Abstract
Lipopolysaccharide (LPS)-induced pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. Epigenetic regulation of thymocyte differentiation antigen 1 (Thy-1) is associated with lung fibroblast phenotype transformation that results in aberrant cell proliferation. However, it is not clear whether the epigenetic regulation of Thy-1 expression is required for LPS-induced lung fibroblast proliferation. To address this issue and better understand the relative underlying mechanisms, we used mouse lung fibroblasts as model to observe the changes of Thy-1 expression and histone deacetylation after LPS challenge. The results showed that cellular DNA synthesis, measured by BrdU incorporation, was impacted less in the early stage (24 hrs) after the challenge of LPS, but significantly increased at 48 or 72 hrs after the challenge of LPS. Meanwhile, Thy-1 expression, which was detected by real-time PCR and Western blot, in lung fibroblasts decreased with increased time after LPS challenge and diminished at 72 hrs. We also found that the acetylation of either histone H3 or H4 decreased in the LPS-challenged lung fibroblasts. ChIP assay revealed that the acetylation of histone H4 (Ace-H4) decreased in the Thy-1 promoter region in response to LPS. In addition, all the above changes could be attenuated by depletion of TLR4 gene. Our studies indicate that epigenetic regulation of Thy-1 gene expression by histone modification is involved in LPS-induced lung fibroblast proliferation.
Highlights
The formation and development of pulmonary fibrosis are associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which is characterized by aberrant proliferation and activation of lung fibroblasts
Changes in histone modifications in lung fibroblasts in response to LPS challenge acetylated H3 (Ace-H3) and acetylated H4 (Ace-H4), as well as Total-H3 and Total-H4 levels were measured, by Western blot, in lung fibroblasts infected with TLR4siRNA-lentivirus 72 hrs after LPS challenge
Our study investigated the role of LPS in the epigenetic regulation of thymocyte differentiation antigen 1 (Thy-1) expression associated with lung fibroblast proliferation
Summary
The formation and development of pulmonary fibrosis are associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which is characterized by aberrant proliferation and activation of lung fibroblasts. Lipopolysaccharide (LPS), a component of bacteria membranes, plays an important role in the development of pulmonary fibrosis [1, 2]. Thy-1, a cell-surface glycoprotein presents on normal lung fibroblasts [11], is absent from the fibroblastic foci of idiopathic pulmonary fibrosis (IPF) [12]. The expression of Thy-1 correlates inversely with fibrogenic phenotypic characteristics. Thereby, it is known as a ‘fibrosis suppressor’.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have