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Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model

Tanner, L. LU ; Single, A. B. LU ; Bhongir, R. K.V. LU orcid ; Heusel, M. LU ; Mohanty, T. LU ; Karlsson, C. A.Q. LU ; Pan, L. ; Clausson, C. M. LU ; Bergwik, J. LU and Wang, K. , et al. (2023) In Nature Communications 14(1).
Abstract

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in... (More)

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
article number
643
publisher
Nature Publishing Group
external identifiers
  • scopus:85147460531
  • pmid:36746968
ISSN
2041-1723
DOI
10.1038/s41467-023-36314-5
language
English
LU publication?
yes
id
5465c2f5-57cc-4b50-aac5-0d79704583f1
date added to LUP
2023-02-20 14:13:07
date last changed
2023-09-25 03:46:12
@article{5465c2f5-57cc-4b50-aac5-0d79704583f1,
  abstract     = {{<p>Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.</p>}},
  author       = {{Tanner, L. and Single, A. B. and Bhongir, R. K.V. and Heusel, M. and Mohanty, T. and Karlsson, C. A.Q. and Pan, L. and Clausson, C. M. and Bergwik, J. and Wang, K. and Andersson, C. K. and Oommen, R. M. and Erjefält, J. S. and Malmström, J. and Wallner, O. and Boldogh, I. and Helleday, T. and Kalderén, C. and Egesten, A.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-36314-5}},
  doi          = {{10.1038/s41467-023-36314-5}},
  volume       = {{14}},
  year         = {{2023}},
}