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 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.
Subject(s)
DNA Glycosylases , Idiopathic Pulmonary Fibrosis , Pneumonia , Male , Mice , Humans , Animals , Lung/pathology , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Fibrosis , Pneumonia/metabolism , Bleomycin/toxicity , DNA Glycosylases/genetics , DNA Glycosylases/metabolismABSTRACT
The Medical Department of Sabah, in collaboration with various governmental and non-governmental agencies and 'Surgeons International' conducted a state-wide campaign for the 'Early Detection of Cancer' over a period of 3 months from July 1992. The purpose of the campaign was to educate the population about the early signs and symptoms of common cancers, to remove the myth that cancer was incurable and to impress on the public the need to detect cancer early for a possible cure and a better prognosis.
