title: Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5).
abstract: Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose-dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5-induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5-induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets.
authors.affiliation: 1Department of Physiology, Brody School of Medicine, 6N-98, East Carolina University, 600 Moye Blvd., Greenville, NC 27834, USA. waltersd@ecu.edu.
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Walters
authors.forename: Kevin M
authors.initials: KM
authors.lastname: White
authors.forename: Ushma
authors.initials: U
authors.lastname: Patel
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Veluci-Marlow
authors.forename: Solomon Raju
authors.initials: SR
authors.lastname: Bhupanapadu Sunkesula
authors.forename: James C
authors.initials: JC
authors.lastname: Bonner
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Martin
authors.forename: Wes
authors.initials: W
authors.lastname: Gladwell
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D017968:Vanadium Compounds / Q000633:toxicity*
chemical_list: D016212:Transforming Growth Factor beta; D017968:Vanadium Compounds; C066075:vanadium pentoxide
keywords: collagen; haplotype; inflammation; lung injury; mapping