Abstract
ABSTRACTTGFβ-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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most progressive and fatal of all fibrotic conditions, with a median survival of 3 years
This study revealed that concomitant viral infection on the background of pre-existing bleomycin-induced fibrosis in mice leads to prominent and extensive inflammatory changes that are reminiscent of ground-glass opacities and consolidation reported in individuals with acute exacerbation of IPF (AE-IPF)
Blocking TGFβ-activin receptor-like kinase 5 (ALK5) signalling by therapeutic dosing with the potent and selective ALK5 antagonist SB525334 was highly effective in blocking the progression of fibrosis in the single-hit bleomycin-alone injured mouse model, but the anti-fibrotic effect of this agent was dramatically reduced in the presence of concomitant viral infection
Summary
Idiopathic pulmonary fibrosis (IPF) is the most progressive and fatal of all fibrotic conditions, with a median survival of 3 years. The pathomechanisms involved remain poorly understood, but current hypotheses propose that this condition arises as a result of repetitive. The aetiology of IPF remains unknown, studies examining the role of infection in IPF implicate viral infections, especially human herpesviruses (HHVs), as important contributors to the initiation and progression of this condition (reviewed in Molyneaux and Maher, 2013). There is evidence linking viral infection with the incidence of acute exacerbation of IPF (AE-IPF) (Wootton et al, 2011), a life-threatening complication that presents as worsening of dyspnoea and an accelerated decline in lung function (Collard et al, 2007)
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