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The anti-fibrotic effect of inhibition of TGFβ-ALK5 signalling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent γ-herpesvirus infection.

Smoktunowicz N, Alexander RE, Franklin L, Williams AE, Holman B, Mercer PF, Jarai G, Scotton CJ, Chambers RC - Dis Model Mech (2015)

Bottom Line: Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography (µCT) analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response.In contrast, inhibition of TGFβ-ALK5 signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNγ.These data reveal newly identified intricacies for the TGFβ-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection.

View Article: PubMed Central - PubMed

Affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.

No MeSH data available.


Related in: MedlinePlus

Voxel density distribution analysis shows key differences between the single- and two-hit models. Density distribution histograms show the mean number of voxels plotted against greyscale density values (0=air/black, 255=dense tissue/white) for each experimental group. (A) A shift towards higher voxel densities is observed for bleomycin (Bleo)-treated lungs due to Bleo-induced injury, and a further shift to the right for the two-hit Bleo+MHV-68 group is indicative of additional injury. This density shift is reduced in the Bleo+SB525334 group, suggestive of attenuated fibrosis but not in Bleo+MHV-68+SB525334 lungs. (B) The differences in proportion of density voxels for each greyscale bin between Bleo-instilled groups (n=5 animals per group), which account for the shifts in the histograms, were analyzed by Student’s t-test at each bin. The data are shown as graphs of probability (y-axis) versus greyscale density value (x-axis), with the significance cut-off set at 0.05 (indicated by the dotted line). (C-E) Distribution of significantly different voxel densities was visualized on representative µCT scans (red pixels): (C) Bleo and Bleo+SB525334 show voxel localization to fibrotic lesions; (D) Bleo+MHV-68 and Bleo lungs show voxel distribution in fibrotic lesions and dispersed throughout the parenchyma; (E) Bleo+MHV-68 and Bleo+MHV-68+SB525334 lungs show voxel distribution dispersed throughout the parenchyma.
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DMM019984F3: Voxel density distribution analysis shows key differences between the single- and two-hit models. Density distribution histograms show the mean number of voxels plotted against greyscale density values (0=air/black, 255=dense tissue/white) for each experimental group. (A) A shift towards higher voxel densities is observed for bleomycin (Bleo)-treated lungs due to Bleo-induced injury, and a further shift to the right for the two-hit Bleo+MHV-68 group is indicative of additional injury. This density shift is reduced in the Bleo+SB525334 group, suggestive of attenuated fibrosis but not in Bleo+MHV-68+SB525334 lungs. (B) The differences in proportion of density voxels for each greyscale bin between Bleo-instilled groups (n=5 animals per group), which account for the shifts in the histograms, were analyzed by Student’s t-test at each bin. The data are shown as graphs of probability (y-axis) versus greyscale density value (x-axis), with the significance cut-off set at 0.05 (indicated by the dotted line). (C-E) Distribution of significantly different voxel densities was visualized on representative µCT scans (red pixels): (C) Bleo and Bleo+SB525334 show voxel localization to fibrotic lesions; (D) Bleo+MHV-68 and Bleo lungs show voxel distribution in fibrotic lesions and dispersed throughout the parenchyma; (E) Bleo+MHV-68 and Bleo+MHV-68+SB525334 lungs show voxel distribution dispersed throughout the parenchyma.

Mentions: In order to further investigate differences in lung morphology, we next performed voxel density distribution analysis for each lung based on the unsegmented µCT data. The mean number of voxels per lung at each greyscale density value (0-255) was calculated and plotted as a histogram (Fig. 3A). Statistically significant differences in the density voxel distribution between individual experimental groups were evaluated by a probability t-test (Fig. 3B). A clear separation in the density distribution was observed between Sal, Bleo and Bleo+MHV-68 lungs, with a marked shift towards higher density voxels in the Bleo group, which was further increased in the Bleo+MHV-68 group.Fig. 3.


The anti-fibrotic effect of inhibition of TGFβ-ALK5 signalling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent γ-herpesvirus infection.

Smoktunowicz N, Alexander RE, Franklin L, Williams AE, Holman B, Mercer PF, Jarai G, Scotton CJ, Chambers RC - Dis Model Mech (2015)

Voxel density distribution analysis shows key differences between the single- and two-hit models. Density distribution histograms show the mean number of voxels plotted against greyscale density values (0=air/black, 255=dense tissue/white) for each experimental group. (A) A shift towards higher voxel densities is observed for bleomycin (Bleo)-treated lungs due to Bleo-induced injury, and a further shift to the right for the two-hit Bleo+MHV-68 group is indicative of additional injury. This density shift is reduced in the Bleo+SB525334 group, suggestive of attenuated fibrosis but not in Bleo+MHV-68+SB525334 lungs. (B) The differences in proportion of density voxels for each greyscale bin between Bleo-instilled groups (n=5 animals per group), which account for the shifts in the histograms, were analyzed by Student’s t-test at each bin. The data are shown as graphs of probability (y-axis) versus greyscale density value (x-axis), with the significance cut-off set at 0.05 (indicated by the dotted line). (C-E) Distribution of significantly different voxel densities was visualized on representative µCT scans (red pixels): (C) Bleo and Bleo+SB525334 show voxel localization to fibrotic lesions; (D) Bleo+MHV-68 and Bleo lungs show voxel distribution in fibrotic lesions and dispersed throughout the parenchyma; (E) Bleo+MHV-68 and Bleo+MHV-68+SB525334 lungs show voxel distribution dispersed throughout the parenchyma.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4582104&req=5

DMM019984F3: Voxel density distribution analysis shows key differences between the single- and two-hit models. Density distribution histograms show the mean number of voxels plotted against greyscale density values (0=air/black, 255=dense tissue/white) for each experimental group. (A) A shift towards higher voxel densities is observed for bleomycin (Bleo)-treated lungs due to Bleo-induced injury, and a further shift to the right for the two-hit Bleo+MHV-68 group is indicative of additional injury. This density shift is reduced in the Bleo+SB525334 group, suggestive of attenuated fibrosis but not in Bleo+MHV-68+SB525334 lungs. (B) The differences in proportion of density voxels for each greyscale bin between Bleo-instilled groups (n=5 animals per group), which account for the shifts in the histograms, were analyzed by Student’s t-test at each bin. The data are shown as graphs of probability (y-axis) versus greyscale density value (x-axis), with the significance cut-off set at 0.05 (indicated by the dotted line). (C-E) Distribution of significantly different voxel densities was visualized on representative µCT scans (red pixels): (C) Bleo and Bleo+SB525334 show voxel localization to fibrotic lesions; (D) Bleo+MHV-68 and Bleo lungs show voxel distribution in fibrotic lesions and dispersed throughout the parenchyma; (E) Bleo+MHV-68 and Bleo+MHV-68+SB525334 lungs show voxel distribution dispersed throughout the parenchyma.
Mentions: In order to further investigate differences in lung morphology, we next performed voxel density distribution analysis for each lung based on the unsegmented µCT data. The mean number of voxels per lung at each greyscale density value (0-255) was calculated and plotted as a histogram (Fig. 3A). Statistically significant differences in the density voxel distribution between individual experimental groups were evaluated by a probability t-test (Fig. 3B). A clear separation in the density distribution was observed between Sal, Bleo and Bleo+MHV-68 lungs, with a marked shift towards higher density voxels in the Bleo group, which was further increased in the Bleo+MHV-68 group.Fig. 3.

Bottom Line: Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography (µCT) analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response.In contrast, inhibition of TGFβ-ALK5 signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNγ.These data reveal newly identified intricacies for the TGFβ-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection.

View Article: PubMed Central - PubMed

Affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.

No MeSH data available.


Related in: MedlinePlus