Force Propagation of Emphysema in Vivo

描述(申请人提供)：肺气肿是慢性阻塞性肺疾病的一种常见形式，影响着150万至200万美国人，是世界各地人数的3-4倍。在很大程度上基于遗传性α-1抗蛋白酶缺乏症患者疾病进展的经典范例，推测肺气肿的组织破坏是促进和抑制肺组织酶破坏的相反因素之间的失衡的结果。这种失衡导致肺气肿弹性蛋白-胶原网络的破坏，在大多数情况下，被认为是由于吸烟引起的炎症，导致中性粒细胞和单核细胞释放蛋白水解酶。虽然炎症在肺气肿的最初发展中发挥了核心作用，但最近的实验和临床观察表明，其他因素可能在导致疾病进展方面起着重要作用。在这里，我们假设机械应力通过导致被机械削弱的重塑组织的肺泡壁破裂来促进疾病的进展。我们的研究小组已经证明，潮气呼吸过程中产生的机械力可以在体外破坏弹性蛋白-胶原纤维网络或重塑的肺气肿组织。虽然没有证据支持体内机械力的这种直接作用，但在肺减容手术或单肺移植患者中观察到的FEV1加速下降的速度与这一概念是一致的。目前的研究将在一个特征良好的异质性肺气肿绵羊模型中检验这一假设，该模型具有许多晚期人类疾病的特征。这些实验结果将为机械力在促进完整肺气肿肺损伤中的作用以及机械力对组织重塑的影响提供新的见解。

DESCRIPTION (provided by applicant): Emphysema, a common form of chronic obstructive lung disease, affects between 1.5 and 2 million Americans, and 3-4 times that many individuals worldwide. Based largely on the classic paradigm of disease progression in patients with inherited alpha-1 anti-protease deficiency, it is postulated that tissue destruction in emphysema is a consequence of an imbalance between opposing factors that promote and inhibit enzymatic destruction of lung tissue. This imbalance causes damage to the elastin-collagen network in emphysema, and is thought, in most instances, to be due to smoking-related inflammation which causes release of proteolytic enzymes by neutrophils and mononuclear cells. While there is little doubt that inflammation plays a central role in the initial development of emphysema, recent experimental and clinical observations suggest that other factors may be important in causing disease progression. Here we hypothesize that mechanical stress promotes disease progression by causing rupture of alveolar walls in remodeled tissues that are mechanically weakened. Our research group has shown that mechanical forces generated during tidal breathing can rupture the elastin-collagen fiber network or remodeled emphysema tissues in vitro. Although no evidence exists to support such a direct role for mechanical force in vivo, the accelerated rate of decline in FEV1 observed in patients following lung volume reduction surgery or single lung transplantation is consistent with this notion. The present study will examine this hypothesis in a well characterized sheep model of heterogeneous emphysema that possesses many features of advanced human disease. The results of these experiments will provide new insight into the role of mechanical forces in promoting injury in the intact emphysema lung, and the effect of mechanical forces on tissue remodeling.