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

描述（由申请人提供）：成人骨髓来源的细胞参与损伤后的肺重塑。这为肺气肿等肺部疾病提供了一种令人兴奋的潜在治疗方法，肺气肿是一种毁灭性的、高度流行的肺部疾病，至今仍无法治愈。然而，肺气肿主要是老年患者的疾病。评估肺上皮再生的研究已在幼鼠中进行。目前尚不清楚骨髓源性细胞的肺重塑是否发生在老年肺，特别是老年病变肺中。肺上皮细胞释放的可溶性介质在成体骨髓源性细胞向肺募集中起重要作用。然而，对于这个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/或成年骨髓源性细胞对介质的反应随着年龄的增长而减少。这是一个关键的考虑，如果成人骨髓来源的细胞是用于肺气肿。目前的提案将在体外使用从年轻和老年小鼠获得的肺上皮细胞和骨髓源性细胞的原代培养物来评估这一假设，并在体内评估成年骨髓源性细胞在小鼠肺气肿模型中的移植。评估将包括对骨髓源性细胞肺重塑的最新评估，包括对骨髓源性细胞肺重塑的潜在生理效应的复杂功能测量。我们的总体目标是为骨髓来源细胞治疗与衰老和肺气肿相关的肺部疾病的潜在治疗用途建立科学基础。Lay声明-使用成人骨髓源性细胞是包括肺气肿在内的许多肺部疾病的潜在治疗方法。本研究将探讨成人骨髓源性细胞参与肺气肿肺修复的机制，为今后的临床试验设计提供重要的基础科学信息和坚实的科学依据。

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.