Limitation to Exercise After Pneumonectomy

描述（由申请人提供）：成年犬全肺切除术（PNX）后，剩余肺的机械应变增加是代偿肺泡生长和组织重塑的主要信号。其余叶的应变和生长响应的均匀性随切除的大小和位置而变化。在较低水平的切除和应变（例如，左侧PNX），补偿通过现有储备的补充和结构重塑发生。在新的组织生长之前，必须超过一个应变阈值。当肺劳损超过这个阈值时（如右PNX），现有储备的补充、组织重塑和新肺泡组织的生长使最大氧摄取保持在正常水平的80%以上。随着更多的肺被切除，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固定，导致游离或“异常”生长。当应变诱导生长接近上限（阈值）时，异常生长通过1)提高呼吸功率需求和2)减少心输出量来限制补偿。我们已经表明，pnx后肺叶应变在其余肺内变化很大。这两个阈值的区域位置也会有所不同。有些肺叶未达到肺泡开始生长的阈值。在其他脑叶中，会超过发育障碍的阈值，从而限制进一步的补偿。我们假设a)不均匀的大叶应变分布削弱了剩余肺对给定机械信号的反应；b)运动训练促进大叶劳损分布更均匀，从而优化整体补偿。我们将通过对成年犬进行不同程度肺切除术前后的连续CT扫描来表征大叶应变。将评估大叶空气、血管和血管外肺组织体积以及气道和胸腔的尺寸。我们将把大叶应变与整体功能补偿、特定生长因子通路的区域激活以及最终与形态测量评估的腺泡和气道结构的局部变化联系起来。单独的队列将在pnx后进行运动训练或静坐6个月，以确定训练是否改变了大叶应变分布或结构-功能适应。这些研究将在一个成熟的应变诱导代偿性肺生长模型中定义基本的信号-反应关系，并将探索一种治疗干预措施来潜在地增强内源性反应。

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.