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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

μCT characterization and quantification of the pathological changes in the single- and two-hit models. 3D volume reconstruction (left panels, dorsal view) and representative coronal µCT sections (middle panels) with higher (4×) magnification of the highlighted insert (right panel). Mice treated with saline (Sal; A) or Sal+MHV-68 (B) show normal lung morphology; Bleomycin (Bleo)-treated mice (C) show dense subpleural fibrotic lesions, which are attenuated in the Bleo+SB525334 group (D); Bleo+MHV-68 mice (E) show evidence of extensive ground-glass opacities radiating from airways and overlying areas of dense consolidation; Bleo+MHV-68+SB525334 mice (F) reveal dense consolidation with reduced areas of ground-glass opacities. InForm analysis demonstrates an increase in the percentage of abnormal lung area (G) and density (H) in Bleo lungs above the Sal control (dotted line). No significant difference was observed between the Bleo and Bleo+MHV-68 groups. Administration of SB525334 from day 15 post-bleomycin-instillation (and 1 day p.i.) significantly attenuated lung pathology in the Bleo group but not in the two-hit Bleo+MHV-68 model. The data are representative of mean±s.e.m., one-way ANOVA, *P<0.05, **P<0.01, comparison of all Bleo-challenged groups (n=5).
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DMM019984F2: μCT characterization and quantification of the pathological changes in the single- and two-hit models. 3D volume reconstruction (left panels, dorsal view) and representative coronal µCT sections (middle panels) with higher (4×) magnification of the highlighted insert (right panel). Mice treated with saline (Sal; A) or Sal+MHV-68 (B) show normal lung morphology; Bleomycin (Bleo)-treated mice (C) show dense subpleural fibrotic lesions, which are attenuated in the Bleo+SB525334 group (D); Bleo+MHV-68 mice (E) show evidence of extensive ground-glass opacities radiating from airways and overlying areas of dense consolidation; Bleo+MHV-68+SB525334 mice (F) reveal dense consolidation with reduced areas of ground-glass opacities. InForm analysis demonstrates an increase in the percentage of abnormal lung area (G) and density (H) in Bleo lungs above the Sal control (dotted line). No significant difference was observed between the Bleo and Bleo+MHV-68 groups. Administration of SB525334 from day 15 post-bleomycin-instillation (and 1 day p.i.) significantly attenuated lung pathology in the Bleo group but not in the two-hit Bleo+MHV-68 model. The data are representative of mean±s.e.m., one-way ANOVA, *P<0.05, **P<0.01, comparison of all Bleo-challenged groups (n=5).

Mentions: Ex vivo µCT was subsequently used to further investigate the effect of SB525334 treatment in this two-hit model. Fig. 2 shows representative 3D volume reconstructions (left panels) with corresponding mid-lung coronal µCT sections (middle panels) and magnification of key pathological changes (right panels) for lungs at day 28. Sal+MHV-68 lungs were indistinguishable from Sal control lungs, with both groups displaying an equally homogenous appearance with a network of airways in a virtually transparent parenchyma (Fig. 2A,B). In the Bleo group, peripheral dense fibrotic lesions were clearly visible, particularly on the dorsal side of the lungs (Fig. 2C), as previously reported for oropharyngeal bleomycin instillation (Lakatos et al., 2006; Scotton et al., 2013). Coronal sections revealed prominent sub-pleural scarring, interlobular septal thickening and traction bronchiectasis (Fig. 2C). In Bleo+SB525334 lungs, scarring and fibrosis were noticeably reduced (Fig. 2D). In contrast, in the two-hit model, lungs displayed extensive areas of dense consolidation with overlapping diffuse ground-glass opacities indicative of inflammatory changes concentrated around the airways (Fig. 2E). SB525334 treatment visibly reduced the ground-glass appearance in the two-hit model but the fibrotic lesions remained largely unaffected (Fig. 2F).Fig. 2.


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)

μCT characterization and quantification of the pathological changes in the single- and two-hit models. 3D volume reconstruction (left panels, dorsal view) and representative coronal µCT sections (middle panels) with higher (4×) magnification of the highlighted insert (right panel). Mice treated with saline (Sal; A) or Sal+MHV-68 (B) show normal lung morphology; Bleomycin (Bleo)-treated mice (C) show dense subpleural fibrotic lesions, which are attenuated in the Bleo+SB525334 group (D); Bleo+MHV-68 mice (E) show evidence of extensive ground-glass opacities radiating from airways and overlying areas of dense consolidation; Bleo+MHV-68+SB525334 mice (F) reveal dense consolidation with reduced areas of ground-glass opacities. InForm analysis demonstrates an increase in the percentage of abnormal lung area (G) and density (H) in Bleo lungs above the Sal control (dotted line). No significant difference was observed between the Bleo and Bleo+MHV-68 groups. Administration of SB525334 from day 15 post-bleomycin-instillation (and 1 day p.i.) significantly attenuated lung pathology in the Bleo group but not in the two-hit Bleo+MHV-68 model. The data are representative of mean±s.e.m., one-way ANOVA, *P<0.05, **P<0.01, comparison of all Bleo-challenged groups (n=5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM019984F2: μCT characterization and quantification of the pathological changes in the single- and two-hit models. 3D volume reconstruction (left panels, dorsal view) and representative coronal µCT sections (middle panels) with higher (4×) magnification of the highlighted insert (right panel). Mice treated with saline (Sal; A) or Sal+MHV-68 (B) show normal lung morphology; Bleomycin (Bleo)-treated mice (C) show dense subpleural fibrotic lesions, which are attenuated in the Bleo+SB525334 group (D); Bleo+MHV-68 mice (E) show evidence of extensive ground-glass opacities radiating from airways and overlying areas of dense consolidation; Bleo+MHV-68+SB525334 mice (F) reveal dense consolidation with reduced areas of ground-glass opacities. InForm analysis demonstrates an increase in the percentage of abnormal lung area (G) and density (H) in Bleo lungs above the Sal control (dotted line). No significant difference was observed between the Bleo and Bleo+MHV-68 groups. Administration of SB525334 from day 15 post-bleomycin-instillation (and 1 day p.i.) significantly attenuated lung pathology in the Bleo group but not in the two-hit Bleo+MHV-68 model. The data are representative of mean±s.e.m., one-way ANOVA, *P<0.05, **P<0.01, comparison of all Bleo-challenged groups (n=5).
Mentions: Ex vivo µCT was subsequently used to further investigate the effect of SB525334 treatment in this two-hit model. Fig. 2 shows representative 3D volume reconstructions (left panels) with corresponding mid-lung coronal µCT sections (middle panels) and magnification of key pathological changes (right panels) for lungs at day 28. Sal+MHV-68 lungs were indistinguishable from Sal control lungs, with both groups displaying an equally homogenous appearance with a network of airways in a virtually transparent parenchyma (Fig. 2A,B). In the Bleo group, peripheral dense fibrotic lesions were clearly visible, particularly on the dorsal side of the lungs (Fig. 2C), as previously reported for oropharyngeal bleomycin instillation (Lakatos et al., 2006; Scotton et al., 2013). Coronal sections revealed prominent sub-pleural scarring, interlobular septal thickening and traction bronchiectasis (Fig. 2C). In Bleo+SB525334 lungs, scarring and fibrosis were noticeably reduced (Fig. 2D). In contrast, in the two-hit model, lungs displayed extensive areas of dense consolidation with overlapping diffuse ground-glass opacities indicative of inflammatory changes concentrated around the airways (Fig. 2E). SB525334 treatment visibly reduced the ground-glass appearance in the two-hit model but the fibrotic lesions remained largely unaffected (Fig. 2F).Fig. 2.

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