Pneumografting - a novel cell-based therapy for emphysema

描述（由申请人提供）：最近的研究表明，有助于肺部损伤后愈合的修复细胞也具有再生能力。尽管出生后肺再生的生物学原理尚不清楚，但机械预应力似乎是组织再生发生的绝对要求。肺气肿是一种以组织破坏为特征的疾病，是细胞治疗的潜在目标。这种疾病与：1）常驻修复细胞的损失； 2）传递预应激信号的细胞外基质丧失； 3）以及预应力本身的丧失，而预应力本身正是触发再生反应所需的信号。尽管这些因素阻碍了肺气肿再生治疗策略的发展，但我们实验室的初步研究表明，使用成纤维细胞生长因子家族成员与生物相容性聚合物中的载体分子复合来调节间充质和上皮细胞增殖可以促进实质组织的扩张。聚合物支架是一种含有空气的泡沫，其机械性能与健康肺组织相似，可有效地将压力传递至修复/祖细胞，以促进增殖和重塑。这里提出的研究将检验以下假设：1) 治疗性肺气肿的产后肺组织生长可以通过在局部轻度损伤后使用生长因子指导内源性修复性肺细胞来增强肺部的先天愈合反应来实现； 2) 这种反应的强度可以通过改变预应力来调节，同时使用支气管镜肺减容疗法来增加跨肺压。我们打算在医生资助的新药研究申请中将这种称为肺移植的方法推进到人体试验中。

DESCRIPTION (provided by applicant): Recent studies suggest that reparative cells which contribute to healing in the lung following injury also possess regenerative capacity. Although the biology of post-natal lung regeneration is not well understood, mechanical pre-stress appears to be an absolute requirement for tissue regeneration to occur. Emphysema, a disease characterized by tissue destruction, is a potential target for cell-based therapy. This disease is associated with: 1) loss of resident reparative cells; 2) loss of the extracellular matrix that transmits pre-stress signaling; 3) and loss of pre-stress itself, the very signal required to trigger regenerative responses. Although these factors represent obstacles to the development of regenerative therapeutic strategies for emphysema, preliminary studies in our lab show that modulation of mesenchymal and epithelial cell proliferation using members of the fibroblast growth factor family complexed to carrier molecules in a biocompatible polymer can promote expansion of parenchymal tissues. The polymer scaffold, an air containing foam with mechanical properties similar to healthy lung tissue, effectively transmits stress to reparative/progenitor cells to promote proliferation and remodeling. Studies proposed here will test the hypothesis that 1) therapeutic post-natal lung tissue growth in emphysema can be achieved by augmenting the lung's innate healing response using growth factors to direct endogenous reparative lung cells following a localized mild injury; and that 2) the magnitude of this response can be modulated by altering pre-stress using concomitant bronchoscopic lung volume reduction therapy to increase transpulmonary pressures. We intend to advance this approach, known as pneumografting, into human trials under a physician-sponsored Investigation New Drug Application.