Retinoic Acid and Post-pneumonectomy Lung Growth

描述（由申请方提供）：成年犬的肺切除术（PNX）后代偿性肺生长是双相的：在第一阶段，细胞增殖和/或肥大增加间隔组织体积和厚度，而不增加表面积或改善气体交换。在第二阶段，间隔重塑恢复正常的结构，增加表面积和功能补偿。外源性维甲酸（RA）选择性地促进肺泡内皮细胞生长的第一阶段后，右PNX，但没有增加气体交换在休息。结构-功能二分法与RA治疗的肺气肿大鼠中观察到的二分法相似。我们的目标是确定RA促进肺生长的时间进程、机制和生理后果。假设是：a）伊拉在双相反应的第一阶段中选择性地增强PNX后内皮相对于上皮的生长（适应不良的间隔生长），从而扭曲间隔结构。尽管增强了细胞生长，但畸变限制了O2交换中的补偿，但在第二重塑阶段得到纠正。B）RA通过限制气道扩张和加重通常的PNX后气道-实质分离（适应不良肺生长）来损害气道适应。受损的气道适应性降低了代偿性代偿，尽管增强的中隔细胞生长。c）RA增强的内皮细胞生长与上皮细胞不成比例对应于相对于表皮生长因子（EGF）轴的血管内皮生长因子（VEGF）轴的选择性激活。匹配的成年犬将在右侧PNX后接受RA或安慰剂4个月，停止治疗后再随访8个月。详细的研究包括休息和运动时的肺功能，胸部CT扫描和腺泡和气道结构的形态学分析。将在RA治疗期间和治疗后的不同时间点研究单独的队列;将测定肺组织的弹性蛋白和胶原蛋白含量以及EGF、VEGF、其受体、细胞增殖标志物和表面活性蛋白的蛋白质和mRNA表达。该建议整合了结构-功能原则，以确定代偿性肺生长的决定因素，而不仅仅是明确RA的治疗效用。结果为理解一般现象提供了一个模型，即，当自然代偿反应被药理学操纵扭曲时的后果，药理学操纵选择性地改变了自然反应的某些方面，但不是所有方面。

DESCRIPTION (provided by applicant): Post-pneumonectomy (PNX) compensatory lung growth in adult dogs is biphasic: In the Ist phase, cell proliferation and/or hypertrophy increases septal tissue volume and thickness without increasing surface areas or improving gas exchange. In the 2nd phase, septal remodeling restores normal architecture with increasing surface areas and functional compensation. Exogenous retinoic acid (RA) selectively enhanced alveolar endothelial growth in the 1st phase after right PNX but did not enhance gas exchange at rest. The structure-function dichotomy is similar to the dichotomy seen in RA-treated emphysematous rats. Our objective is to define the time course, mechanisms and physiologic consequences of RA-enhanced lung growth. Hypotheses are: a) IRA in the 1st phase of a biphasic response selectively augments post-PNX endothelial growth relative to the epithelium (dysanaptic septal growth), thereby distorting septal architecture. Distortion limits compensation in 02 exchange in spite of enhanced cell growth but is corrected in the 2nd remodeling phase, b) RA impairs airway adaptation by restricting airway dilatation and aggravating the usual post-PNX airway-parenchyma dissociation (dysanaptic lung growth). Impaired airway adaptation reduces ventilatory compensation in spite of enhanced septal cell growth, c) Enhanced endothelial cell growth by RA out of proportion to the epithelium corresponds to selective activation of the vascular endothelial growth factor (VEGF) axis relative to the epidermal growth factor (EGF) axis. Matched adult dogs will receive RA or placebo for 4 mo after right PNX with follow-up for another 8 mo after cessation of treatment. Detailed studies include lung function at rest and exercise, thoracic CT scan and morphometric analysis of acinar and airway structure. Separate cohorts will be studied at different time points during and after RA treatment; lung tissue will be assayed for elastin and collagen content as well as protein and mRNA expression of EGF, VEGF, their receptors, cell proliferation markers, and surfactant proteins. This proposal integrates structure-function principles to define the determinants of compensatory lung growth beyond the immediate goal of clarifying the therapeutic utility of RA. Results provide a model for understanding a general phenomenon, i.e., the consequences when a natural compensatory response is distorted by pharmacological manipulation that selectively alters some but not all aspects of the natural response.