ASBESTOS-INDUCED LUNG EPITHELIAL PERMEABILITY - POTENTIAL ROLE OF NONOXIDANT PATHWAYS

Asbestos fibers are an important cause of lung fibrosis; however, the biological mechanisms are incompletely understood. The lung epithelium serves an important barrier function in the lung, and disrupting the epithelial barrier can contribute to lung fibrosis. Lung epithelial pe rmeability is increased in patients with asbestosis, and asbestos fibe rs increase permeability across cultured human lung epithelium. Howeve r, the mechanism of this increased permeability is not known. Many of the biological effects of asbestos are postulated to be due to its abi lity to generate oxidants, and oxidants are known to increase epitheli al permeability. However, we previously reported that altering the iro n content of asbestos (important in oxidant generation) had no effect on its ability to increase permeability. For that reason, we undertook these studies to determine whether asbestos increases epithelial perm eability through nonoxidant pathways. Both extracellular (H2O2) and in tracellular (menadione) oxidants increase paracellular permeability ac ross human lung epithelial monolayers. Extracellular catalase but not superoxide dismutase prevented increased permeability after both oxida nt exposures. However, catalase offered no protection from asbestos-in duced permeability. We next depleted the cells of glutathione or catal ase to determine whether depleting normal cellular antioxidants would increase the sensitivity to asbestos. Permeability was the same in con trol cells and in cells depleted of these antioxidants. In addition to generating oxidants, asbestos also activates signal transduction path ways. Blocking protein kinase C activation did not prevent asbestos-in duced permeability; however, blocking tyrosine kinase with tyrophostin A25 did prevent asbestos-induced permeability, and blocking tyrosine phosphatase with sodium vanadate enhanced the effect of asbestos. Thes e data demonstrate that asbestos may increase epithelial permeability through nonoxidant pathways that involve tyrosine kinase activation. T his model offers an important system for studying pathways involved in regulating lung epithelial permeability.