TITLE:
Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury
AUTHORS:
Viranuj Sueblinvong, Wendy A. Neveu, David C. Neujahr, Stephen T. Mills, Mauricio Rojas, Jesse Roman, David M. Guidot
KEYWORDS:
Lung Fibrosis; Thy-1, Fibrocytes; Extracellular Matrix; Fibronectin; TGFβ1
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.5 No.1,
January
8,
2014
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 was assessed. Bone
marrowderived 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 transdifferentiation that renders the “aging lung”
susceptible to fibrosis.