title: Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes.
abstract: Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resemblance, but lack the chronic nature of human granulomatous disease. Carbon nanoparticles are generated as byproducts of combustion. Interestingly, experimental exposures to carbon nanoparticles induce pulmonary granuloma-like lesions. However, the recruited cellular populations and extracellular matrix gene expression profiles within these lesions have not been explored. Because of the rapid resolution of granulomas in current animal models, the mechanisms responsible for persistence have been elusive. To overcome the limitations of previous models, we investigated whether a model using multiwall carbon nanoparticles would resemble chronic human lung granulomatous inflammation. We hypothesized that pulmonary exposure to multiwall carbon nanoparticles would induce granulomas, elicit a macrophage and T-cell response, and mimic other granulomatous disorders with an up-regulation of osteopontin. This model demonstrates: (1) granulomatous inflammation, with macrophage and T-cell infiltration; (2) resemblance to the chronicity of human granulomas, with persistence up to 90 days; and (3) a marked elevation of osteopontin, metalloproteinases, and cell adhesion molecules in granulomatous foci isolated by laser-capture microdissection and in alveolar macrophages from bronchoalveolar lavage. The establishment of such a model provides an important platform for mechanistic studies on the persistence of granuloma.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 3E-149 Brody Medical Sciences Building, Greenville, NC 27834, USA. huizari@ecu.edu
authors.forename: Isham
authors.initials: I
authors.lastname: Huizar
authors.forename: Anagha
authors.initials: A
authors.lastname: Malur
authors.forename: Yasmeen A
authors.initials: YA
authors.lastname: Midgette
authors.forename: Cindy
authors.initials: C
authors.lastname: Kukoly
authors.forename: Pengyu
authors.initials: P
authors.lastname: Chen
authors.forename: Pu Chun
authors.initials: PC
authors.lastname: Ke
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Podila
authors.forename: Apparao M
authors.initials: AM
authors.lastname: Rao
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wingard
authors.forename: Larry
authors.initials: L
authors.lastname: Dobbs
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Barna
authors.forename: Mani S
authors.initials: MS
authors.lastname: Kavuru
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Thomassen
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006099:Granuloma / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D016023:Integrins / Q000235:genetics; D007834:Lasers; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D045726:Metalloproteases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D042282:Microdissection / Q000295:instrumentation; D037742:Nanotubes, Carbon; D053495:Osteopontin / Q000235:genetics; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D016023:Integrins; D037742:Nanotubes, Carbon; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; D053495:Osteopontin; D045726:Metalloproteases