TGF-beta1 induces progressive pleural scarring and subpleural fibrosis

Our plain-English summary of TGF-beta1 induces progressive pleural scarring and subpleural fibrosis, by N. Decologne, M. Kolb, P.J. Margetts, et al (The Journal of Immunology, 2007).

The study

• Authors: N. Decologne, M. Kolb, P.J. Margetts, F. Menetrier, Y. Artur, C. Garrido, J. Gauldie, P. Camus, P. Bonniaud
• Journal: The Journal of Immunology
• Published: 2007;179(9):6043-51
• Cited by: 110 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pleural fibrosis is a misunderstood disorder which can cause severe restrictive lung disease with high morbidity and even mortality. The condition can develop in response to a large variety of diseases and tissue injury, among them infectious disease, asbestos, drugs, and radiation therapy. There is no efficient treatment to reverse established pleural fibrosis. TGF-beta1 is suspected, even if not proven, as a key cytokine in this process. In this study, we used adenoviral gene transfer of TGF-beta1 to the pleural mesothelium in rats. We show that local and transient TGF-beta1 overexpression induces homogenous, prolonged, and progressive pleural fibrosis without pleurodesis, associated with severe impairment of pulmonary function. We further demonstrate that pleural fibrosis can expand into the lung parenchyma from the visceral layer, but not into the muscle from the parietal layer. We provide evidence that matrix accumulation and fibrosis within the parenchyma evolved through a process involving "mesothelial-fibroblastoid transformation" and suggest that the pleural mesothelial cell may be an important player involved in the development of the subpleural distribution pattern known to be a hallmark of pulmonary fibrosis. This new model of pleural fibrosis will allow us to better understand the mechanisms of progressive fibrogenesis, and to explore novel antifibrotic therapies in the pleural cavity.

In plain English

This was a laboratory experiment in female Sprague-Dawley rats. The authors used a modified virus (an adenovirus) to deliver the gene for active TGF-beta1, a growth factor, to the lining of the chest cavity (the pleura). It was a single right-sided injection. Control rats received viruses without this gene. No asbestos was given to the animals. TGF-beta1 in the pleural fluid was strongly raised at days 4 and 7 but no longer raised by day 14. The product made from the added gene was no longer detectable after day 14. Even so, the pleura thickened from day 4 and kept thickening through day 64. Collagen, a scar protein, also built up in the lung tissue just beneath the pleura, but not in the diaphragm or chest wall muscle. Adhesions between the pleural layers were rare. By day 64, removed lungs from treated rats took 30% less formalin to inflate than control lungs. The authors used this as an estimate of lung volume. The authors reported that pleural lining (mesothelial) cells took on features of scar-forming cells. The authors concluded that this is a new model for studying pleural 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 (gene transfer by adenoviral vector in rats, compared with control-vector rats)
• Who was studied: Female Sprague-Dawley rats weighing 200 to 225 g, studied at INSERM in Dijon, France. Animals were examined at days 4, 7, 14, 21 and 64 after injection. There were about five TGF-beta1-treated rats and three to four control rats per time point.
• Exposure: A single right-sided injection into the pleural space of an adenovirus carrying an active form of the TGF-beta1 gene. Controls received an empty vector (AdDL) or a marker-gene vector (AdLacZ). No asbestos or other fibers were studied.
• Main results:
  • In the pleural fluid of TGF-beta1-treated rats, active TGF-beta1 measured 4717 pg/ml at day 4 and 2872 pg/ml at day 7. In control rats it measured 61 and 48 pg/ml.
  • The product of the added TGF-beta1 gene was no longer detectable in pleural fluid after day 14.
  • TGF-beta1-treated rats had a pleural effusion of 3.3 ml at day 4. It decreased over time and was gone by day 14. Control rats had no effusion.
  • In TGF-beta1-treated rats, pleural thickening began by day 4 and increased progressively through days 21 and 64. The pleura of control rats appeared normal.
  • Collagen built up in the lung tissue beneath the visceral pleura of TGF-beta1-treated rats. It was most intense right under the pleura and increased up to day 64.
  • No fibrosis was seen in the muscle of the diaphragm or chest wall.
  • By day 64, lung volume in TGF-beta1-treated rats was 30% lower than in control rats (7.45 ml versus 10.17 ml). Lung volume was estimated from the volume of formalin needed to inflate the removed lungs at a constant pressure.
  • Adhesions between the parietal and visceral pleura were rare in treated rats.
  • At days 7 and 14, cells carrying both a lining-cell marker (cytokeratin) and a scar-cell marker (smooth muscle actin) appeared within the fibrotic tissue of TGF-beta1-treated rats. The authors interpreted this as mesothelial-fibroblastoid transformation.
  • Total cell counts in pleural fluid did not differ significantly between TGF-beta1-treated and control rats.
• The authors' conclusion: The authors concluded that they had created a new model for studying the development of pleural fibrosis. In this model the fibrosis was progressive and extended into the lung tissue beneath the pleura. They speculated that the pleural mesothelium may be involved in the subpleural pattern of pulmonary fibrosis.
• Limitations the authors state:
  • The authors noted that the role of TGF-beta in other pleural fibrotic disorders is not definitively proven.
  • Some TGF-beta1-treated rats had to be euthanized early because of poor condition. They had pleural fibrosis but were left out of the data analysis.
  • The authors did not find obvious fibroblastic foci, a feature of human pulmonary fibrosis, in their model.

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Restrictive Lung Disease, Cytokine, Mesothelium, Pleurodesis, Parenchyma, Mesothelial Cells, Pulmonary Fibrosis.

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• Transforming growth factor-beta(1) overexpression in tumor necrosis factor-alpha receptor knockout mice induces fibroproliferative lung disease — J.Y. Liu, P.J. Sime, et al. (2001)
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