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Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

¹ Graduate Program in Immunology, ² Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and ⁴ Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan; and ³ Department of Microbiology, University of Colorado School of Medicine, Aurora, Colorado

Correspondence and requests for reprints should be addressed to Bethany B. Moore, Ph.D., 4062 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. E-mail: bmoore{at}umich.edu

Rationale: 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.

Objectives: 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.

Methods: Mice were infected with murine herpesvirus 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.

Measurements and Main Results: Herpesvirus 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-β1, and cysteinyl leukotrienes in alveolar epithelial cells.

Conclusions: Latent herpesvirus 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 herpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

Key Words: chemokine • epithelial cells • fibrocyte • interstitial lung disease

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Herpesviruses have been associated with idiopathic pulmonary fibrosis clinically, and animal models have suggested a role for lytic infection as a fibrotic cofactor. What This Study Adds to the Field This study describes the first animal model for latent herpesvirus-induced augmentation of lung fibrosis. Viral augmentation of fibrosis is associated with fibrocyte recruitment and induction of profibrotic mediators by latently infected alveolar epithelial cells.