Retinoic Acid and Post-pneumonectomy Lung Growth

描述(申请人提供)：成年犬肺切除(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的体积和厚度，而不增加表面积或改善气体交换。在第二阶段，间隔重塑通过增加表面积和功能代偿恢复正常结构。外源性视黄酸(RA)选择性地促进右PNX后第1时相的肺泡内皮细胞生长，但不促进静息状态下的气体交换。结构-功能二分法类似于RA治疗的肺气肿大鼠的二分法。我们的目标是明确RA促进肺生长的时间进程、机制和生理后果。假设是：a)在双相反应的第一阶段，IRA选择性地增加PNX后相对于上皮的内皮生长(失调性隔膜生长)，从而扭曲隔膜结构。扭曲限制了02交换中的补偿，尽管细胞生长增强，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PNX后常见的气道-实质分离(呼吸紊乱肺生长)而损害气道适应。尽管间隔细胞生长增强，但气道适应性受损降低了呼吸补偿；c)RA促进的内皮细胞生长与上皮细胞比例不成比例对应着血管内皮生长因子(VEGF)轴相对于表皮生长因子(EGF)轴的选择性激活。匹配的成年犬在右侧PNX后接受RA或安慰剂4mo，停止治疗后继续随访8mo。详细的研究包括休息和运动时的肺功能、胸部CT扫描以及腺泡和呼吸道结构的形态计量分析。将在RA治疗期间和治疗后的不同时间点对不同的队列进行研究；将检测肺组织的弹性蛋白和胶原含量以及EGF、VEGF、它们的受体、细胞增殖标志物和表面活性蛋白的蛋白和mRNA表达。这项建议整合了结构-功能原则，以确定代偿性肺生长的决定因素，而不仅仅是澄清RA的治疗效用。结果为理解一个普遍现象提供了一个模型，即，当自然代偿反应被选择性地改变自然反应的某些方面而不是所有方面的药物操纵扭曲时的后果。

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.