Role of Mechanical Forces in the Progession of Emphysema

描述(申请人摘要)：人们普遍认为肺气肿 通过蛋白酶和抗蛋白酶活性的不平衡而发展 肺，导致肺泡内弹性蛋白纤维的酶促破坏 墙。然而，我们实验室的初步数据显示，肺气肿 可以以不涉及弹性蛋白的方式诱导。我们观察到， 单用弹性蛋白酶处理大鼠肺组织中的胶原纤维 在正常呼吸所需的机械力作用下破裂。 因为胶原蛋白比弹性蛋白坚固得多，并保护肺泡不受 在高扩张压力下破裂，即使弹性蛋白受损，肺泡 除非胶原蛋白减弱，否则壁层不可能破裂，因此容易发生 机械故障。这一观察结果使我们形成了两个假设：1) 在蛋白水解性损伤导致肺气肿的发病初期进展之后， 达到了一个临界点，在这个临界点上，需要维持的机械力 正常的呼吸足以逐渐损害和破坏重塑的 肺泡壁；2)肺气肿的一个关键因素是细胞外修复和 肺气肿的各种动物模型之间的共同联系是 重塑的弱胶原纤维，可在机械力作用下断裂。至 测试这些假设，我们将确定机械力是否会破裂 三种小鼠急性肺损伤模型(弹性蛋白酶、胶原酶)的肺泡壁 和蛋白多糖消化治疗)的肺气肿，和“击倒”和 转基因自发性肺气肿小鼠模型。改建的措施和 炎症将在两个时间点与肺功能相关 肺气肿的进展。生理测量、生化和分子测量 生物学研究以及同时进行的机械故障测试和 显微结构成像将被用于：1)评估胶原蛋白 重塑是所有类型心肌梗死病理生理学的重要共同特征。 肺气肿；2)确定胶原蛋白衰竭的结构基础；以及3) 评估观察到的肺气肿的持续进展 临床上是由于在治疗过程中发生的自我传播的失败 呼吸正常。

DESCRIPTION (Applicant's abstract): It is generally accepted that emphysema develops through an imbalance of protease and anti-protease activity in the lung, resulting in enzymatic destruction of elastin fibers within the alveolar wall. However, preliminary data from our laboratory demonstrate the emphysema can be induced in ways that do not involve elastin. We have observed that collagen fibers in the lung tissue of rats treated only with elastase can rupture under the mechanical forces that are required for normal breathing. Since collagen is much stronger than elastin, and protects the alveoli from rupture at high distending pressures, even if elastin is damaged, the alveolar wall can not possibly rupture unless collagen is weakened, and thus prone to mechanical failure. This observation has led us to formulate two hypotheses: 1) Following the onset initial progression of emphysema due to proteolytic injury, a critical point is reached at which the mechanical forces required to maintain normal breathing are sufficient to gradually damage and rupture the remodeled alveolar walls; 2) A key element of emphysema is extracellular repair and the common link among the various animal models of emphysema is the generation of remodeled weak collagen fibers that can rupture under mechanical forces. To test these hypotheses we will determine whether mechanical forces can rupture the alveolar walls in three acute injury murine models (elastase, collagenase and proteoglycan digestion treatments) of emphysema, and "knock out" and transgenic murine models of spontaneous emphysema. Measures of remodeling and inflammation will be correlated with lung function at 2 time points during the progression of emphysema. Physiological measurements, biochemical and molecular biology studies as well as simultaneously mechanical failure testing and microstructural imaging will be utilized to: 1) assess whether collagen remodeling is a critical common feature in the pathophysiology of all types of emphysema; 2) determine the structural basis for collagen failure; and 3) assess whether the relentless progression of emphysema that is observed clinically is due to self-propagating failure that occurs during the process of normal breathing.