Limitation to Exercise After Pneumonectomy

描述(申请人提供)：成年犬全肺切除(PNX)后，剩余肺的机械应变增加为代偿性肺泡生长和组织重塑提供主要信号。剩余叶的应变和生长响应的一致性因切除的大小和位置而不同。在较低水平的切除和劳损(例如，左PNX)时，通过招募现有储备和结构重塑进行补偿。在启动新的组织生长之前，必须超过应变的阈值。当肺应变超过这一阈值(例如，右PNX)时，现有储备的重新招募、组织重塑和新的肺泡组织生长使最大吸氧量保持在正常的80%以上。当更多的肺被切除时，肺泡间隔的体积和表面继续扩大，而传导气道和血管的数量保持不变，导致分离或“分裂”的生长。当紧张诱导的生长接近上限(阈值)时，异常生长通过1)提高呼吸的能量需求和2)减少心输出量来限制补偿。我们已经证明，PNX后，剩余肺内的肺叶应变差异很大。这两个门槛的区域位置也将有所不同。有些肺叶达不到肺泡开始生长的阈值。在其他叶中，将超过异常生长的门槛，以限制进一步的补偿。我们假设a)非均匀的肺叶应变分布削弱了剩余肺对给定机械信号的反应；b)运动训练促进了肺叶应变的更均匀分布，从而优化了整体补偿。我们将在成年犬接受不同程度的肺切除之前和之后通过系列CT扫描来描述肺叶劳损的特征。将评估肺叶空气、血管和血管外肺组织体积以及呼吸道和胸腔的大小。我们将大叶性劳损与整体功能代偿、选定生长因子通路的局部激活以及通过形态计量学评估的腺泡和呼吸道结构的局部变化相关联。不同的队列将在PNX术后6个月内接受运动训练或保持久坐状态，以确定训练是否改变了肺叶应变分布或结构-功能适应。这些研究将在一个公认的应变诱导的代偿性肺生长模型中定义基本的信号-反应关系，并将探索潜在地增强内源性反应的治疗干预。

DESCRIPTION (provided by applicant): After pneumonectomy (PNX) in adult dogs, increased mechanical strain of the remaining lung provides the major signal for compensatory alveolar growth and tissue remodeling. The uniformity of strain and growth response in remaining lobes varies with the size and location of resection. At lower levels of resection and strain (e.g., left PNX) compensation occurs by recruitment of existing reserves and structural remodeling. A threshold of strain must be exceeded before new tissue growth is invoked. As lung strain exceeds this threshold (e.g., right PNX), recruitment of existing reserves, tissue remodeling and new alveolar tissue growth keep maximal O2 uptake above 80% of normal. As more lung is resected, alveolar septal volume and surface continue to expand while the number of conducting airways and blood vessels remain fixed, resulting in dissociated or "dysanaptic" growth. As strain-induced growth approaches an upper limit (threshold), dysanaptic growth limits compensation by 1) raising power requirements of breathing and 2) reducing cardiac output. We have shown that post-PNX lobar strain varies widely within the remaining lung. The regional location of these 2 thresholds will also vary. In some lobes the threshold for alveolar growth initiation will not be reached. In other lobes the threshold for dysanaptic growth will be exceeded to limit further compensation. We hypothesize that a) non-uniform lobar strain distribution weakens the response of the remaining lung to a given mechanical signal; and b) exercise training promotes more uniform distribution of lobar strain thereby optimizing overall compensation. We will characterize lobar strain by serial CT scans in adult dogs before and after undergoing different degrees of lung resection. Lobar air, vascular and extravascular lung tissue volumes will be assessed along with dimensions of the airway and thorax. We will relate lobar strain to overall functional compensation, to regional activation of selected growth factor pathways and terminally to local changes in acinar and airway structure assessed by morphometry. Separate cohorts will be either exercise trained or remain sedentary for 6 months post-PNX to determine if training alters lobar strain distribution or structure-function adaptation. These studies will define fundamental signal-response relationships within a well-established model of strain-induced compensatory lung growth, and will explore a therapeutic intervention to potentially enhance the endogenous response.