Latent herpesvirus infection augments experimental pulmonary fibrosis.

Graduate Program in Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 11.04). 03/2010; 181(5):465-77. DOI: 10.1164/rccm.200905-0798OC
Source: PubMed

ABSTRACT No effective treatment exists for idiopathic pulmonary fibrosis, and its pathogenesis remains unclear. Accumulating evidence implicates herpesviruses as cofactors (either initiating or exacerbating agents) of fibrotic lung disease, but a role for latent herpesvirus infection has not been studied.
To develop a murine model to determine whether latent herpesvirus infection can augment fibrotic responses and to gain insight into potential mechanisms of enhanced fibrogenesis.
Mice were infected with murine gammaherpesvirus 14 to 70 days before a fibrotic challenge with fluorescein isothiocyanate or bleomycin so that the virus was latent at the time of fibrotic challenge. Measurements were made after viral infection alone or after the establishment of fibrosis.
gammaHerpesvirus is latent by 14 days post infection, and infection 14 to 70 days before fibrotic challenge augmented fibrosis. Fibrotic augmentation was not dependent on reactivation of the latent virus to a lytic state. Total cell numbers and fibrocyte numbers were increased in the lungs of latently infected mice administered fibrotic challenge compared with mock-infected mice that received fibrotic challenge. Latent infection up-regulates expression of proinflammatory chemokines, transforming growth factor-beta1, and cysteinyl leukotrienes in alveolar epithelial cells.
Latent gammaherpesvirus infection augments subsequent fibrotic responses in mice. Enhanced fibrosis is associated with the induction of profibrotic factors and the recruitment of fibrocytes. Our data complement existing human and animal data supporting the hypothesis that gammaherpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary fibrosis is a devastating and often progressive condition leading to exercise intolerance and frequently the demise of the animal. Although uncommonly encountered in horses, the condition is intensely researched both in human medicine and animal models. Viral infections have long been suspected to play a part in the development of pulmonary fibrosis and neoplastic conditions in other species. In 2007, an association between equine herpesvirus 5 (EHV-5) infection and nodular pulmonary fibrosis in horses was suggested and the name equine multinodular pulmonary fibrosis (EMPF) was introduced. Recently, the presence of EHV-5 in equine lymphoma has also emerged. The case report by Schwarz et al. in this issue describes a horse suffering from concurrent T cell leukaemia and EMPF in association with EHV-5. This article summarises current knowledge about EMPF and EHV-5 infections in horses, recent developments in the understanding of pulmonary fibrosis in man and the proposed contribution of viral infections to pulmonary fibrosis and neoplastic conditions.
    04/2012; 24(4). DOI:10.1111/j.2042-3292.2011.00340.x
  • [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by severe and progressive scar formation in the gas-exchange regions of the lung. Despite years of research, therapeutic treatments remain elusive and there is a pressing need for deeper mechanistic insights into the pathogenesis of the disease. In this manuscript, we review our current knowledge of the triggers and/or perpetuators of pulmonary fibrosis with special emphasis on the alveolar epithelium and the underlying mesenchyme. In doing so, we raise a number of questions highlighting critical voids in our current understanding of how IPF develops and progresses.
    AJP Cell Physiology 04/2014; 306(11). DOI:10.1152/ajpcell.00321.2013 · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with idiopathic pulmonary fibrosis (IPF) often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus (γHV-68) could exacerbate established lung fibrosis following administration of fluorescein isothiocyanate. In this study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram negative bacteria (Pseudomonas aeruginosa), or with H1N1 or γHV-68 viruses. Measurements were then made on days 15, 21 or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop worse lung fibrosis when infected with γHV-68, but not when infected with H1N1. The differential ability of γHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from γHV-68-infected mice displayed increased expression of TGFβ receptor 1, increased SMAD3 phosphorylation and evidence of apoptosis measured by cleaved poly ADP ribose polymerase (PARP). The ability of γHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to γHV-68, as the β herpes virus, cytomegalovirus, did not have the same effect.
    AJP Lung Cellular and Molecular Physiology 05/2014; 307(3). DOI:10.1152/ajplung.00300.2013 · 4.04 Impact Factor