Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness
Scott S. Wagers, … , Burton E. Sobel, Charles G. Irvin
Scott S. Wagers, … , Burton E. Sobel, Charles G. Irvin
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):104-111. https://doi.org/10.1172/JCI19569.
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Article Pulmonology

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

Scott S. Wagers, Ryan J. Norton, Lisa M. Rinaldi, Jason H.T. Bates, Burton E. Sobel, Charles G. Irvin

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The effect of nebulized fibrinolytic agent, tPA, on the response to meth...
The effect of nebulized fibrinolytic agent, tPA, on the response to methacholine in mice with allergic airway inflammation. The response to a single dose of 12.5 mg/ml of nebulized methacholine administered 15 minutes after administration of saline (black bars) or tPA (white bars) is shown on the ordinate as the percentage of increase from baseline. An increased value indicates an increased response to methacholine. Mice with allergic airway inflammation (n = 7) that had been exposed to tPA had a significantly reduced response to methacholine compared with those exposed to saline alone (n = 7): Rn, 99.2% ± 16% compared with 267% ± 62% (P < 0.03); Gti, 102% ± 23% compared with 225% ± 30% (P < 0.01); and Hti, 71% ± 30% compared with 284% ± 92% (P < 0.05). In terms of Rn and Gti, the response to methacholine in mice with airway inflammation that had been exposed to nebulized tPA (n = 7) was similar to the response in mice without airway inflammation exposed to saline (n = 10): Rn, 99.2% ± 16% compared with 119% ± 14%; Gti, 102% ± 23% compared with 137% ± 21%. Nebulized tPA did not completely reduce the response in terms of Hti to the level seen in controls: 71.2% ± 30% compared with 25.6% ± 2.7%.