Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disorder of unknown cause. Several studies demonstrate an association between pulmonary infection with the herpesvirus, EBV, and IPF. Based on those observations, we have developed a mouse model in which interferon-gamma receptor-deficient (IFNgR2/2) mice infected with herpesvirus develop lung fibrosis that progresses up to at least 180 days after initial infection (AJP Lung Cell Mol Physiol 289:L711). The purpose of this study was to determine whether antiviral treatment given in this model after infection but before maximal fibrosis would alter progressive lung fibrogenesis. The antiviral agent chosen, cidofovir, is effective at clearing lytic, but not latent, virus. The lungs of IFNgR2/2 mice were infected with MHV68 by nasal sniff. After 45 days, mice were treated with 7.5 mg/kg cidofovir (or saline) ip weekly for 4 months and then sacrificed 150-180 days after initial infection. Although antiviral-treated animals had persistent lymphocytic infiltrates in subpleural and perivascular areas of the lung, they had significantly less pulmonary fibrosis than controls, reflected in a significant reduction in lung collagen deposition. Bronchoalveolar lavage fluid (BAL) from antiviral-treated animals had lower levels of proinflammatory cytokines (IFNg, IL-6, and TNFa as well as the Th2 cytokine IL-5. BAL levels of the monocyte chemokines MIP1a and MCP-1 were also lower after antiviral treatment. Decreased fibrosis with cidofovir treatment was associated with lower lung expression of TGFb and fibronectin and lower lung MMP-9 activity. We conclude that eliminating active replication of herpesvirus in the lung prevents progressive fibrosis in this model and that the persistence of mild inflammatory changes may be due to persistent latent infection. We speculate that antiviral therapy might be therapeutic in humans with IPF and lung herpesvirus infection by preventing progressive fibrosis.
Funded by ALA Dalsemer Research Grant and McKelvey Lung Transplantation Center.
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