaluations will include state of the art assessments of marrow-derived cell lung remodeling including sophisticated functional measurements of potential physiologic effects of lung remodeling by the marrow-derived cells. Our overall goal is to establish a scientific basis for the potential therapeutic use of marrow-derived cells for lung disease associated with aging and emphysema. Lay Statement - Use of adult marrow-derived cells is a potential therapeutic approach for a number of lung diseases including emphysema. The proposed studies will investigate mechanisms by which adult marrow-derived cells might participate in repair of emphysematous lungs and provide important basic scientific information and a firm scientific basis for which to design future clinical trials.