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Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

Sueblinvong, Viranuj and Neveu, Wendy A and Neujahr, David C and Mills, Stephen T and Rojas, Mauricio and Roman, Jesse and Guidot, David M (2014) Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury. Adv Biosci Biotechnol, 5 (1). 19 - 30. ISSN 2156-8456

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sueblinvong, Viranuj
Neveu, Wendy A
Neujahr, David C
Mills, Stephen T
Rojas, Mauriciomar176@pitt.eduMAR176
Roman, Jesse
Guidot, David M
Date: January 2014
Date Type: Publication
Journal or Publication Title: Adv Biosci Biotechnol
Volume: 5
Number: 1
Page Range: 19 - 30
DOI or Unique Handle: 10.4236/abb.2014.51004
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Uncontrolled Keywords: Extracellular Matrix, Fibrocytes, Fibronectin, Lung Fibrosis, TGF β1, Thy-1
ISSN: 2156-8456
Funders: NIAAA NIH HHS (K08 AA021404), NIAAA NIH HHS (P50 AA013757), NIAAA NIH HHS (R01 AA017627), NHLBI NIH HHS (T32 HL116271)
Date Deposited: 01 Jun 2015 21:16
Last Modified: 30 Oct 2017 22:56
URI: http://d-scholarship.pitt.edu/id/eprint/24783

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