Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts

Our plain-English summary of Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts, by J.C. Bonner, A.L. Goodell, P.G. Coin, et al (The Journal of Clinical Investigation, 1993).

The study

• Authors: J.C. Bonner, A.L. Goodell, P.G. Coin, A.R. Brody
• Journal: The Journal of Clinical Investigation
• Published: 1993;92(1):425-30
• Cited by: 58 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

PDGF isoforms have been postulated to serve as mediators of fibroblast proliferation and chemotaxis during lung fibrogenesis induced by asbestos inhalation. We have studied the interaction of chrysotile asbestos fibers with rat lung fibroblasts (RLF) in vitro and the consequent changes in PDGF receptor mRNA expression, PDGF binding, and mitogenic activity of PDGF isoforms. Northern blot analysis revealed that mRNA for the PDGF-receptor alpha subtype (PDGF-R alpha) on RLF was upregulated after a 24-h exposure to asbestos in culture (0.5-15 micrograms fibers/cm2). [125I]PDGF-BB receptor assays showed that normal RLF possess mainly PDGF-R beta and a paucity of PDGF-R alpha. In agreement with the Northern data, saturation binding of [125I]PDGF-BB to RLF exposed to asbestos demonstrated an approximately 40% increase in binding sites accompanied by a twofold decrease in receptor affinity. Treating asbestos-exposed RLF with PDGF-AA, which binds only PDGF-R alpha, blocked the PDGF binding sites that were upregulated by fiber exposure. PDGF-AA had increased mitogenic potency for fiber-exposed RLF, but PDGF-BB was a less potent mitogen for these RLF. Nonfibrogenic carbonyl iron spheres induced similar changes in PDGF growth responses. These data show that inorganic particulates alter the PDGF-R alpha population on RLF without significant change in PDGF-R beta.

In plain English

This was a laboratory study of rat lung fibroblasts grown in culture, not a study of people or live animals. The authors exposed the cells to chrysotile asbestos for 24 hours, at 0.5 to 15 micrograms per square centimetre of culture surface. They then measured the alpha subtype of the receptor for platelet-derived growth factor (PDGF). Unexposed cells had barely detectable levels of the alpha-receptor message, and asbestos-exposed cells showed a nearly twofold increase. At 5 micrograms per square centimetre, PDGF binding capacity was 120 fmol per million cells, compared with 60-70 in unexposed cells. The authors called this a 40% increase, though their own figures imply a larger one. Binding affinity fell twofold. The added sites were alpha receptors, and beta receptors showed no appreciable change. Asbestos-exposed cells grew more in response to PDGF-AA and less in response to PDGF-BB. Nonfibrogenic carbonyl iron spheres produced a similar growth pattern. The authors concluded that this receptor change after asbestos exposure could be a mechanism involved in lung fibrogenesis. They stated that how particles cause the change is not known.

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 laboratory experiment on cultured cells
• Who was studied: Early passage rat lung fibroblasts (RLF). Swiss mouse 3T3 cells were used for comparison, A549 epithelial cells as a negative control, and human lung fibroblasts as a positive control for alpha-receptor expression.
• Exposure: Chrysotile asbestos at 0.5 to 15 micrograms per square centimetre for 24 hours in the gene-expression experiments, and 5 micrograms per square centimetre in the binding and growth experiments. Carbonyl iron spheres at the same dose served as a nonfibrogenic comparison particle in the growth experiments.
• Main results:
  • PDGF alpha-receptor mRNA was barely detectable in unexposed rat lung fibroblasts. It showed a nearly twofold increase after 24 hours of asbestos exposure, with the maximal increase at 0.5 to 5 micrograms per square centimetre. The results were typical of three experiments.
  • Unexposed rat lung fibroblasts had a maximal binding capacity of 60-70 fmol per million cells, with a Kd of 0.12 nM.
  • Rat lung fibroblasts exposed to 5 micrograms per square centimetre of chrysotile for 24 hours had a maximal binding capacity of 120 fmol per million cells. Their Kd was 0.25 nM, a twofold decrease in affinity. The authors described the change as a 40% increase in binding sites, although the printed capacities (60-70 versus 120) imply a larger increase.
  • Pretreatment with PDGF-AA reduced PDGF-BB binding by less than 5% in unexposed rat lung fibroblasts and by about 50% in Swiss 3T3 cells. In asbestos-exposed rat lung fibroblasts, the same pretreatment blocked the asbestos-related increase in binding sites.
  • Unexposed rat lung fibroblasts had mainly beta receptors (about 20,000 binding sites per cell). Asbestos increased alpha receptors but had no appreciable effect on the number of beta receptors.
  • Unexposed rat lung fibroblasts proliferated minimally or not at all in response to PDGF-AA. Asbestos-exposed cells showed a significant concentration-dependent increase in growth in response to PDGF-AA.
  • Asbestos exposure made rat lung fibroblasts less responsive to PDGF-BB at 0.5 to 20 ng/ml.
  • Carbonyl iron spheres at 5 micrograms per square centimetre produced a growth response to PDGF-AA and PDGF-BB similar to that seen with asbestos.
  • Without added PDGF, asbestos at 5 micrograms per square centimetre had opposite effects depending on growth state. Cells in log phase growth had about 25% mortality after 3 days, while quiescent cells had about a 40% increase in cell number.
• The authors' conclusion: The authors concluded that a change in the PDGF alpha-receptor population on lung fibroblasts after asbestos exposure could be a mechanism involved in pulmonary fibrogenesis. They also noted that in vitro both fibrogenic and nonfibrogenic particles had this effect, and that the two behave differently in the living lung.
• Limitations the authors state:
  • The authors stated that the mechanism by which inorganic particles upregulate the alpha receptor is not known.
  • The authors stated that the reason for the decreased growth response to PDGF-BB after asbestos exposure is unknown, although they offered a hypothesis.

Topics

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

Medical terms in this study, explained in our Lexicon: Chrysotile, Platelet-Derived Growth Factor (PDGF), Fibroblast.

Related studies

• Chrysotile asbestos stimulates platelet-derived growth factor-AA production by rat lung fibroblasts in vitro: evidence for an autocrine loop — J.A. Lasky, P.G. Coin, et al. (1995)
• Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages — J.C. Bonner, A.R. Osornio-Vargas, et al. (1991)
• Rat alveolar macrophage-derived platelet-derived growth factor is chemotactic for rat lung fibroblasts — A.R. Osornio-Vargas, J.C. Bonner, et al. (1990)
• Chrysotile asbestos induces PDGF-A chain-dependent proliferation in human and rat lung fibroblasts in vitro — J.A. Lasky, J.C. Bonner, et al. (1996)
• Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats — J.A. Lasky, B. Tonthat, et al. (1998)
• Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression — A.W. Langerak, K.A. Williamson, et al. (1995)

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