Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats

Our plain-English summary of Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats, by J.Y. Liu, G.F. Morris, W.H. Lei, et al (American Journal of Respiratory Cell and Molecular Biology, 1997).

The study

• Authors: J.Y. Liu, G.F. Morris, W.H. Lei, C.E. Hart, J.A. Lasky, A.R. Brody
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 1997;17(2):129-40
• Cited by: 72 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The development of interstitial pulmonary fibrosis is associated with a variety of inflammatory mediators, including peptide growth factors and cytokines. In the work presented here, we have asked whether or not platelet-derived growth factor (PDGF)-A and -B genes and proteins are expressed in anatomic and temporal patterns consistent with this factor playing a role in the disease process. Using an established rat model of asbestos-induced fibroproliferative lung disease, we demonstrate elevated levels of PDGF-A and -B mRNAs in total lung RNA immediately after a single 5-h exposure to approximately 1,000 fibers/ml of chrysotile asbestos. In situ hybridization revealed the PDGF-A and -B in RNAs primarily in macrophages and bronchiolar-alveolar epithelial cells at sites of initial fiber deposition and lung injury. There was clear evidence of PDGF-A and -B mRNAs in interstitial cells as well. The pattern of in situ hybridization was entirely consistent with the appearance (established by immunohistochemistry) of PDGF-A and -B proteins by 24 h post-exposure in the same cell types. Both mRNAs and proteins remained detectable at the fiber deposition sites for almost 2 wk post-exposures. These findings are consistent with our previous studies showing increased mesenchymal cell proliferation and fibroproliferative lesions that progress at the sites where PDGF-A and -B are expressed. Although it is clear that multiple growth factors are produced simultaneously at sites of initial injury, we suggest that the PDGF isoforms could be playing a central role in the disease process based upon their potent mitogenic effects upon mesenchymal cells.

In plain English

This was an animal experiment in rats by researchers at Tulane University Medical Center, New Orleans. Groups of 35 rats breathed chrysotile asbestos (10 mg/m3 respirable mass, about 1,000 fibers/ml), carbonyl iron particles, or air for a single 5-hour period. Five rats per group were killed at times from immediately after exposure to 30 days later. The authors measured the A and B chains of platelet-derived growth factor (PDGF), whose paired forms stimulate the growth of connective-tissue cells, as messenger RNA and as protein. In asbestos-exposed rats, lung PDGF-A and -B mRNA rose 3.5 to 4.0-fold. It was higher immediately after exposure and remained high at 2 weeks. Iron did not cause a significant increase. PDGF-A and -B appeared mainly in bronchiolar and alveolar epithelial cells, macrophages and interstitial cells at sites of fiber deposition, peaking at 48 hours. Protein first appeared at 24 hours, waned by 2 weeks and was back to normal low levels by 1 month. The authors suggested PDGF could play a central role in fibrotic lung disease. They stated they were only slightly closer to knowing whether it plays a mechanistic role.

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 (rats) with time-course measurement of PDGF-A and -B chain mRNA (RNase protection assay, in situ hybridization) and protein (immunohistochemistry); results combined from 2 separate exposures
• Who was studied: Rats in three exposure groups (chrysotile asbestos, iron, air) of 35 animals each. Five animals per group were killed immediately after exposure and at 1, 2, 4, 8, 14 and 30 days. Rat strain is not stated in this text.
• Exposure: A single 5-hour inhalation exposure to chrysotile asbestos at 10 mg/m3 respirable mass (described as about 1,000 fibers/ml). Controls were exposed to carbonyl iron spheres (50 mg/m3) or sham-exposed to air.
• Main results:
  • In asbestos-exposed rats, whole-lung PDGF-A and PDGF-B mRNA levels increased 3.5 to 4.0-fold, measured by densitometry. The densitometry data were not shown.
  • In asbestos-exposed rats, higher PDGF mRNA levels were detected immediately after the 5-hour exposure and remained high at the 2-week time point.
  • In iron-exposed rats, carbonyl iron particles did not induce a significant increase in PDGF-A or PDGF-B mRNA at any time.
  • In asbestos-exposed rats, in situ hybridization showed the largest number of cells containing PDGF-A and -B mRNA at 48 hours after exposure. Labeled cells included Clara cells of the terminal bronchioles, epithelial cells at alveolar duct bifurcations, scattered type II alveolar cells, macrophages and interstitial cells.
  • In asbestos-exposed rats, Clara cells of the bronchioles, type II alveolar cells and cuboidal epithelial cells at the alveolar duct bifurcations stained strongly for PDGF-A and -B protein.
  • In asbestos-exposed rats, no PDGF protein staining was seen immediately after the 5-hour exposure. Protein first appeared at 24 hours and the most intense reaction was at 48 hours.
  • In asbestos-exposed rats, the number of protein-positive cells was maintained for 8 days, waned by 2 weeks, and had returned to the normal low level by 1 month.
  • In asbestos-exposed rats, there were about twice as many stained epithelial cells as stained interstitial cells through the 2-week time point.
  • Unexposed and iron-exposed rats showed few labeled cells at any time during the observation period.
• The authors' conclusion: The authors suggested that the PDGF isoforms could be playing a central role in the fibroproliferative lung disease process. They based this on the potent growth-stimulating effects of these isoforms on mesenchymal cells. The article describes the isoforms (AA, AB, BB) as active only in their paired (dimeric) forms. The authors noted that multiple growth factors are produced at the same time at sites of injury.
• Limitations the authors state:
  • The authors stated that although the expression pattern fits their hypothesis, they were only slightly closer to knowing whether PDGF plays a mechanistic role. They said transgenic and knockout experiments are needed.
  • The authors could not establish the precise cell type of every stained cell.
  • The authors said the stronger hybridization seen in epithelial cells did not lend itself well to quantitation.
  • The authors stated they do not know whether epithelial, mesenchymal or macrophage-derived factors, alone or together, are the central mediators of lesion development.

Topics

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

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

Related studies

• Asbestos-induced alveolar injury. Evidence for macrophage-derived PDGF as a mediator of the fibrogenic response — J.C. Bonner, A.R. Brody (1991)
• Relationship of fiber surface iron and active oxygen species to expression of procollagen, PDGF-A, and TGF-beta(1) in tracheal explants exposed to amosite asbestos — J. Dai, A. Churg (2001)
• Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats — J.A. Lasky, B. Tonthat, et al. (1998)
• 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)
• 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)
• 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)

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