Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia

Our plain-English summary of Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia, by K. Vuorinen, F. Gao, T.D. Oury, et al (Experimental Lung Research, 2007).

The study

• Authors: K. Vuorinen, F. Gao, T.D. Oury, V.L. Kinnula, M. Myllärniemi
• Journal: Experimental Lung Research
• Published: 2007;33(7):357-73
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Profibrogeneic cytokines contribute to the accumulation of myofibroblasts in the lung interstitium in idiopathic pulmonary fibrosis (IPF). Imatinib mesylate, a tyrosine kinase inhibitor specific for Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinases, has been shown to inhibit fibrosis and profibrotic signaling in mouse models of inflammation-mediated lung reactions. The authors tested imatinib mesylate in vivo in a mouse model of crocidolite asbestos-induced progressive fibrosis. The ability of imatinib mesylate to inhibit profibrogeneic cytokine-induced human pulmonary fibroblast migration was tested in vitro and the expression of its target protein tyrosine kinases was assessed with immunofluorescence. In vivo, 10 mg/kg/day imatinib mesylate inhibited histological parenchymal fibrosis and led to a decrease in collagen deposition, but had no significant effect on asbestos-induced neutrophilia. However, 50 mg/kg/day imatinib mesylate did not inhibit collagen deposition. In vitro, IPF fibroblasts expressed Abl, PDGFR-alpha, PDGF-beta, but not c-Kit, and 1 microM imatinib mesylate inhibited profibrogeneic cytokine-induced IPF fibroblast migration. These results suggest that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis.

In plain English

This was a laboratory study in mice and in human lung cells. It tested whether imatinib mesylate, a cancer drug that blocks certain enzymes called tyrosine kinases, could reduce lung scarring (fibrosis) caused by crocidolite asbestos. Male mice had crocidolite asbestos or inert titanium dioxide placed into the windpipe. They received daily injections of the drug or of plain vehicle and were examined 14 days later. At 10 mg per kg per day, the drug significantly lowered a chemical measure of collagen (scar tissue) in asbestos-treated mice, and microscope scoring of a small number of lungs supported this. At 50 mg per kg per day it had no such effect. Neither dose changed the large rise in neutrophils, an inflammatory cell, in lung washings. Lung fibroblasts from patients with idiopathic pulmonary fibrosis carried the drug's target proteins Abl and PDGF receptors but not c-Kit. In these cells the drug reduced growth-factor-driven fibroblast movement. The authors concluded that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis. They noted that the two doses were tested on separate occasions.

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 (mice) combined with in vitro experiments on human lung fibroblast cell lines
• Who was studied: Six- to 8-week-old male C57BL6 mice, randomly divided into 3 groups, 5 to 8 mice per group. Animal work was approved by the University of Pittsburgh. Human cells studied were normal human pulmonary fibroblasts (CCL-190), IPF fibroblasts (CCL-134), and primary human IPF fibroblasts grown from lung transplants of patients with IPF and biopsy-proven UIP. No study dates are given.
• Exposure: Crocidolite asbestos (0.1 mg in saline) or titanium dioxide (inert particle control) given once into the trachea. Daily intraperitoneal injections of vehicle or imatinib mesylate at 10 or 50 mg/kg started 1 day before instillation. Mice were sacrificed 14 days after treatment.
• Main results:
  • In asbestos-treated mice, 10 mg/kg/day imatinib mesylate significantly decreased lung collagen deposition, measured as hydroxyproline (P < .001; figure legend gives n = 4 per group).
  • In asbestos-treated mice, 50 mg/kg/day imatinib mesylate showed no corresponding reduction in collagen deposition.
  • Histological scoring supported the hydroxyproline findings for 10 mg/kg/day. This scoring was based on 2 asbestos-with-vehicle mice and 3 asbestos-with-imatinib mice.
  • Neutrophils made up 64.0% of lung lavage cells in asbestos-treated mice, compared with 0.59% in titanium dioxide-treated mice. The figure was 68.3% in asbestos-treated mice given imatinib mesylate. Neither dose prevented asbestos-induced neutrophilia and lung inflammation.
  • TGF-beta levels in lung lavage fluid showed no statistically significant differences between imatinib-treated (10 and 50 mg/kg/day) and control animals. The data were not shown.
  • All 4 primary human IPF fibroblast lines stained strongly for Abl and PDGFR-alpha, and less strongly for PDGFR-beta. None stained for c-Kit. Normal fibroblasts showed weak c-Kit staining.
  • In human pulmonary fibroblasts stimulated with EGF and PDGF-AB, imatinib mesylate reduced the number of migrated cells by 26.5%, 27.7% and 51.6% at the three increasing concentrations tested (n = 3). At the middle concentration, it reduced migration of normal fibroblasts (P = .002) and of IPF and primary IPF fibroblasts (P < .0001) by 23% to 40%.
  • The two lower imatinib concentrations did not cause marked apoptosis (cell death) compared with serum-starved control cells. The highest concentration showed more apoptotic cells, but still less than in serum-starved control cells.
• The authors' conclusion: The authors concluded that their results suggest imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis, when used at a specific dosage, with little effect on the inflammatory changes.
• Limitations the authors state:
  • The 10 and 50 mg/kg/day experiments were performed on 2 separate occasions, so there is a small possibility of differences between experiments. The mechanism behind the different effects of the two doses needs further study.

Topics

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

Medical terms in this study, explained in our Lexicon: Interstitial, Cytokine, Idiopathic, Pulmonary Fibrosis, Tyrosine Kinase Inhibitor, Platelet-Derived Growth Factor (PDGF), Fibrosis, Inflammation.

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