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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

Histological analysis of the single- and two-hit models. Representative H&E and MSB sections (100× original magnification; scale bars: 600 μm) are shown for each experimental group as annotated. Saline (Sal) and Saline+MHV-68 lungs show normal morphology (A,B); (C) typical examples of the fibrotic lesions with evidence of collagen deposition observed in the Bleo group. These are greatly reduced in Bleo+SB525334 lungs (D); Bleo+MHV-68 lungs show extensive fibrotic lesions with collagen deposition and dense inflammatory cell aggregates that appear less frequent and more dispersed in Bleo+MHV-68+SB525334 lungs (E,F, boxed area is 200× magnification; scale bars: =300 μm). FB, fibrosis; COL, collagen; IA, inflammatory cell aggregates.
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DMM019984F4: Histological analysis of the single- and two-hit models. Representative H&E and MSB sections (100× original magnification; scale bars: 600 μm) are shown for each experimental group as annotated. Saline (Sal) and Saline+MHV-68 lungs show normal morphology (A,B); (C) typical examples of the fibrotic lesions with evidence of collagen deposition observed in the Bleo group. These are greatly reduced in Bleo+SB525334 lungs (D); Bleo+MHV-68 lungs show extensive fibrotic lesions with collagen deposition and dense inflammatory cell aggregates that appear less frequent and more dispersed in Bleo+MHV-68+SB525334 lungs (E,F, boxed area is 200× magnification; scale bars: =300 μm). FB, fibrosis; COL, collagen; IA, inflammatory cell aggregates.

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)

Histological analysis of the single- and two-hit models. Representative H&E and MSB sections (100× original magnification; scale bars: 600 μm) are shown for each experimental group as annotated. Saline (Sal) and Saline+MHV-68 lungs show normal morphology (A,B); (C) typical examples of the fibrotic lesions with evidence of collagen deposition observed in the Bleo group. These are greatly reduced in Bleo+SB525334 lungs (D); Bleo+MHV-68 lungs show extensive fibrotic lesions with collagen deposition and dense inflammatory cell aggregates that appear less frequent and more dispersed in Bleo+MHV-68+SB525334 lungs (E,F, boxed area is 200× magnification; scale bars: =300 μm). FB, fibrosis; COL, collagen; IA, inflammatory cell aggregates.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4582104&req=5

DMM019984F4: Histological analysis of the single- and two-hit models. Representative H&E and MSB sections (100× original magnification; scale bars: 600 μm) are shown for each experimental group as annotated. Saline (Sal) and Saline+MHV-68 lungs show normal morphology (A,B); (C) typical examples of the fibrotic lesions with evidence of collagen deposition observed in the Bleo group. These are greatly reduced in Bleo+SB525334 lungs (D); Bleo+MHV-68 lungs show extensive fibrotic lesions with collagen deposition and dense inflammatory cell aggregates that appear less frequent and more dispersed in Bleo+MHV-68+SB525334 lungs (E,F, boxed area is 200× magnification; scale bars: =300 μm). FB, fibrosis; COL, collagen; IA, inflammatory cell aggregates.
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