title: Pulmonary fibrosis induced by γ-herpesvirus in aged mice is associated with increased fibroblast responsiveness to transforming growth factor-β.
abstract: Young (4 month) and aged (15-18 months) mice were given intranasal saline or γ--herpesvirus-68 infection. After 21 days, aged, but not young mice, showed significant increases in collagen content and fibrosis. There were no differences in viral clearance or inflammatory cells (including fibrocytes) between infected aged and young mice. Enzyme-linked immunosorbent assays showed increased transforming growth factor-β in whole lung homogenates of infected aged mice compared with young mice. When fibroblasts from aged and young mice were infected in vitro, aged, but not young, fibroblasts upregulate alpha-smooth muscle actin and collagen I protein. Infection with virus in vivo also demonstrates increased alpha-smooth muscle actin and collagen I protein and collagen I, collagen III, and fibronectin messenger RNA in aged fibroblasts. Furthermore, evaluation revealed that aged fibroblasts at baseline have increased transforming growth factor-β receptor 1 and 2 levels compared with young fibroblasts and are resistant to apoptosis. Increased responsiveness to transforming growth factor-β was verified by increased collagen III and fibronectin messenger RNA after treatment in vitro with transforming growth factor-β.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Payal N
authors.initials: PN
authors.lastname: Naik
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D017209:Apoptosis; D024061:Collagen Type III / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000502:physiology*; D005353:Fibronectins / Q000096:biosynthesis; D018142:Gammaherpesvirinae / Q000472:pathogenicity*; D006566:Herpesviridae Infections / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000209:etiology*; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014775:Virus Activation
chemical_list: D024061:Collagen Type III; D016207:Cytokines; D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta