Responses to Surgical and Bronchoscopic Volume Reduction

描述（由申请人提供）：肺减容手术（LVRS）是一种 有效辅助药物治疗终末期肺气肿。临床 结果表明，LVRS通过消除严重疾病的区域， 功能失调的肺我们之前假设有效的减容 可能使用非手术方法导致永久性肺不张 特定的目标区域。通过折叠这些区域并应用 纤维蛋白为基础的密封剂，我们已经表明，这是可能实现肺容量 在绵羊肺气肿模型中进行非手术复位。虽然这些研究 证实了我们最初的假设，他们也证明了几个重要的 缺点仅通过机械塌陷和应用 纤维蛋白密封剂经常是不完全的。只有1/2到1/3的目标区域 2个月随访时仍塌陷。此外，几个目标区域 出现组织坏死。为了解决这些限制，我们修改了 接近BVR。已经开发了新一代试剂， 调节局部细胞反应，促进成纤维细胞向内生长和瘢痕形成 无坏死形成。初步研究表明， 修改解决了我们最初研究中发现的局限性。我们现在 假设：使用冲洗液+胶水可实现BVR改善 引起位点特异性塌陷和调节成纤维细胞的试剂， 上皮细胞生物学以产生受控的、有效的瘢痕形成。的 该提案的目标是：1）表征生理和 使用这些改进的试剂在绵羊模型中的生物学反应， 肺气肿，和2）比较结果与使用传统手术获得的结果 疗法我们认为，通过实现这些目标，我们可以帮助推动 将这项技术应用于临床竞技场。

DESCRIPTION (provided by applicant): Lung volume reduction surgery (LVRS) is an effective adjunct to medical treatment for end stage emphysema. Clinical results suggest that LVRS works by eliminating areas of severely diseased and dysfunctional lung. We previously hypothesized that effective volume reduction might be possible using a non-surgical approach to cause permanent atelectasis of specific target regions. By collapsing these regions and applying a fibrin-based sealant, we have shown that it is possible to achieve lung volume reduction without surgery in a sheep model of emphysema. While these studies confirmed our initial hypothesis, they have also demonstrated several important shortcomings. BVR achieved solely by mechanical collapse and application of fibrin sealant is frequently incomplete. Only 1/2 to 1/3 of the target regions remained collapsed at 2month follow-up. Furthermore, several target regions developed tissue necrosis. To address these limitations, we have modified our approach to BVR. A new generation of reagents has been developed which modulates local cellular responses, and promotes fibroblast in-growth and scar formation without necrosis. Preliminary studies indicate that these modifications address the limitations identified in our original study. We now hypothesize that: improved BVR can be achieved using washout solution + glue reagents which cause site-specific collapse, and modulation of fibroblast and epithelial cell biology to generate controlled, efficient scar formation. The objectives of this proposal are to: 1) characterize physiological and biological responses using these improved reagents in a sheep model of emphysema, and 2) compare results to those obtained using conventional surgical therapy. We believe that by accomplishing these objectives, we can help advance this technology into the clinical arena.