EXTRAVASCULAR FIBRIN AND FIBRINOLYTIC SYSTEM PROTEINS IN ASTHMA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们的工作和其他人的工作提供了证据，证明纤维蛋白和纤溶酶原激活物抑制物-1(PAI-1)在哮喘的两个基本特征--气道高反应性和气道重塑中发挥作用。哮喘所见的呼吸道炎症的一个后果是血浆蛋白渗漏到肺腔表面。这些血浆蛋白包括纤维蛋白原和凝血酶，它们是纤维蛋白的酶前体，纤维蛋白是血液凝块的主要结构成分。众所周知，纤维蛋白可以使表面活性物质失活。表面活性物质可降低表面张力，主要存在于肺远端的管腔表面。因此，血管外纤维蛋白的形成可以增加远端肺的管腔表面的表面张力，从而增加远端肺的气道和肺泡关闭和保持关闭的倾向。呼吸道高反应性不仅包括气道收缩，还包括气道关闭。这一点在最近的偏振氦核磁共振成像工作中得到了最显著的证明。我们以前的工作证明了血管外纤维蛋白是呼吸道高反应性病理生理过程中不可或缺的一部分，这表明血管外纤维蛋白聚集在哮喘小鼠远端肺的管腔表面，是充分的，而且在一定程度上是小鼠气道高反应性所必需的。其他研究表明，PAI-1是纤溶的负性调节因子，是呼吸道上皮下胶原沉积的决定因素，是气道重塑的特征，PAI-1的多态与哮喘有关。这项提议将寻求将纤维蛋白和纤溶系统蛋白是哮喘病理生理学不可或缺的概念的证据从小鼠研究扩展到哮喘患者。一组有哮喘的人和一组没有肺部疾病的人将被研究。我们将使用支气管镜对两组患者的肺进行采样，然后尝试将气道表面纤维蛋白浓度和血浆PAI-1浓度与衡量气道高反应性的指标以及血浆PAI-1与上皮下胶原沉积和气道壁厚度之间的相关性进行关联。此外，哮喘患者将接受普伐他汀的盲法安慰剂对照试验，普伐他汀可降低血浆PAI-1浓度。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our work and the work of others have provided evidence that fibrin and plasminogen activator inhibitor type -1 (PAI-1) have a role in two of the cardinal features of asthma, airway hyperresponsiveness and airway remodeling. A consequence of the airway inflammation seen in asthma is leakage of plasma proteins onto the luminal surface of the lung. Included in these plasma proteins are fibrinogen and thrombin the enzyme precursors of fibrin, a major structural component of blood clots. Fibrin is known to inactivate surfactant. Surfactant reduces surface tension and is found predominantly on the luminal surface of distal lung. Extravascular fibrin formation therefore can increase the surface tension of the luminal surface of the distal lung and thereby increase the propensity of airways and alveoli of the distal lung to close and remained closed. Airway hyperresponsiveness involves not only airway constriction, but also airway closure. This is most dramatically demonstrated in recent work with polarized helium MRI imaging. Our previous work has provided proof of concept that extravascular fibrin is integral to the pathophysiology of airway hyperresponsiveness by showing that extravascular fibrin accumulation occurs on luminal surface of the distal lung in asthma and is sufficient, and somewhat necessary for airway hyperresponsiveness in mice. Others have shown in mice that PAI-1, a negative regulator of fibrinolysis, is a determinant of airway subepithelial collagen deposition, a feature of airway remodeling and that polymorphisms of PAI-1 are associated with asthma. This proposal will seek to extend the proof of concept that fibrin and fibrinolytic system proteins are integral to the pathophysiology of asthma from mouse studies to individuals with asthma. A group of individuals with asthma and a group of individuals without lung disease will be studied. We will sample the lungs of both groups of individuals using bronchoscopy and then attempt to correlate the concentration of fibrin on the airway surface and the plasma concentration of PAI-1 with a measure of airway hyperresponsiveness as well as the correlation between plasma PAI-1 and subepithelial collagen deposition and airway wall thickness. In addition the individuals with asthma will undergo a blinded placebo controlled trial of pravastatin which is known to reduce the concentration of plasma PAI-1.