title: Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness.
abstract: Mechanisms underlying airway hyperresponsiveness are not yet fully elucidated. One of the manifestations of airway inflammation is leakage of diverse plasma proteins into the airway lumen. They include fibrinogen and thrombin. Thrombin cleaves fibrinogen to form fibrin, a major component of thrombi. Fibrin inactivates surfactant. Surfactant on the airway surface maintains airway patency by lowering surface tension. In this study, immunohistochemically detected fibrin was seen along the luminal surface of distal airways in a patient who died of status asthmaticus and in mice with induced allergic airway inflammation. In addition, we observed altered airway fibrinolytic system protein balance consistent with promotion of fibrin deposition in mice with allergic airway inflammation. The airways of mice were exposed to aerosolized fibrinogen, thrombin, or to fibrinogen followed by thrombin. Only fibrinogen followed by thrombin resulted in airway hyperresponsiveness compared with controls. An aerosolized fibrinolytic agent, tissue-type plasminogen activator, significantly diminished airway hyperresponsiveness in mice with allergic airway inflammation. These results are consistent with the hypothesis that leakage of fibrinogen and thrombin and their accumulation on the airway surface can contribute to the pathogenesis of airway hyperresponsiveness.
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05405-0075, USA. Scott.Wagers@uvm.edu
authors.forename: Scott S
authors.initials: SS
authors.lastname: Wagers
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Norton
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rinaldi
authors.forename: Jason H T
authors.initials: JH
authors.lastname: Bates
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D005337:Fibrin / Q000378:metabolism*; D005340:Fibrinogen / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D010960:Plasminogen Activators / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D005343:Fibrinolytic Agents; D015849:Plasminogen Inactivators; D005337:Fibrin; D005340:Fibrinogen; D010960:Plasminogen Activators; D013917:Thrombin; D010959:Tissue Plasminogen Activator