title: γ-Herpes virus-68, but not Pseudomonas aeruginosa or influenza A (H1N1), exacerbates established murine lung fibrosis.
abstract: Patients with idiopathic pulmonary fibrosis (IPF) often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus (γHV-68) could exacerbate established lung fibrosis following administration of fluorescein isothiocyanate (McMillan et al. Am J Respir Crit Care Med 177: 771-780, 2008). In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria (Pseudomonas aeruginosa), or with H1N1 or γHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop worse lung fibrosis when infected with γHV-68, but not when infected with H1N1. The differential ability of γHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from γHV-68-infected mice displayed increased expression of TGFβ receptor 1, increased SMAD3 phosphorylation, and evidence of apoptosis measured by cleaved poly-ADP ribose polymerase (PARP). The ability of γHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to γHV-68, as the β-herpes virus, cytomegalovirus, did not have the same effect.
authors.affiliation: Immunology Graduate Program, University of Michigan, Ann Arbor, Michigan;
authors.forename: Shanna L
authors.initials: SL
authors.lastname: Ashley
authors.affiliation: Department of Internal Medicine, Ulsan University Hospital, College of Medicine, University of Ulsan, Ulsan, Korea;
authors.forename: Yangjin
authors.initials: Y
authors.lastname: Jegal
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; Bmoore@umich.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.affiliation: Departments of Microbiology and Immunology, University of Colorado, Denver, Colorado; and.
authors.forename: Linda F
authors.initials: LF
authors.lastname: van Dyk
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Laouar
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000009:adverse effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology / Q000473:pathology / Q000821:virology; D006564:Herpesviridae / Q000472:pathogenicity*; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology* / Q000821:virology*; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: bacteria; collagen; fibrosis; lung; virus