Increased phosphorylated extracellular signal-regulated kinase immunoreactivity associated with proliferative and morphologic lung alterations after chrysotile asbestos inhalation in mice

Our plain-English summary of Increased phosphorylated extracellular signal-regulated kinase immunoreactivity associated with proliferative and morphologic lung alterations after chrysotile asbestos inhalation in mice, by R.F. Robledo, S.A. Buder-Hoffmann, A.B. Cummins, et al (The American Journal of Pathology, 2000).

The study

• Authors: R.F. Robledo, S.A. Buder-Hoffmann, A.B. Cummins, E.S. Walsh, D.J. Taatjes, B.T. Mossman
• Journal: The American Journal of Pathology
• Published: 2000;156(4):1307-16
• Cited by: 58 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Activation of extracellular signal-regulated kinases (ERK) has been associated with the advent of asbestos-associated apoptosis and proliferation in mesothelial and alveolar epithelial cells and may be linked to the development of pulmonary fibrosis. The objective of studies here was to characterize the development of inflammation, cellular proliferation, and fibrosis in asbestos-exposed C57Bl/6 mice in relationship to patterns of ERK phosphorylation. Inflammation occurred after 10 and 20 days of asbestos exposure as evidenced by increases in total protein and neutrophils in bronchoalveolar lavage fluid. Increases in cell proliferation were observed at 30 days in bronchiolar epithelia and at 4, 14, and 30 days in the alveolar compartment of the lung. Trichrome-positive focal lesions of pulmonary fibrosis developed at 30 days in the absence of elevations in lung hydroxyproline or procollagen mRNA levels. Striking increases in ERK phosphorylation were observed within pulmonary epithelial cells at sites of developing fibrotic lesions after 14 and 30 days of inhalation. In addition to characterizing a murine inhalation model of asbestosis, we provide the first evidence showing activation of ERK signaling within lung epithelium in vivo, following inhalation of asbestos fibers.

In plain English

In this animal experiment, male C57Bl/6 mice breathed either ordinary air or chrysotile asbestos for 6 hours a day, 5 days a week, at a target concentration of 10 mg/m3 of air. Groups of 4 mice were exposed for 10 or 20 days, and groups of 5 for 4, 14 or 30 days. One further group was exposed for 30 days and then kept in clean air for 28 days. Compared with unexposed mice, exposed mice had lung inflammation at 10 and 20 days, with a higher proportion of neutrophils and more protein in lung-wash fluid. Small areas of fibrosis appeared at 30 days, without increases in lung hydroxyproline, a collagen marker. These areas did not appear to progress during recovery. Cell division increased in the alveolar regions at 4, 14 and 30 days, and in the bronchiolar lining at 30 days. Phosphorylated ERK, a sign of an active cell-signaling pathway, was seen in clusters of bronchiolar cells at 14 and 30 days and in developing lesions at 30 days. The authors concluded that ERK signaling may be a key mediator of asbestos-associated lung disease.

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: Animal inhalation experiment (two experiments in mice, chrysotile-exposed versus sham-exposed to ambient air)
• Who was studied: Two- to three-month-old male C57Bl/6 mice from the National Institutes of Health, studied at the University of Vermont. Experiment 1 used 4 mice per group (10 or 20 days). Experiment 2 used 5 mice per group (4, 14 or 30 days, plus a group with 30 days of exposure followed by 28 days of recovery).
• Exposure: Inhalation of NIEHS reference chrysotile asbestos, or ambient air for controls, 6 hours per day, 5 days a week. The target concentration was 10 mg/m3 air. Measured average concentrations were 8.43 and 9.35 mg/m3 air in the two experiments.
• Main results:
  • After 10 and 20 days of exposure, chrysotile-exposed mice had higher percentages of neutrophils and lower percentages of alveolar macrophages in bronchoalveolar lavage fluid than sham controls, along with increased total protein. Total cell numbers did not differ significantly between groups.
  • In exposed mice, there were no remarkable changes in lung structure at 4 days and moderate areas of cellular inflammation at 14 days. Focal fibrotic lesions appeared at 30 days, but were not associated with increases in lung hydroxyproline or procollagen type I mRNA.
  • The severity and extent of lung injury and fibrosis seen at 30 days did not appear to progress during the 4-week recovery period.
  • Cell proliferation (BrdU incorporation) in exposed mice was increased in the alveolar regions after 4, 14 and 30 days. Increases in proliferating bronchiolar epithelial cells were not statistically significant until 30 days.
  • During the 4-week recovery period after 30 days of exposure, the numbers of proliferating cells decreased substantially but remained elevated compared with controls.
  • Clusters of cells positive for phosphorylated ERK were seen within bronchiolar bifurcations and epithelium after 14 and 30 days of chrysotile exposure, and within developing fibrotic lesions at 30 days. Sham-exposed lungs showed this staining only in an occasional interstitial cell.
  • After the 4-week recovery period, ERK phosphorylation in exposed mice was comparable to that in sham-exposed mice (observations not shown).
• The authors' conclusion: The authors concluded that the focal ERK phosphorylation seen in developing fibrotic lesions provides further evidence that ERK signaling may be a key mediator in asbestos-associated lung disease. They also stated that this was the first evidence of ERK activation in lung epithelium in living animals after asbestos inhalation.

Topics

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

Medical terms in this study, explained in our Lexicon: Chrysotile, Apoptosis, Pulmonary Fibrosis, Inflammation, Fibrosis, Asbestos Exposure, Bronchoalveolar Lavage (BAL), Alveolar Compartment.

Related studies

• Asbestos inhalation induces tyrosine nitration associated with extracellular signal-regulated kinase 1/2 activation in the rat lung — A. Iwagaki, N. Choe, et al. (2003)
• Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis — A.B. Cummins, C. Palmer, et al. (2003)
• The duration of nuclear extracellular signal-regulated kinase 1 and 2 signaling during cell cycle reentry distinguishes proliferation from apoptosis in response to asbestos — Z. Yuan, D.J. Taatjes, et al. (2004)
• Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells — S. Buder-Hoffmann, C. Palmer, et al. (2001)
• Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2 — L.A. Jiménez, C. Zanella, et al. (1997)
• Comparative proliferative and histopathologic changes in rat lungs after inhalation of chrysotile or crocidolite asbestos — K.A. BéruBé, T.R. Quinlan, et al. (1996)

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