Asbestos-induced lung epithelial permeability: potential role of nonoxidant pathways

Our plain-English summary of Asbestos-induced lung epithelial permeability: potential role of nonoxidant pathways, by M.W. Peterson, J. Kirschbaum (The American Journal of Physiology, 1998).

The study

• Authors: M.W. Peterson, J. Kirschbaum
• Journal: The American Journal of Physiology
• Published: 1998;275(2):L262-8
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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 permeability is increased in patients with asbestosis, and asbestos fibers increase permeability across cultured human lung epithelium. However, the mechanism of this increased permeability is not known. Many of the biological effects of asbestos are postulated to be due to its ability to generate oxidants, and oxidants are known to increase epithelial permeability. However, we previously reported that altering the iron 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 permeability through nonoxidant pathways. Both extracellular (H2O2) and intracellular (menadione) oxidants increase paracellular permeability across human lung epithelial monolayers. Extracellular catalase but not superoxide dismutase prevented increased permeability after both oxidant exposures. However, catalase offered no protection from asbestos-induced permeability. We next depleted the cells of glutathione or catalase to determine whether depleting normal cellular antioxidants would increase the sensitivity to asbestos. Permeability was the same in control cells and in cells depleted of these antioxidants. In addition to generating oxidants, asbestos also activates signal transduction pathways. Blocking protein kinase C activation did not prevent asbestos-induced 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. These data demonstrate that asbestos may increase epithelial permeability through nonoxidant pathways that involve tyrosine kinase activation. This model offers an important system for studying pathways involved in regulating lung epithelial permeability.

In plain English

This laboratory study used cultured human bronchial epithelial (HBE162) monolayers, grown on filter inserts, to ask how asbestos increases paracellular permeability, measured as the movement of radiolabelled mannitol from the apical to the basolateral side. Hydrogen peroxide (an extracellular oxidant) and menadione (which generates oxidants inside cells) both increased mannitol permeability. Extracellular catalase, but not superoxide dismutase, prevented the menadione effect, whereas neither enzyme protected against asbestos. Chrysotile and amosite asbestos, which differ in iron content, raised permeability to a similar degree. Depleting cells of glutathione with buthionine sulfoximine (a 90% reduction) or of catalase with aminotriazole (a 60% reduction in the presence of either hydrogen peroxide or asbestos) did not increase asbestos-induced permeability; aminotriazole had no effect on catalase in control cells, which the authors took as evidence of some oxidant generation in asbestos-exposed cells. Blocking protein kinase C with GF 109203X did not block the asbestos effect; the tyrosine kinase inhibitor tyrophostin A25 did, and sodium vanadate enhanced it. The authors concluded that these data suggest asbestos may increase epithelial permeability through nonoxidant pathways involving tyrosine kinase activation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro experimental study using cultured human lung epithelial cell monolayers and a mannitol permeability assay
• Who was studied: Immortalized human bronchial epithelial (HBE162) cell monolayers grown on collagen-coated filter inserts; each figure bar represented 6 or 8 monolayers (University of Iowa laboratory)
• Exposure: Chrysotile (cryogenically ground Calidria) and amosite asbestos at 100 µg/ml, plus H2O2, menadione, catalase, superoxide dismutase, buthionine sulfoximine, aminotriazole, GF 109203X, phorbol 12,13-dibutyrate, tyrophostin A25 and sodium vanadate
• Main results:
  • Hydrogen peroxide increased mannitol permeability across the monolayers in a concentration- and time-dependent way
  • Neither extracellular superoxide dismutase nor extracellular catalase protected the monolayers against asbestos-induced permeability
  • Extracellular catalase, but not superoxide dismutase, blocked the permeability increase caused by the intracellular oxidant generator menadione
  • Amosite and chrysotile asbestos, which differ in iron content, increased mannitol permeability to a similar degree
  • Buthionine sulfoximine reduced cellular glutathione by 90%, but asbestos did not raise permeability more in glutathione-depleted cells than in native cells
  • Aminotriazole reduced cellular catalase by 60% in cells exposed to either H2O2 or asbestos, but catalase depletion did not change asbestos-induced permeability
  • Aminotriazole did not lower catalase in control cells but did in asbestos-exposed cells, which the authors read as evidence of oxidant generation in asbestos-exposed cells
  • Blocking protein kinase C with GF 109203X did not prevent asbestos-induced permeability, although it did block permeability induced by phorbol 12,13-dibutyrate
  • The tyrosine kinase inhibitor tyrophostin A25 prevented asbestos-induced permeability at 24 and 48 h, and the tyrosine phosphatase blocker sodium vanadate (100 µM) enhanced the asbestos effect
• The authors' conclusion: The authors concluded that their data suggest asbestos has nonoxidant biological effects and may increase epithelial permeability through nonoxidant pathways involving tyrosine kinase activation
• Limitations the authors state:
  • The authors noted that their cultured-cell system differed from other experimental systems in that no exogenous hydrogen peroxide source and no inflammatory cells were present
  • The authors stated that their tyrosine kinase experiments did not identify the target protein(s)

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Santa Rita mine, Joaquin Ridge near Coalinga, California

All asbestos mines

Topics

The National Library of Medicine indexes this study under subjects our site covers: Amosite, Chrysotile.

Medical terms in this study, explained in our Lexicon: Fibrosis, Epithelium, Superoxide, Glutathione (GSH).

Related studies

• Cytotoxicity of oxidants and asbestos fibers in cultured human mesothelial cells — V.L. Kinnula, K. Aalto, et al. (1994)
• Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways — A. Baldys, P. Pande, et al. (2007)
• Chrysotile asbestos and H2O2 increase permeability of alveolar epithelium — S.Y. Gardner, A.R. Brody, et al. (1997)
• Asbestos directly increases lung epithelial permeability — M.W. Peterson, M.E. Walter, et al. (1993)
• Asbestos causes apoptosis in alveolar epithelial cells: role of iron-induced free radicals — A. Aljandali, H. Pollack, et al. (2001)
• High levels of catalase and glutathione peroxidase activity dampen H2O2 signaling in human alveolar macrophages — A.B. Carter, L.A. Tephly, et al. (2004)

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