Limits...
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

Detection of viral genes in the lung and splenomegaly indicate ongoing MHV-68 infection. Viral gene expression was detected in lung tissue 14 days post infection. The viral genes measured included (A) gB, (B) DNApol and (C) M3. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, **P<0.01. (D) Splenomegaly is detected in all virally-infected groups. Data are representative of mean±s.e.m., n=5 for saline groups and n=13 for bleomycin groups. One-way ANOVA, ***P<0.001 compared to non-infected groups; +P<0.05, ++P<0.01 comparison within virally-infected groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4582104&req=5

DMM019984F6: Detection of viral genes in the lung and splenomegaly indicate ongoing MHV-68 infection. Viral gene expression was detected in lung tissue 14 days post infection. The viral genes measured included (A) gB, (B) DNApol and (C) M3. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, **P<0.01. (D) Splenomegaly is detected in all virally-infected groups. Data are representative of mean±s.e.m., n=5 for saline groups and n=13 for bleomycin groups. One-way ANOVA, ***P<0.001 compared to non-infected groups; +P<0.05, ++P<0.01 comparison within virally-infected groups.

Mentions: It has been previously reported that active viral replication is required for exacerbation of experimental pulmonary fibrosis (Ashley et al., 2014; McMillan et al., 2008). We therefore evaluated the expression of three viral genes encoding the MHV-68 DNA polymerase and the viral envelope proteins glycoprotein B and M3. In accordance with previous studies (Vannella et al., 2010; McMillan et al., 2008), we show that the viral genes are readily detected in whole lung tissue at the peak of lytic infection 7 days post-infection (p.i.) (supplementary material Fig. 2A-C). By 14 days p.i. the MHV-68 infection had entered a latent phase as demonstrated by decreased levels of viral gene expression in the lung. Blocking TGFβ signalling with the ALK5 inhibitor SB525334 had no impact on viral load in the fibrotic lungs (Fig. 6A-C).Fig. 6.


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)

Detection of viral genes in the lung and splenomegaly indicate ongoing MHV-68 infection. Viral gene expression was detected in lung tissue 14 days post infection. The viral genes measured included (A) gB, (B) DNApol and (C) M3. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, **P<0.01. (D) Splenomegaly is detected in all virally-infected groups. Data are representative of mean±s.e.m., n=5 for saline groups and n=13 for bleomycin groups. One-way ANOVA, ***P<0.001 compared to non-infected groups; +P<0.05, ++P<0.01 comparison within virally-infected groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM019984F6: Detection of viral genes in the lung and splenomegaly indicate ongoing MHV-68 infection. Viral gene expression was detected in lung tissue 14 days post infection. The viral genes measured included (A) gB, (B) DNApol and (C) M3. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups. One-way ANOVA, **P<0.01. (D) Splenomegaly is detected in all virally-infected groups. Data are representative of mean±s.e.m., n=5 for saline groups and n=13 for bleomycin groups. One-way ANOVA, ***P<0.001 compared to non-infected groups; +P<0.05, ++P<0.01 comparison within virally-infected groups.
Mentions: It has been previously reported that active viral replication is required for exacerbation of experimental pulmonary fibrosis (Ashley et al., 2014; McMillan et al., 2008). We therefore evaluated the expression of three viral genes encoding the MHV-68 DNA polymerase and the viral envelope proteins glycoprotein B and M3. In accordance with previous studies (Vannella et al., 2010; McMillan et al., 2008), we show that the viral genes are readily detected in whole lung tissue at the peak of lytic infection 7 days post-infection (p.i.) (supplementary material Fig. 2A-C). By 14 days p.i. the MHV-68 infection had entered a latent phase as demonstrated by decreased levels of viral gene expression in the lung. Blocking TGFβ signalling with the ALK5 inhibitor SB525334 had no impact on viral load in the fibrotic lungs (Fig. 6A-C).Fig. 6.

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