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

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. 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.

Substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) reprograms mucosal adaptations to chronic airway injury

“…Treatment with TH5487 also decreased collagen deposition and structural deformation of the alveoli, indicating that TH5487 may be an effective inhibitor of bleomycin-induced fibrosis as characterized by histological lung damage. Finally, TH5487 decreased immune cell recruitment, levels of proinflammatory and profibrotic mediators in addition to alleviating weight loss and rejuvenating pulmonary health in experimental animals (94). These data show promising preclinical support for future studies investigating the clinical utility of TH5487 for treatment of IPF.…”

“…OGG1targeting siRNA and inhibition (TH5487) of OGG1 significantly inhibit pro-migratory effects of TGFb. Bioanalytical liquid chromatography tandem mass spectrometry data-independent acquisition (LC-MS/MS DIA) analysis showed significant downregulation of OGG1-dependent GO terms, including collagen biosynthesis processes, wound healing involved in inflammatory response, endothelial cell proliferation, collagen metabolic processes, response to fibroblast growth factor, regulation of cytokine production, wound healing, and response to wounding in fibrotic tissue (94). These studies suggest that TH5487 is clinically relevant to the observed decreases in fibrotic processes.…”

“…In the same study, supraphysiological OGG1 levels were recorded after repeated TGFb treatment using primary human lung fibroblast and murine-derived fibroblast cells, which paralleled with increased cell migration and with an enhanced wound healing capacity of the cells. Importantly, in lung sections of IPF patients, OGG1 immunoreactivity is significantly higher than in healthy controls, supporting the functional roles of OGG1 in fibrotic disease (94). Moreover, adeno-associated virus-driven OGG1 overexpression in rodent lungs promoted EMT in alveolar epithelia and resulted in progressive fibrosis (95).…”

“…In the absence of OGG1 function, the production of ECM proteins (like FN1, VIM and COL1A1) is inhibited within these transitioned cell states. Ogg1 KO or inhibition of its reader function with TH5487 can be utilized in ameliorating oxidation-induced inflammation (71,103), and to treat pulmonary fibrosis (94,95) or allergic asthma (68). In bleomycin-induced lung injury, OGG1 KO mice show decreased collagen deposition and tissue damage (96).…”

“…Both nintedanib and pirfenidone have documented limitations, such as modest slowing of disease progression that is often coupled with poor tolerability (106-108), which highlights the need for novel therapeutic strategies. The effects of both drugs were compared to TH5487 in a bleomycin-induced mouse model of IPF (94). Similar to nintedanib, TH5487 decreased TGFb-induced wound healing, fibroblast migration, morphological changes in epithelial cells and F-actin reorganization, as well as production of collagen around small airways (57, 94).…”