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Comparison between conventional and "clinical" assessment of experimental lung fibrosis.

Ask K, Labiris R, Farkas L, Moeller A, Froese A, Farncombe T, McClelland GB, Inman M, Gauldie J, Kolb MR - J Transl Med (2008)

Bottom Line: Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before.The histomorphological scores correlated both to radiological (r2 = 0.29, p < 0.01) and functional changes (r2 = 0.51, p < 0.0001).This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada. askkj@mcmaster.ca

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis. Major concerns of current PF models are spontaneous resolution and high variability of fibrosis, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs.

Methods: PF was induced in rats by adenoviral gene transfer of transforming growth factor-beta. Morphological and functional changes were assessed for up to 56 days by micro-CT, lung compliance (measured via a mechanical ventilator) and VO2max and compared to histomorphometry and hydroxyproline content.

Results: Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before. The histomorphological scores correlated both to radiological (r2 = 0.29, p < 0.01) and functional changes (r2 = 0.51, p < 0.0001). VO2max did not correlate with fibrosis.

Conclusion: The progression of pulmonary fibrosis can be reliably assessed and followed in living animals over time using invasive, non-terminal compliance measurements and micro-CT. This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.

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Representative lung histology. (A) naïve lungs, (B) day 14, (C) day 21, (D) day 35, (E) day 56 and (F) day 225 after intratracheal AdTGF-β1 administration (40×). (G) Fibrotic index (Ashcroft). (G) Hydroxyproline content per mg dry lung. Group comparison was performed using one way ANOVA with Dunnett's multiple comparison test. All values are given as mean, SE, n = 4–6 in each group, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. naïve.
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Figure 1: Representative lung histology. (A) naïve lungs, (B) day 14, (C) day 21, (D) day 35, (E) day 56 and (F) day 225 after intratracheal AdTGF-β1 administration (40×). (G) Fibrotic index (Ashcroft). (G) Hydroxyproline content per mg dry lung. Group comparison was performed using one way ANOVA with Dunnett's multiple comparison test. All values are given as mean, SE, n = 4–6 in each group, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. naïve.

Mentions: The extent of PF after transfer of active TGF-β1 was assessed histologically and biochemically and confirmed findings we reported earlier [10]. Figure 1 shows representative images of lung architecture from naïve (A) and fibrotic lungs from day 14 to 56 (B-E). Peribronchially accentuated fibrosis, not associated with inflammatory changes and loss of normal lung architecture was observed up to day 56, as well as subpleural and pleural thickening (see figure 1D). Persistent fibrosis including honeycombing was seen in later stages (up to 7 months after AdTGF-β1) (Figure 1F). Histomorphometric and hydroxyproline analysis was performed to quantify the severity of PF up to 56 days after AdTGF-β1 (Figure 1G–H).


Comparison between conventional and "clinical" assessment of experimental lung fibrosis.

Ask K, Labiris R, Farkas L, Moeller A, Froese A, Farncombe T, McClelland GB, Inman M, Gauldie J, Kolb MR - J Transl Med (2008)

Representative lung histology. (A) naïve lungs, (B) day 14, (C) day 21, (D) day 35, (E) day 56 and (F) day 225 after intratracheal AdTGF-β1 administration (40×). (G) Fibrotic index (Ashcroft). (G) Hydroxyproline content per mg dry lung. Group comparison was performed using one way ANOVA with Dunnett's multiple comparison test. All values are given as mean, SE, n = 4–6 in each group, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. naïve.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2365932&req=5

Figure 1: Representative lung histology. (A) naïve lungs, (B) day 14, (C) day 21, (D) day 35, (E) day 56 and (F) day 225 after intratracheal AdTGF-β1 administration (40×). (G) Fibrotic index (Ashcroft). (G) Hydroxyproline content per mg dry lung. Group comparison was performed using one way ANOVA with Dunnett's multiple comparison test. All values are given as mean, SE, n = 4–6 in each group, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. naïve.
Mentions: The extent of PF after transfer of active TGF-β1 was assessed histologically and biochemically and confirmed findings we reported earlier [10]. Figure 1 shows representative images of lung architecture from naïve (A) and fibrotic lungs from day 14 to 56 (B-E). Peribronchially accentuated fibrosis, not associated with inflammatory changes and loss of normal lung architecture was observed up to day 56, as well as subpleural and pleural thickening (see figure 1D). Persistent fibrosis including honeycombing was seen in later stages (up to 7 months after AdTGF-β1) (Figure 1F). Histomorphometric and hydroxyproline analysis was performed to quantify the severity of PF up to 56 days after AdTGF-β1 (Figure 1G–H).

Bottom Line: Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before.The histomorphological scores correlated both to radiological (r2 = 0.29, p < 0.01) and functional changes (r2 = 0.51, p < 0.0001).This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada. askkj@mcmaster.ca

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis. Major concerns of current PF models are spontaneous resolution and high variability of fibrosis, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs.

Methods: PF was induced in rats by adenoviral gene transfer of transforming growth factor-beta. Morphological and functional changes were assessed for up to 56 days by micro-CT, lung compliance (measured via a mechanical ventilator) and VO2max and compared to histomorphometry and hydroxyproline content.

Results: Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before. The histomorphological scores correlated both to radiological (r2 = 0.29, p < 0.01) and functional changes (r2 = 0.51, p < 0.0001). VO2max did not correlate with fibrosis.

Conclusion: The progression of pulmonary fibrosis can be reliably assessed and followed in living animals over time using invasive, non-terminal compliance measurements and micro-CT. This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.

Show MeSH
Related in: MedlinePlus