Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice

Our plain-English summary of Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice, by P. Cheresh, L. Morales-Nebreda, S.J. Kim, et al (American Journal of Respiratory Cell and Molecular Biology, 2015).

The study

• Authors: P. Cheresh, L. Morales-Nebreda, S.J. Kim, A. Yeldandi, D.B. Williams, Y. Cheng, G.M. Mutlu, G.R. Budinger, K. Ridge, P.T. Schumacker, V.A. Bohr, D.W. Kamp
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2015;52(1):25-36
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos causes asbestosis and malignancies by mechanisms that are not fully established. Alveolar epithelial cell (AEC) injury and repair are crucial determinants of the fibrogenic potential of noxious agents such as asbestos. We previously showed that mitochondrial reactive oxygen species mediate asbestos-induced AEC intrinsic apoptosis and that mitochondrial human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme, prevents oxidant-induced AEC apoptosis. We reasoned that OGG1 deficiency augments asbestos-induced pulmonary fibrosis. Compared with intratracheal instillation of PBS (50 μl) or titanium dioxide (100 μg/50 μl), crocidolite or Libby amphibole asbestos (100 μg/50 μl) each augmented pulmonary fibrosis in wild-type C57BL/6J (WT) mice after 3 weeks as assessed by histology, fibrosis score, lung collagen via Sircol, and type 1 collagen expression; these effects persisted at 2 months. Compared with WT mice, Ogg1 homozygous knockout (Ogg1(-/-)) mice exhibit increased pulmonary fibrosis after crocidolite exposure and apoptosis in cells at the bronchoalveolar duct junctions as assessed via cleaved caspase-3 immunostaining. AEC involvement was verified by colocalization studies using surfactant protein C. Asbestos increased endoplasmic reticulum stress in the lungs of WT and Ogg1(-/-) mice. Compared with WT, alveolar type 2 cells isolated from Ogg1(-/-) mice have increased mtDNA damage, reduced mitochondrial aconitase expression, and increased P53 and cleaved caspase-9 expression, and these changes were enhanced 3 weeks after crocidolite exposure. These findings suggest an important role for AEC mtDNA integrity maintained by OGG1 in the pathogenesis of pulmonary fibrosis that may represent a novel therapeutic target.

In plain English

This was a laboratory experiment in mice. In wild-type C57BL/6J mice, the authors compared a single intratracheal instillation of PBS (50 microlitres), titanium dioxide, UICC crocidolite asbestos or Libby amphibole fibers (100 micrograms in 50 microlitres), with lungs examined after 3 weeks or 2 months; male 8- to 10-week-old Ogg1 homozygous knockout (Ogg1-/-) mice were compared with wild-type mice 3 weeks after crocidolite. In wild-type mice, crocidolite raised the lung fibrosis score to 5.0 plus or minus 0.3 (0 plus or minus 0 for PBS and for titanium dioxide) and Sircol collagen to 0.59 plus or minus 0.03 mg/ml, changes that persisted at 2 months; Libby amphibole gave a higher fibrosis score than crocidolite (7.5 plus or minus 0.5 versus 4 plus or minus 0.4). After crocidolite, Ogg1-/- mice had higher fibrosis scores (7.0 plus or minus 0.5), more collagen, more cleaved caspase-3 positive cells at bronchoalveolar duct junctions (15.8 versus 11.8 percent), more alveolar type 2 cell mitochondrial DNA damage and increased P53; aconitase-2 was numerically lower in Ogg1-/- than in crocidolite-exposed wild-type cells, but not significantly. The authors concluded OGG1 deficiency augments these changes.

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: controlled animal experiment comparing Ogg1 knockout and wild-type mice, with isolated primary alveolar type 2 cell assays
• Who was studied: Male 8- to 10-week-old wild-type C57BL/6J mice and Ogg1 homozygous knockout mice, given control or asbestos instillations, with lungs harvested after 3 weeks or 2 months
• Exposure: Single intratracheal instillation of UICC reference crocidolite asbestos or Libby amphibole fibers, 100 micrograms in 50 microlitres, compared with PBS vehicle and titanium dioxide particulate control; the Libby amphibole comparison was made in wild-type mice, and the knockout comparison used crocidolite
• Main results:
  • In wild-type mice at 3 weeks, crocidolite raised the lung fibrosis score compared with PBS and titanium dioxide (5.0 plus or minus 0.3 versus 0 plus or minus 0 and 0 plus or minus 0; P less than 0.05) and Sircol collagen (0.59 plus or minus 0.03 versus 0.31 plus or minus 0.05 and 0.24 plus or minus 0.02 mg/ml)
  • In wild-type mice, Libby amphibole for 3 weeks produced worse fibrosis than crocidolite (fibrosis score 7.5 plus or minus 0.5 versus 4 plus or minus 0.4; Sircol 0.74 plus or minus 0.06 versus 0.48 plus or minus 0.03 mg/ml; P less than 0.05)
  • The fibrotic changes seen in wild-type mice 3 weeks after crocidolite persisted at 2 months
  • After crocidolite, Ogg1-/- mice had higher fibrosis scores than wild-type (7.0 plus or minus 0.5 versus 5.0 plus or minus 0.3) and higher Sircol collagen (0.86 plus or minus 0.02 versus 0.59 plus or minus 0.03 mg/ml), both P less than 0.05
  • Cleaved caspase-3 positive cells at bronchoalveolar duct junctions after crocidolite: 15.8 plus or minus 0.8 percent in Ogg1-/- mice versus 11.8 plus or minus 0.7 percent in wild-type mice (per 220 cells; P less than 0.05); in controls fewer than 1 percent of 220 cells were positive
  • Of about 200 cells assessed in crocidolite-exposed Ogg1-/- lungs, alveolar type 2 cells (surfactant protein C positive) accounted for nearly 40 percent of the apoptotic cells, with non-alveolar epithelial cells also apoptotic
  • Mitochondrial DNA lesions in isolated alveolar type 2 cells: wild-type crocidolite 0.056 plus or minus 0.007 versus wild-type titanium dioxide 0.0 plus or minus 0 lesions per 10 kb; Ogg1-/- titanium dioxide 0.073 plus or minus 0.011 and Ogg1-/- crocidolite 0.105 plus or minus 0.005 (P less than 0.05, n = 4); nuclear DNA damage was negligible
  • In alveolar type 2 cells, crocidolite reduced ACO-2 in wild-type mice (0.44 plus or minus 0.03 versus 1.0 plus or minus 0 relative density units for titanium dioxide; P less than 0.05), and ACO-2 was lower in Ogg1-/- cells than in wild-type cells after titanium dioxide and after crocidolite; however, the difference between Ogg1-/- cells and crocidolite-exposed wild-type cells did not reach statistical significance
  • P53 expression in alveolar type 2 cells after crocidolite was higher in Ogg1-/- than wild-type mice (3.90 plus or minus 0.59 versus 1.55 relative density units; P less than 0.05)
  • Crocidolite, unlike titanium dioxide, induced endoplasmic reticulum stress (HSPA5) at bronchoalveolar duct junctions in both strains: in apoptotic cells 12.9 percent (wild-type) and 16.1 percent (Ogg1-/-), and in nonapoptotic cells 84.0 and 92.0 percent respectively
• The authors' conclusion: The authors concluded that OGG1 deficiency augments alveolar epithelial cell mitochondrial DNA damage and apoptosis in vivo, which appear crucial for the development of pulmonary fibrosis after asbestos exposure, and suggested mitochondrial OGG1 and ACO-2 as possible therapeutic targets
• Limitations the authors state:
  • Only a single dose of asbestos was used
  • The study cannot exclude a role for other cells, such as inflammatory cells or macrophages, in the fibrotic response
  • The causal role of alveolar epithelial cells or other cell types in mediating the fibrosis is not established by this study

Mines named here

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

• Libby vermiculite mine, Montana

All asbestos mines

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite.

Medical terms in this study, explained in our Lexicon: Pulmonary Fibrosis, Fibrogenic, Reactive Oxygen Species (ROS), Apoptosis, Crocidolite, Libby amphiboles, Histology, Fibrosis.

Related studies

• SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis — R.P. Jablonski, S.J. Kim, et al. (2017)
• Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells — S.J. Kim, P. Cheresh, et al. (2014)
• The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis — S.J. Kim, P. Cheresh, et al. (2015)
• Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage — S.J. Kim, P. Cheresh, et al. (2016)
• The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes — P. Cheresh, S.J. Kim, et al. (2020)
• Bronchiolar and alveolar lesions in the pathogenesis of crocidolite-induced pulmonary fibrosis in mice — D.H. Bowden, I.Y. Adamson (1985)

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