8‐Oxoguanine DNA glycosylase modulates the cell transformation process in pulmonary fibrosis by inhibiting Smad2/3 and interacting with Smad7

Abstract

The DNA repair enzyme 8‐oxoguanine DNA glycosylase‐1 (OGG1) is involved in early embryonic development, as well as in multiple conditions, including cardiac fibrosis, diabetes, and neurodegenerative diseases. But, function of OGG1 in pulmonary fibrosis was not entirely clear. In this study, we identified a novel function of OGG1 in the cell transformation process in pulmonary fibrosis. We demonstrated that OGG1 and Smad7 co‐localize and interact in A549 cells. Bleomycin‐induced pulmonary fibrosis was established in wild‐type (WT) and Ogg1‐/‐ mice. Upon treatment with transforming growth factor (TGF)‐β1, increased OGG1 expression was observed in WT mice with pulmonary fibrosis as well as in A549 cells, MRC‐5 cells, and primary rat type II alveolar epithelial cells. The increased expression of OGG1 promoted cell migration, while OGG1 depletion decreased migration ability. Expression of the transformation‐associated markers vimentin and alpha‐smooth muscle actin were also affected by OGG1. We also observed that OGG1 promoted TGF‐β1‐induced cell transformation and activated Smad2/3 by interacting with Smad7. The interaction between OGG1 and the TGF‐β/Smad axis modulates the cell transformation process in lung epithelial cells and fibroblasts. Moreover, we demonstrated that Ogg1 deficiency relieved pulmonary fibrosis in bleomycin‐treated mice. Ogg1 knockout decreased the bleomycin‐induced expression of Smad7 and phosphorylation of Smad2/3 in mice. These findings suggest that OGG1 has multiple biological functions in the pathogenesis of pulmonary fibrosis.

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

“…Reported data indicate that OGG1 binds 8-oxoG at regulatory gene domains, mediating transcriptional activation of inflammatory responses 11,45,54,[46][47][48][49][50][51][52][53] . OGG1 is increased in lung epithelial cells and fibroblasts following TGF-β1 addition 26 , with IPF-derived fibroblasts generating higher levels of ROS 55 . Furthermore, abnormal wound healing of the alveolar epithelium in response to micro-injuries plays a crucial role in IPF progression [56][57][58] .…”

“…To elucidate the mechanism by which these effects were mediated, we examined murine and human lung samples. OGG1 has displayed a crucial role in the TGF-β/SMAD axis, modulating EMT/FMT transition through the phosphorylation of SMAD 2/3 by SMAD 7 26 . This is supported in this study by proteomic analysis, immunostaining, and immunofluorescence which show that decreases in both SMAD 7 and OGG1, as well as several base excision repair-associated proteins, result in amelioration of fibrotic damage in both human and murine samples.…”

“…Comprehensive proteomic analyses further elucidated the pathways by which TH5487 attenuates pulmonary fibrosis, confirming the involvement of nucleotide excision repair and Mothers against decapentaplegic homolog (SMAD) family of proteins. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation 26,29 , with both being increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF.…”

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

“…Ensuing TGF-β production following lung injury results in the upregulation of tissue repair genes, including the DNA base excision repair gene OGG1 (14,24,25). Previously reported data indicate that OGG1 is increased in lung epithelial cells and fibroblasts following TGF-β stimulation addition (10).…”

“…8-oxoG bases are recognized by the enzyme 8-oxoG DNA glycosylase 1 (OGG1), whereby OGG1 binding triggers DNA base excision processes. It has been shown that Ogg1-deficient ( Ogg1 -/- ) mice are resistant to DNA damage inducing agents (10). Furthermore, the increased expression of OGG1 is an important marker of inflammation and resultant fibrotic processes (11, 12).…”