Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism

Our plain-English summary of Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism, by D. Upadhyay, V. Panduri, D.W. Kamp (American Journal of Respiratory Cell and Molecular Biology, 2005).

The study

• Authors: D. Upadhyay, V. Panduri, D.W. Kamp
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2005;32(3):232-8
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos induces alveolar epithelial cell (AEC) DNA damage and apoptosis by the mitochondria-regulated death pathway and oxidative stress. Fibroblast growth factor-10 (FGF-10), an alveolar epithelial type II cell mitogen that is required for the lung development, prevents H(2)O(2)-induced AEC DNA damage by a mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)-dependent mechanism. In this study, we show that FGF-10 attenuates asbestos-induced AEC DNA strand break formation and apoptosis. MAPK/ERK kinase (MEK) inhibitors, U0126 or PD98059, each blocked the protective effect of FGF-10 against asbestos-induced DNA damage and apoptosis, whereas a p38-MAPK inhibitor had a negligible effect, suggesting a crucial role for MEK/ERK activation in mediating the protective effects of FGF-10. Further, we show that FGF-10 attenuates asbestos-induced change in AEC mitochondrial membrane potential and caspase 9 activation, both of which are blocked by U0126. We conclude that FGF-10 decreases asbestos-induced AEC DNA damage and apoptosis in part by mechanisms involving MEK/ERK-dependent signaling that affects the mitochondria-regulated death pathway.

In plain English

This was a laboratory study of cells grown in dishes, not a study of people. The authors tested whether fibroblast growth factor-10 (FGF-10), a protein needed for lung development, protects alveolar epithelial cells (cells lining the lung's air sacs) from damage caused by amosite asbestos. They used A549 cells and type II alveolar cells taken from rats. The cells were treated with FGF-10 for 1 hour and then exposed to amosite for 24 hours. In A549 cells, asbestos alone caused a 64% reduction in intact double-stranded DNA, a sign of DNA strand breaks. FGF-10 reduced these breaks by nearly 50% in A549 cells and almost completely in the rat cells. FGF-10 completely blocked one measure of asbestos-induced cell death (TUNEL staining) and partly reduced another (DNA fragmentation). FGF-10 also nearly completely blocked activation of caspase 9. It completely blocked the loss of mitochondrial membrane potential at the lower asbestos dose. At the higher dose, the protection was partial and not statistically significant. Drugs that block the MEK/ERK signaling pathway removed FGF-10's protection. Blockers of p38-MAPK or PI3K had negligible effect. The authors concluded that FGF-10 reduces asbestos-induced DNA damage and cell death partly through MEK/ERK signaling. They said its relevance in living animals still needs study.

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: laboratory (in vitro) cell culture experiment
• Who was studied: A549 cells obtained from the American Type Culture Collection, and alveolar type II (AT2) cells isolated from specific pathogen-free adult Harlan Sprague-Dawley rats
• Exposure: Amosite asbestos (UICC reference standard samples), given for 24 hours at doses printed as 1, 5, 25 and 50 'g/cm2'. Cells were first pretreated with FGF-10 (mainly 10 ng/ml for 1 hour), in some experiments after MEK/ERK, p38-MAPK or PI3K inhibitors.
• Main results:
  • In A549 cells, asbestos alone caused a 64% reduction in double-stranded DNA compared with control (a measure of DNA strand breaks)
  • In A549 cells, FGF-10 reduced asbestos-induced DNA strand breaks by nearly 50%, with no clear dose-dependent effect of FGF-10
  • In rat AT2 cells, FGF-10 nearly completely protected against asbestos-induced DNA strand breaks
  • In A549 and rat AT2 cells, the MEK/ERK inhibitors U0126 and PD98059 each blocked FGF-10's protection against asbestos-induced DNA strand breaks
  • In A549 cells, FGF-10 completely blocked asbestos-induced TUNEL staining and partially prevented DNA fragmentation (the percentage is preceded by an unreadable symbol in the text)
  • In A549 cells, FGF-10 completely blocked the asbestos-induced (25 dose) reduction in mitochondrial membrane potential. It partially blocked the effect of the high dose (50), but this difference did not reach statistical significance.
  • In A549 cells, FGF-10 nearly completely blocked asbestos-induced caspase 9 activation
  • In A549 cells, U0126 blocked FGF-10's protection against asbestos-induced apoptosis and mitochondrial changes. Inhibitors of p38-MAPK or PI3K had a negligible effect on FGF-10's protection.
• The authors' conclusion: The authors concluded that FGF-10 attenuates asbestos-induced alveolar epithelial cell DNA damage and apoptosis. They concluded that MEK/ERK activation plays a role, in part by preventing mitochondria-regulated cell death.
• Limitations the authors state:
  • The authors stated that the downstream mechanisms and the in vivo relevance of the findings remain to be determined
  • The authors stated that the molecular mechanisms behind FGF-10's protective effects are not fully established

Topics

Medical terms in this study, explained in our Lexicon: Fibroblast, Apoptosis, Oxidative Stress.

Related studies

• P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis — V. Panduri, S. Surapureddi, et al. (2006)
• Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells — S.J. Kim, P. Cheresh, et al. (2014)
• Asbestos causes apoptosis in alveolar epithelial cells: role of iron-induced free radicals — A. Aljandali, H. Pollack, et al. (2001)
• 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)
• Oxidants and signaling by mitogen-activated protein kinases in lung epithelium — B.T. Mossman, K.M. Lounsbury, et al. (2006)

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