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

The anti-fibrotic effect of TGFβ-ALK5 signalling inhibition is attenuated in the two-hit model of MHV-68 infection on the background of pre-existing fibrosis. Total lung collagen was quantified by reverse-phase HPLC 28 days post-oropharyngeal bleomycin instillation (corresponding to 14 days p.i. with MHV-68). The ALK5 inhibitor SB525334 was administered according to a therapeutic dosing regimen during the progressive fibrotic phase (from day 15 post-bleomycin-instillation; corresponding to 1 day p.i.). MHV-68 infection in saline control lung did not significantly increase lung collagen levels. SB525334 attenuated lung collagen accumulation in the single-hit model of lung fibrosis, but the anti-fibrotic effect of SB525334 was attenuated in the two-hit model of fibrosis with concomitant infection of fibrotic lung. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups; statistical analysis, Student’s t-test, *P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM019984F1: The anti-fibrotic effect of TGFβ-ALK5 signalling inhibition is attenuated in the two-hit model of MHV-68 infection on the background of pre-existing fibrosis. Total lung collagen was quantified by reverse-phase HPLC 28 days post-oropharyngeal bleomycin instillation (corresponding to 14 days p.i. with MHV-68). The ALK5 inhibitor SB525334 was administered according to a therapeutic dosing regimen during the progressive fibrotic phase (from day 15 post-bleomycin-instillation; corresponding to 1 day p.i.). MHV-68 infection in saline control lung did not significantly increase lung collagen levels. SB525334 attenuated lung collagen accumulation in the single-hit model of lung fibrosis, but the anti-fibrotic effect of SB525334 was attenuated in the two-hit model of fibrosis with concomitant infection of fibrotic lung. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups; statistical analysis, Student’s t-test, *P<0.05.

Mentions: Total lung collagen was measured by quantifying hydroxyproline levels by reverse-phase high performance liquid chromatography (HPLC) (Fig. 1). MHV-68 infection alone [saline (Sal)+MHV68] had no significant effect on total lung collagen levels when compared to uninfected control lungs (Sal). Administration of bleomycin (Bleo) resulted in a doubling of lung collagen deposition, which was significantly attenuated by SB525334 treatment in the Bleo+SB525334 group (mean±s.e.m. of Bleo vs Bleo+SB525334, 3.8±0.4 mg vs 2.97±0.14 mg, P=0.04). MHV-68 infection on the background of existing lung fibrosis (Bleo+MHV-68) did not increase total lung collagen levels compared to the Bleo group. Interestingly, in the two-hit model, there was no difference in total lung collagen between the Bleo+MHV-68+SB525334 group compared with the Bleo+MHV-68 group (mean±s.e.m. of Bleo+MHV-68 vs Bleo+MHV-68+SB525334, 4±1 mg vs 3.5±0.4 mg, P=0.6). These observations were further confirmed by the Sircol assay (supplementary material Fig. S1). Taken together, these data led us to conclude that SB525334 attenuates fibrosis in the single-hit model but that the therapeutic effect of this inhibitor is largely lost in the two-hit model.Fig. 1.


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)

The anti-fibrotic effect of TGFβ-ALK5 signalling inhibition is attenuated in the two-hit model of MHV-68 infection on the background of pre-existing fibrosis. Total lung collagen was quantified by reverse-phase HPLC 28 days post-oropharyngeal bleomycin instillation (corresponding to 14 days p.i. with MHV-68). The ALK5 inhibitor SB525334 was administered according to a therapeutic dosing regimen during the progressive fibrotic phase (from day 15 post-bleomycin-instillation; corresponding to 1 day p.i.). MHV-68 infection in saline control lung did not significantly increase lung collagen levels. SB525334 attenuated lung collagen accumulation in the single-hit model of lung fibrosis, but the anti-fibrotic effect of SB525334 was attenuated in the two-hit model of fibrosis with concomitant infection of fibrotic lung. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups; statistical analysis, Student’s t-test, *P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM019984F1: The anti-fibrotic effect of TGFβ-ALK5 signalling inhibition is attenuated in the two-hit model of MHV-68 infection on the background of pre-existing fibrosis. Total lung collagen was quantified by reverse-phase HPLC 28 days post-oropharyngeal bleomycin instillation (corresponding to 14 days p.i. with MHV-68). The ALK5 inhibitor SB525334 was administered according to a therapeutic dosing regimen during the progressive fibrotic phase (from day 15 post-bleomycin-instillation; corresponding to 1 day p.i.). MHV-68 infection in saline control lung did not significantly increase lung collagen levels. SB525334 attenuated lung collagen accumulation in the single-hit model of lung fibrosis, but the anti-fibrotic effect of SB525334 was attenuated in the two-hit model of fibrosis with concomitant infection of fibrotic lung. Data are representative of mean±s.e.m., n=3 for saline groups and n=8 for bleomycin groups; statistical analysis, Student’s t-test, *P<0.05.
Mentions: Total lung collagen was measured by quantifying hydroxyproline levels by reverse-phase high performance liquid chromatography (HPLC) (Fig. 1). MHV-68 infection alone [saline (Sal)+MHV68] had no significant effect on total lung collagen levels when compared to uninfected control lungs (Sal). Administration of bleomycin (Bleo) resulted in a doubling of lung collagen deposition, which was significantly attenuated by SB525334 treatment in the Bleo+SB525334 group (mean±s.e.m. of Bleo vs Bleo+SB525334, 3.8±0.4 mg vs 2.97±0.14 mg, P=0.04). MHV-68 infection on the background of existing lung fibrosis (Bleo+MHV-68) did not increase total lung collagen levels compared to the Bleo group. Interestingly, in the two-hit model, there was no difference in total lung collagen between the Bleo+MHV-68+SB525334 group compared with the Bleo+MHV-68 group (mean±s.e.m. of Bleo+MHV-68 vs Bleo+MHV-68+SB525334, 4±1 mg vs 3.5±0.4 mg, P=0.6). These observations were further confirmed by the Sircol assay (supplementary material Fig. S1). Taken together, these data led us to conclude that SB525334 attenuates fibrosis in the single-hit model but that the therapeutic effect of this inhibitor is largely lost in the two-hit model.Fig. 1.

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