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1 Center for Translational Research of the Lung, Atlanta, GA, USA; Division of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, GA, USA; McKelvey Lung Transplantation Center, Emory University, Atlanta, GA, USA
2 Center for Translational Research of the Lung, Atlanta, GA, USA; Division of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, GA, USA
3 Division of Pathology; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
4 Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
5 Division of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: amora{at}emory.edu.
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic, lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since more than 95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine if pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine gammaherpesvirus 68 (MHV68). Since IPF patients have a Th2 pulmonary phenotype, we used IFN
R-/- a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFNR-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features that are typically seen in IPF, increased TGF-
expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7 were also present in chronically infected IFNR-/- mice. There also was altered synthesis of surfactant proteins which is seen in some patients with familial IPF. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFNR-/- mice causes progressive pulmonary fibrosis and many of the pathologic features seen in IPF.
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