EXTRAVASCULAR FIBRIN AND FIBRINOLYTIC SYSTEM PROTEINS IN ASTHMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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剂-1型（PAI-1）在哮喘的两个主要特征，气道高反应性和气道重塑中起作用。哮喘气道炎症的一个后果是血浆蛋白渗漏到肺管腔表面。这些血浆蛋白包括纤维蛋白原和凝血酶（纤维蛋白的酶前体，是血凝块的主要结构成分）。纤维蛋白可以使表面活性剂失活。表面活性剂降低表面张力，主要见于远端肺腔表面。因此，血管外纤维蛋白的形成可以增加远端肺管腔表面的表面张力，从而增加远端肺气道和肺泡关闭和保持关闭的倾向。气道高反应性不仅包括气道收缩，还包括气道关闭。这在最近的极化氦核磁共振成像工作中得到了最显著的证明。我们之前的工作已经证明了血管外纤维蛋白是气道高反应性病理生理不可或缺的概念，表明哮喘患者血管外纤维蛋白积聚发生在远端肺腔表面，并且是充分的，并且在一定程度上是小鼠气道高反应性的必要条件。其他研究表明，在小鼠中，纤维蛋白溶解的负调节因子PAI-1是气道上皮下胶原沉积的决定因素，这是气道重塑的一个特征，并且PAI-1的多态性与哮喘有关。该提案将寻求扩展纤维蛋白和纤溶系统蛋白是哮喘病理生理不可或缺的概念的证明，从小鼠研究到哮喘患者。一组患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个体的肺部进行取样，然后尝试将气道表面纤维蛋白浓度和血浆PAI-1浓度与气道高反应性的测量以及血浆PAI-1与上皮下胶原沉积和气道壁厚度之间的相关性联系起来。此外，哮喘患者将接受普伐他汀的盲法安慰剂对照试验，已知普伐他汀可以降低血浆PAI-1的浓度。

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.