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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

ALK5 inhibition attenuates inflammatory cell aggregates and enhances IFNγ levels in the two-hit model of MHV-68 infection on a background of pulmonary fibrosis. (A) Inflammatory aggregates (IAs) were significantly increased in bleomycin- and MHV-68-injured lungs when compared to other bleomycin-challenged groups (n=5). SB525334 treatment reduced the number of IAs, quantified and expressed as region of interest per lung (ROI/mm2, mean±s.e.m., five tissue sections per mouse). Levels of inflammatory and immunomodulatory markers were measured in lung homogenates: CCL2 (B), IFNγ (C), IL-1β (D), TNFα (E), IL-10 (F); representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, *P<0.05, **P<0.01, ***P<0.001.
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DMM019984F5: ALK5 inhibition attenuates inflammatory cell aggregates and enhances IFNγ levels in the two-hit model of MHV-68 infection on a background of pulmonary fibrosis. (A) Inflammatory aggregates (IAs) were significantly increased in bleomycin- and MHV-68-injured lungs when compared to other bleomycin-challenged groups (n=5). SB525334 treatment reduced the number of IAs, quantified and expressed as region of interest per lung (ROI/mm2, mean±s.e.m., five tissue sections per mouse). Levels of inflammatory and immunomodulatory markers were measured in lung homogenates: CCL2 (B), IFNγ (C), IL-1β (D), TNFα (E), IL-10 (F); representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, *P<0.05, **P<0.01, ***P<0.001.

Mentions: The lung abnormalities mapped by µCT analysis were subsequently matched to fibrotic and inflammatory changes identified on hematoxylin and eosin (H&E) and Martius Scarlet Blue (MSB)-stained tissue sections (Fig. 4). Histological analysis confirmed dense patchy fibrosis and collagen deposition in Bleo-injured lungs, which was reduced in mice treated with SB525334. Bleo+MHV-68 lungs displayed evidence of extensive fibrotic lesions and, notably, infiltrations of mononuclear inflammatory cells that formed dense aggregates. We subsequently quantified these inflammatory cell aggregates (IAs) and found that, consistent with our radiological findings, there was little evidence of IAs in Sal+MHV68 lungs. In stark contrast, there were numerous IAs present in the Bleo+MHV-68 two-hit group and these IAs were significantly increased compared with all other experimental groups (Fig. 5A). The number of these IAs was significantly reduced in the two-hit group treated with SB525334 (mean±s.e.m. of Bleo+MHV-68 vs Bleo+MHV-68+SB525334, 1±0.25 vs 0.4±0.13 ROI/mm2, P<0.05).Fig. 4.


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)

ALK5 inhibition attenuates inflammatory cell aggregates and enhances IFNγ levels in the two-hit model of MHV-68 infection on a background of pulmonary fibrosis. (A) Inflammatory aggregates (IAs) were significantly increased in bleomycin- and MHV-68-injured lungs when compared to other bleomycin-challenged groups (n=5). SB525334 treatment reduced the number of IAs, quantified and expressed as region of interest per lung (ROI/mm2, mean±s.e.m., five tissue sections per mouse). Levels of inflammatory and immunomodulatory markers were measured in lung homogenates: CCL2 (B), IFNγ (C), IL-1β (D), TNFα (E), IL-10 (F); representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM019984F5: ALK5 inhibition attenuates inflammatory cell aggregates and enhances IFNγ levels in the two-hit model of MHV-68 infection on a background of pulmonary fibrosis. (A) Inflammatory aggregates (IAs) were significantly increased in bleomycin- and MHV-68-injured lungs when compared to other bleomycin-challenged groups (n=5). SB525334 treatment reduced the number of IAs, quantified and expressed as region of interest per lung (ROI/mm2, mean±s.e.m., five tissue sections per mouse). Levels of inflammatory and immunomodulatory markers were measured in lung homogenates: CCL2 (B), IFNγ (C), IL-1β (D), TNFα (E), IL-10 (F); representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, *P<0.05, **P<0.01, ***P<0.001.
Mentions: The lung abnormalities mapped by µCT analysis were subsequently matched to fibrotic and inflammatory changes identified on hematoxylin and eosin (H&E) and Martius Scarlet Blue (MSB)-stained tissue sections (Fig. 4). Histological analysis confirmed dense patchy fibrosis and collagen deposition in Bleo-injured lungs, which was reduced in mice treated with SB525334. Bleo+MHV-68 lungs displayed evidence of extensive fibrotic lesions and, notably, infiltrations of mononuclear inflammatory cells that formed dense aggregates. We subsequently quantified these inflammatory cell aggregates (IAs) and found that, consistent with our radiological findings, there was little evidence of IAs in Sal+MHV68 lungs. In stark contrast, there were numerous IAs present in the Bleo+MHV-68 two-hit group and these IAs were significantly increased compared with all other experimental groups (Fig. 5A). The number of these IAs was significantly reduced in the two-hit group treated with SB525334 (mean±s.e.m. of Bleo+MHV-68 vs Bleo+MHV-68+SB525334, 1±0.25 vs 0.4±0.13 ROI/mm2, P<0.05).Fig. 4.

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