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.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is a devastating progressive lung disease with an average survival of only 3 to 5 years [1]
There were no significant differences in α-smooth muscle actin (α-SMA) protein expression between fibrocytes cultured on extracellular matrix (ECM) derived from Thy-1(+) or Thy-1(−) fibroblasts in the absence of TGFβ1 (Figure 4C)
In the presence of TGFβ1, fibrocytes cultured on ECM derived from Thy-1(−) lung fibroblasts significantly expressed their expression of Col1A1 and α-SMA mRNA (Figures 4A and B) and α-SMA protein expression (Figure 4C) as compared to fibrocytes cultured on ECM derived from Thy-1(+) lung fibroblasts
Summary
Idiopathic Pulmonary Fibrosis (IPF) is a devastating progressive lung disease with an average survival of only 3 to 5 years [1]. There is little known about how senescence predisposes the lung to ineffective repair and increased fibrosis after injury. Several factors have been linked to pathological lung fibrogenesis including circulating bone marrow-derived fibroblast progenitor cells, known as fibrocytes [6,7,8]. Fibrocytes are bone marrow-derived fibroblast progenitor cells characterized by their expression of both stromal markers (i.e. collagen types I and III and vimentin) and hematopoietic markers (i.e. CD45) [9]. Several studies, both in experimental animal model and humans, demonstrate that fibrocytes are recruited (via the CXCR4 axis) to sites of tissue injury including the lung where they
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