title: Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.
abstract: Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Viranuj
authors.initials: V
authors.lastname: Sueblinvong
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Neveu
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA ; McKelvey Lung Transplantation Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Neujahr
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Mills
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA ; Division of Pulmonary, Allergy and Critical Care Medicine, Atlanta VAMC, Decatur, GA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Guidot
keywords: Extracellular Matrix; Fibrocytes; Fibronectin; Lung Fibrosis; TGF β1; Thy-1