title: 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.
abstract: TGFβ-ALK5 pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of pulmonary fibrosis. In this study we addressed the role of TGFβ-ALK5 signalling during the progression of fibrosis in a two-hit mouse model of murine γ-herpesvirus 68 (MHV-68) infection on the background of pre-existing bleomycin-induced pulmonary fibrosis. 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. Moreover, µCT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFα, IL-1β and IL-10. Blockade of TGFβ-ALK5 signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. 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. These findings raise important considerations for the targeting of TGFβ signalling responses in the context of pulmonary fibrosis.
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Smoktunowicz
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Alexander
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Franklin
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Williams
authors.affiliation: Institute of Nuclear Medicine, University College London, NW1 2BU, UK.
authors.forename: Beverley
authors.initials: B
authors.lastname: Holman
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Mercer
authors.affiliation: Novartis Institutes of Biomedical Research, Horsham, RH12 5AB, UK.
authors.forename: Gabor
authors.initials: G
authors.lastname: Jarai
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Scotton
authors.affiliation: Centre for Inflammation & Tissue Repair, University College London, London, WC1E 6JF, UK r.chambers@ucl.ac.uk.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006564:Herpesviridae; D006566:Herpesviridae Infections / Q000150:complications / Q000378:metabolism*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D016753:Interleukin-10; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse
keywords: Collagen; Pulmonary fibrosis; TGFβ; Viral infection; µCT