Exacerbation of Established Pulmonary Fibrosis in a Murine Model by Gammaherpesvirus

• Published in: American journal of respiratory and critical care medicine 2008-04, Vol.177 (7), p.771-780
• Main Authors: McMillan, Tracy R, Moore, Bethany B, Weinberg, Jason B, Vannella, Kevin M, Fields, W. Brad, Christensen, Paul J, van Dyk, Linda F, Toews, Galen B
• Format: Article
• Language: English
• Subjects: Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Chemokine CCL2 - metabolism; Chemokines; Collagen; Cytokines; Cytokines - metabolism; Disease Models, Animal; Donations; E. Lung Cancer and Oncologic Disorders; Epstein-Barr virus; Female; Fluorescein-5-isothiocyanate; Gammaherpesvirinae; Gammaherpesvirus; Herpes viruses; Herpesviridae Infections - complications; Herpesviridae Infections - immunology; Histology; Infections; Intensive care medicine; Lung diseases; Lungs; Male; Medical prognosis; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocyte Chemoattractant Proteins - metabolism; Mortality; Murine gammaherpesvirus; Pathogenesis; Pneumology; Polymerase chain reaction; Pulmonary fibrosis; Pulmonary Fibrosis - immunology; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - virology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Th1 Cells - immunology; Th2 Cells - immunology; Tumor necrosis factor-TNF; Up-Regulation; Viral infections
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200708-1184OC

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