ASBESTOS EXPOSURE INCREASES PARACELLULAR TRANSPORT OF FIBRIN DEGRADATION PRODUCTS ACROSS HUMAN AIRWAY EPITHELIUM

The inflammatory response to asbestos fiber inhalation suggests that t he distal respiratory epithelium is an important early target of asbes tos-induced injury. We have previously found that asbestos exposure in creases the fibrinolytic activity and mannitol permeability of human a irway epithelial cell monolayers. Because fibrin degradation products (FDP) are potent inflammatory mediators, we asked whether asbestos fib er exposure would increase the transepithelial flux of FDP into the in terstitial space. To simulate the pericellular environment following f iber deposition, asbestos-exposed epithelial monolayers grown on perme able filters were covered with human plasma containing fluorescein iso thiocya nate (FITC)-labeled human fibrinogen. After 24 h, nearly twice as much FITC-FDP appeared in the abluminal chamber of asbestos-expose d monolayers compared with unexposed controls. This did not result sol ely from increased degradation product production because asbestos-exp osed epithelium was more permeable at all apical FDP concentrations. T he proteins that crossed asbestos-exposed monolayers included biologic ally relevant high-molecular-weight FDP, as demonstrated by streptavid in blotting of biotin-labeled FDP. We also found that FDP flux was not vectorial, was not saturable, did not involve proteolytic processing of FDP, and did not require active transport. Thus asbestos exposure i ncreases the paracellular flux of intact FDP across human airway epith elium. This represents a novel mechanism whereby fiber-induced epithel ial dysfunction may initiate and sustain inflammation in the distal ai rspace.