Latent herpesvirus infection augments experimental pulmonary fibrosis.
BACKGROUND
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.


OBJECTIVE
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 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.


RESULTS
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.


CONCLUSIONS
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.
Vannella
Kevin M
KM
Graduate Program in Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Luckhardt
Tracy R
TR
Wilke
Carol A
CA
van Dyk
Linda F
LF
Toews
Galen B
GB
Moore
Bethany B
BB
D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018142:Gammaherpesvirinae / Q000502:physiology; D006566:Herpesviridae Infections / Q000150:complications*; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications* / Q000821:virology; D008168:Lung / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000097:blood; D014775:Virus Activation / Q000502:physiology; D017735:Virus Latency / Q000502:physiology
C491224:Ccl12 protein, mouse; D018932:Chemokine CCL2; D018945:Monocyte Chemoattractant Proteins; D016212:Transforming Growth Factor beta