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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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Related in: MedlinePlus

Lung function. (A) Average pressure/Volume curves from naïve and AdTGF-β1 exposed rats. The curves from fibrotic animals demonstrate marked shifts downward and to the right, indicating stiffer lungs. Note: The upward deviation of the curve at day 14 at pressures above 60 cm H2O reflect the upper limits of the pressure transducer. (B) The parameter K was reduced at all time-points. (C) Lung stiffness was derived from the PV loop in Figure 4A and characterized as the volume of air needed to reach a pressure of 20 cm H2O. All values are given as mean, SE, n = 4–6 per group.
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Figure 4: Lung function. (A) Average pressure/Volume curves from naïve and AdTGF-β1 exposed rats. The curves from fibrotic animals demonstrate marked shifts downward and to the right, indicating stiffer lungs. Note: The upward deviation of the curve at day 14 at pressures above 60 cm H2O reflect the upper limits of the pressure transducer. (B) The parameter K was reduced at all time-points. (C) Lung stiffness was derived from the PV loop in Figure 4A and characterized as the volume of air needed to reach a pressure of 20 cm H2O. All values are given as mean, SE, n = 4–6 per group.

Mentions: Rats were intubated via oropharynx and two pressure-volume (PV) loops were performed for each animal using flexiVent®. Figure 4A shows the average of all PV-loops at different time-points. The factor K of the Salazar-Knowles equation [14] is presented in Figure 4B and demonstrate a significant decrease which persisted over at least 56 days. The day before the end of the experiment, rats were placed on a closed treadmill to run at increasing speeds while oxygen and C02 were measured continuously. VO2 max was reduced on average by 10% but this did not reach statistical significance (data not shown).


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)

Lung function. (A) Average pressure/Volume curves from naïve and AdTGF-β1 exposed rats. The curves from fibrotic animals demonstrate marked shifts downward and to the right, indicating stiffer lungs. Note: The upward deviation of the curve at day 14 at pressures above 60 cm H2O reflect the upper limits of the pressure transducer. (B) The parameter K was reduced at all time-points. (C) Lung stiffness was derived from the PV loop in Figure 4A and characterized as the volume of air needed to reach a pressure of 20 cm H2O. All values are given as mean, SE, n = 4–6 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Lung function. (A) Average pressure/Volume curves from naïve and AdTGF-β1 exposed rats. The curves from fibrotic animals demonstrate marked shifts downward and to the right, indicating stiffer lungs. Note: The upward deviation of the curve at day 14 at pressures above 60 cm H2O reflect the upper limits of the pressure transducer. (B) The parameter K was reduced at all time-points. (C) Lung stiffness was derived from the PV loop in Figure 4A and characterized as the volume of air needed to reach a pressure of 20 cm H2O. All values are given as mean, SE, n = 4–6 per group.
Mentions: Rats were intubated via oropharynx and two pressure-volume (PV) loops were performed for each animal using flexiVent®. Figure 4A shows the average of all PV-loops at different time-points. The factor K of the Salazar-Knowles equation [14] is presented in Figure 4B and demonstrate a significant decrease which persisted over at least 56 days. The day before the end of the experiment, rats were placed on a closed treadmill to run at increasing speeds while oxygen and C02 were measured continuously. VO2 max was reduced on average by 10% but this did not reach statistical significance (data not shown).

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