Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis
| Autor: | Thomas Helleday, Jonas S. Erjefält, Christina Kalderén, Olov A. Wallner, Christoffer Karlsson, Ravi K. V. Bhongir, Lloyd Tanner, Moritz Heusel, Arne Egesten, Tirthankar Mohanty, Carl-Magnus Clausson, A.B. Single, Cecilia Andersson, Johan Malmström, Riya Oommen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Lung
business.industry DNA repair medicine.medical_treatment Pirfenidone respiratory system medicine.disease respiratory tract diseases chemistry.chemical_compound Idiopathic pulmonary fibrosis Cytokine medicine.anatomical_structure chemistry Pulmonary fibrosis medicine Cancer research Nintedanib business Myofibroblast medicine.drug |
| DOI: | 10.21203/rs.3.rs-990197/v1 |
| Popis: | Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. 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 enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both 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. |
| Databáze: | OpenAIRE |
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