Limitation to Exercise After Pneumonectomy

描述（由申请方提供）：成年犬肺切除术（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了主要信号。其余肺叶的应变和生长反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PNX）补偿通过补充现有储备和结构重塑发生。在引起新组织生长之前，必须超过应变阈值。当肺应变超过该阈值时（例如，右PNX），现有储备的补充，组织重塑和新肺泡组织生长使最大O2摄取保持在正常的80%以上。随着更多的肺被切除，肺泡间隔体积和表面继续扩大，而传导气道和血管的数量保持固定，导致分离或“适应不良”生长。当应变诱导的生长接近上限（阈值）时，适应不良生长通过1）提高呼吸的功率需求和2）减少心输出量来限制补偿。我们已经表明，后PNX肺叶应变变化很大，在其余的肺。这两个阈值的区域位置也会有所不同。在某些肺叶中，将不会达到肺泡生长起始的阈值。在其他脑叶中，将超过适应不良生长的阈值以限制进一步的补偿。我们假设a）不均匀的肺叶应变分布减弱了剩余肺对给定机械信号的响应;和B）运动训练促进肺叶应变的更均匀分布，从而优化整体补偿。我们将通过连续CT扫描来描述成年犬在接受不同程度肺切除术之前和之后的肺叶劳损。将沿着气道和胸腔的尺寸评估肺叶空气、血管和血管外肺组织体积。我们将与肺叶应变的整体功能补偿，选择的生长因子途径的区域激活和最终的局部变化，腺泡和气道结构的形态测定评估。单独的队列将在PNX后6个月进行运动训练或保持久坐，以确定训练是否改变了肺叶应变分布或结构-功能适应。这些研究将在应变诱导的代偿性肺生长的成熟模型内定义基本信号-反应关系，并将探索可能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.