title: Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis.
abstract: The etiology of idiopathic pulmonary fibrosis (IPF) is unknown. Because viral pathogenesis of IPF has been suggested, we have established a murine model of progressive pulmonary fibrosis by infecting IFN-gammaR-deficient mice (IFN-gammaR(-/-)) with the murine gamma-herpesvirus 68. Because alveolar macrophages in humans with IPF have been implicated in driving the profibrotic response, we studied their role in our model. Chronic herpesvirus infection of the lung was associated with recruitment of alveolar macrophages to areas with epithelial hyperplasia and fibrosis in infected lungs. Using immunohistochemistry, Western blot, and RT-PCR techniques, we demonstrated that recruited alveolar macrophages showed high levels of expression of the proteins Ym1/2, FIZZ1 (found in inflammatory zone 1), insulin-like growth factor-1, and arginase I, and also active transcription of fibronectin, indicative of activation of macrophages by an alternative pathway. Arginase I expression was also evident in interstitial fibroblasts, and increased arginase activity was found in lungs of infected animals. Lung tissue from patients with IPF showed increased expression of arginase I in epithelial cells, fibroblast foci, and alveolar macrophages compared with normal lung. These results suggest that virus-induced upregulation of arginase I could be a mechanism driving lung fibrogenesis.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Research of the Lung, Emory University, 615 Michael Street Suite 215, Atlanta, GA 30322, USA. amora@emory.edu
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
authors.forename: Edilson
authors.initials: E
authors.lastname: Torres-González
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Claudia
authors.initials: C
authors.lastname: Corredor
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ritzenthaler
authors.forename: Jianguo
authors.initials: J
authors.lastname: Xu
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
authors.forename: Kenneth
authors.initials: K
authors.lastname: Brigham
authors.forename: Arlene
authors.initials: A
authors.lastname: Stecenko
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D002908:Chronic Disease; D005353:Fibronectins / Q000378:metabolism; D018142:Gammaherpesvirinae; D006566:Herpesviridae Infections / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D017471:Receptors, Interferon / Q000235:genetics*; D015398:Signal Transduction; D014162:Transfection; D000096743:Interferon gamma Receptor
chemical_list: D001119:Arginase; D005353:Fibronectins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor