title: Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation.
abstract: Viral infection is an exacerbating factor contributing to chronic airway diseases, such as asthma, via mechanisms that are still unclear. Polyinosine-polycytidylic acid (poly(I:C)), a Toll-like receptor 3 (TLR3) agonist used as a mimetic to study viral infection, has been shown to elicit inflammatory responses in lungs and to exacerbate pulmonary allergic reactions in animal models. Previously, we have shown that poly(I:C) stimulates lung fibroblasts to accumulate an extracellular matrix (ECM), enriched in hyaluronan (HA) and its binding partner versican, which promotes monocyte adhesion. In the current study, we aimed to determine the in vivo role of versican in mediating inflammatory responses in poly(I:C)-induced lung inflammation using a tamoxifen-inducible versican-deficient mouse model (Vcan-/-mice). In C57Bl/6 mice, poly(I:C) instillation significantly increased accumulation of versican and HA, especially in the perivascular and peribronchial regions, which were enriched in infiltrating leukocytes. In contrast, versican-deficient (Vcan-/-) lungs did not exhibit increases in versican or HA in these regions and had strikingly reduced numbers of leukocytes in the bronchoalveolar lavage fluid and lower expression of inflammatory chemokines and cytokines. Poly(I:C) stimulation of lung fibroblasts isolated from control mice generated HA-enriched cable structures in the ECM, providing a substrate for monocytic cells in vitro, whereas lung fibroblasts from Vcan-/-mice did not. Moreover, increases in proinflammatory cytokine expression were also greatly attenuated in the Vcan-/-lung fibroblasts. These findings provide strong evidence that versican is a critical inflammatory mediator during poly(I:C)-induced acute lung injury and, in association with HA, generates an ECM that promotes leukocyte infiltration and adhesion.
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Inkyung
authors.initials: I
authors.lastname: Kang
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Harten
authors.affiliation: the Department of Comparative Medicine and Center for Lung Biology, University of Washington, Seattle, Washington 98109, and.
authors.forename: Mary Y
authors.initials: MY
authors.lastname: Chang
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Braun
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, Washington 98101.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Sheih
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Nivison
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Pamela Y
authors.initials: PY
authors.lastname: Johnson
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Gail
authors.initials: G
authors.lastname: Workman
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kaber
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Evanko
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Christina K
authors.initials: CK
authors.lastname: Chan
authors.affiliation: the Department of Anatomy and Medical Imaging, School of Medical Sciences, University of Auckland, Auckland 1010, New Zealand.
authors.forename: Mervyn J
authors.initials: MJ
authors.lastname: Merrilees
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, Washington 98101.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.affiliation: From the Matrix Biology Program and.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kinsella
authors.affiliation: the Department of Comparative Medicine and Center for Lung Biology, University of Washington, Seattle, Washington 98109, and.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
authors.affiliation: From the Matrix Biology Program and twight@benaroyaresearch.org.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007369:Interferon Inducers / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011070:Poly I-C / Q000633:toxicity*; D053675:Versicans / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D007369:Interferon Inducers; C508323:Vcan protein, mouse; D053675:Versicans; D011070:Poly I-C
keywords: Lung inflammation; Poly(I:C); double-stranded RNA (dsRNA); extracellular matrix; hyaluronan; leukocyte; versican (VCAN)