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.
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