Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats

Our plain-English summary of Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats, by J.A. Lasky, B. Tonthat, J.Y. Liu, et al (American Journal of Respiratory and Critical Care Medicine, 1998).

The study

• Authors: J.A. Lasky, B. Tonthat, J.Y. Liu, M. Friedman, A.R. Brody
• Journal: American Journal of Respiratory and Critical Care Medicine
• Published: 1998;157(5 Pt 1):1652-7
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Platelet-derived growth factor-AA (PDGF-AA) and its matching alpha receptor (PDGF-R alpha) are upregulated in rat lung fibroblasts (RLFs) after exposure to chrysotile asbestos fibers in vitro, which results in asbestos-induced RLF proliferation. We now report our in vivo observations, which show an increase in the expression of PDGF-R alpha mRNA, but not PDGF-beta receptor mRNA, in asbestos-exposed rat lungs when compared with RNA from air-exposed (sham) and iron-exposed lungs. Western analysis of membrane preparations confirmed the observations on mRNA expression by demonstrating an increase in PDGF-R alpha peptide expression in the asbestos-exposed rat lungs, compared with that in the air-exposed lungs. Immunohistochemistry for the PDGF-R alpha was performed on air- and asbestos-exposed rat lungs and revealed a clear increase in staining within interstitial and subepithelial compartments in the exposed animals. These observations, along with our previous report demonstrating an increase in the PDGF-AA isoform expression immediately after asbestos-exposure, suggest a scenario in which a potent lung mesenchymal cell mitogen, PDGF-AA, and its alpha-receptor are upregulated prior to the development of a fibroproliferative lung lesion, and thus may play a central role in the pathogenesis of asbestos-induced lung fibrosis.

In plain English

This was a laboratory experiment in rats, not a study of people. Eight-week-old male Sprague-Dawley rats breathed chrysotile asbestos (10 mg/m3) for 5 hours. Controls breathed air or carbonyl iron (50 mg/m3), which the authors call nonfibrogenic. The authors measured a growth-factor receptor, the PDGF-alpha receptor, in lung tissue right after exposure and 1, 2 or 8 days later. Immediately after exposure, receptor mRNA in asbestos-exposed lungs was 2.55 times the level in air-exposed lungs (4 rats per group, p less than 0.01). At 1, 2 and 8 days the differences were not statistically significant. Iron exposure produced no change in this receptor's mRNA. The mRNA of a related receptor, the PDGF-beta receptor, showed no significant change. Receptor protein was 2.6 times the air-exposed level at 5 hours (p less than 0.05) and declined over the next 2 days. Tissue staining showed more receptor at the alveolar duct bifurcations and along the bronchioles in asbestos-exposed lungs than in air-exposed lungs. The authors concluded that this receptor may play a significant role in the initial events of asbestos-induced lung fibrosis.

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 experiment: inhalation exposure of rats, with sham (air) and carbonyl iron control groups
• Who was studied: Eight-week-old male Sprague-Dawley rats, studied at Tulane University Medical Center, New Orleans; small groups per time point (for example, four asbestos-exposed and four sham-exposed rats for the 5-hour mRNA measurement)
• Exposure: Chrysotile asbestos at 10 mg/m3 for 5 hours in inhalation chambers; control groups breathed ambient air or 50 mg/m3 carbonyl iron; lungs examined immediately after exposure (5-hour time point) and 1, 2 or 8 days later
• Main results:
  • At the 5-hour time point, PDGF-alpha receptor mRNA in asbestos-exposed rat lungs relative to sham-exposed lungs was 2.55 plus or minus 0.68 (SEM), p less than 0.01, n = 4
  • No significant differences in PDGF-alpha receptor mRNA between asbestos-exposed and control rats at 1 day (0.68 plus or minus 0.22), 2 days (0.67 plus or minus 0.25) and 8 days (1.01 plus or minus 0.29); three asbestos-exposed and three sham-exposed rats per time point
  • In iron-exposed rats, PDGF-alpha receptor mRNA showed no change at 5 hours, 1 day or 2 days
  • PDGF-beta receptor mRNA ratio (asbestos-exposed over sham-exposed) at 5 hours was 1.24 plus or minus 0.26, p = 0.4, not statistically significant; the authors report PDGF-beta receptor mRNA as statistically unchanged at all time points tested (5 hours and 1, 2 and 8 days). Only mRNA was reported for this receptor.
  • PDGF-alpha receptor protein (Western analysis) ratio, asbestos-exposed over sham-exposed lung, at 5 hours was 2.6 plus or minus 0.3, p less than 0.05
  • PDGF-alpha receptor protein ratio at 1 day after exposure was 2.2 plus or minus 0.6, p = 0.08
  • PDGF-alpha receptor protein ratio at 2 days after exposure was 1.5 plus or minus 0.4, p = 0.4
  • Immunohistochemical staining for the PDGF-alpha receptor was definite in asbestos-exposed rat lungs at both 5 hours and 2 days
  • Staining was greater at the alveolar duct bifurcations and along the bronchioles in asbestos-exposed lungs than in air-exposed lungs
• The authors' conclusion: The authors concluded that the early increase in PDGF-alpha receptor, together with their earlier work on PDGF-A chain, suggests the receptor may play a significant role in the initial events of asbestos-induced lung fibrosis
• Limitations the authors state:
  • The authors note that the increased staining at 2 days would not have been predicted from their Western (protein) data, and they discuss possible reasons for this discrepancy
  • The authors state that the mechanism by which asbestos increases this receptor is unknown
  • The authors note that the role of this pathway could not be tested with knockout animals, because deleting PDGF-AA or the PDGF-alpha receptor is lethal

Topics

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

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

Related studies

• Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts — J.C. Bonner, A.L. Goodell, et al. (1993)
• Up-regulated expression of transforming growth factor-alpha in the bronchiolar-alveolar duct regions of asbestos-exposed rats — J.Y. Liu, G.F. Morris, et al. (1996)
• Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats — J.Y. Liu, G.F. Morris, et al. (1997)
• Mesothelioma cell proliferation through autocrine activation of PDGF-ββ receptor — M. Honda, T. Kanno, et al. (2012)
• Asbestos-induced fibrosis in rats: increase in lung mast cells and autacoid contents — I. Keith, R. Day, et al. (1987)
• Bidirectional modulation of TNF-alpha production by alveolar macrophages in asbestos-induced pulmonary fibrosis — S. Ouellet, H. Yang, et al. (1993)

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