Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus.
BACKGROUND
Idiopathic pulmonary fibrosis is a progressive disease with high mortality. Although most patients have a slow, progressive course, some patients will have an acute deterioration in function or acute exacerbation, which carries a poor prognosis. In some cases, acute deterioration is associated with infection. Herpesviruses have been associated with this disease. Fibrocytes have also been shown to be important in the pathogenesis of pulmonary fibrosis.


OBJECTIVE
To develop a murine model for infectious exacerbation of preexisting fibrosis, and provide mechanistic insight into the role of herpesviruses in fibrotic disease.


METHODS
We used a model of fluorescein isothiocyanate-induced pulmonary fibrosis in mice. Infection with a murine gammaherpesvirus was given at time of established lung fibrosis. Measurements were made at the time of peak lytic viral replication.


RESULTS
We demonstrate that infection with gammaherpesvirus can exacerbate established fluorescein isothiocyanate-induced fibrosis evidenced by increased total lung collagen, histologic changes of acute lung injury, and diminished lung function. Gammaherpesvirus can exacerbate preexisting fibrosis in a Th1 cytokine environment and in the absence of Th2 cytokines. Gammaherpesvirus increases fibrocyte recruitment to the lung in wild-type, but not CCR2(-/-) mice, in part because viral infection up-regulates production of CCL2 and CCL12, chemokines important for fibrocyte recruitment. In contrast, mouse adenovirus infection did not exacerbate collagen deposition.


CONCLUSIONS
These data provide a new model for gammaherpesvirus exacerbation of established pulmonary fibrosis. The up-regulation of chemokines during viral infection and subsequent recruitment of fibrocytes to the lung likely contribute to augmentation of pulmonary fibrosis.
McMillan
Tracy R
TR
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Moore
Bethany B
BB
Weinberg
Jason B
JB
Vannella
Kevin M
KM
Fields
W Brad
WB
Christensen
Paul J
PJ
van Dyk
Linda F
LF
Toews
Galen B
GB
D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D018142:Gammaherpesvirinae; D006566:Herpesviridae Infections / Q000150:complications* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation
C491224:Ccl12 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D016650:Fluorescein-5-isothiocyanate