nu-7441 and Idiopathic-Pulmonary-Fibrosis

Recent studies have highlighted the contribution of senescent mesenchymal and epithelial cells in Idiopathic Pulmonary Fibrosis (IPF), but little is known regarding the molecular mechanisms that regulate the accumulation of senescent cells in this disease. Therefore, we addressed the hypothesis that the loss of DNA repair mechanisms mediated by DNA protein kinase catalytic subunit (DNA-PKcs) in IPF, promoted the accumulation of mesenchymal progenitors and progeny, and the expression of senescent markers by these cell types.. Surgical lung biopsy samples and lung fibroblasts were obtained from patients exhibiting slowly, rapidly or unknown progressing IPF and lung samples lacking any evidence of fibrotic disease (i.e. normal; NL). The expression of DNA-Pkcs in lung tissue was assessed by quantitative immunohistochemical analysis. Chronic inhibition of DNA-PKcs kinase activity was mimicked using a highly specific small molecule inhibitor, Nu7441. Proteins involved in DNA repair (stage-specific embryonic antigen (SSEA)-4. DNA-PKcs expression was significantly reduced in IPF lung tissues. Chronic inhibition of DNA-PKcs by Nu7441 promoted the proliferation of SSEA4. Together, our results show that the loss of DNA-PKcs promotes the expansion of SSEA4

Topics: Animals; Cell Line; Cell Proliferation; Cellular Senescence; Chromones; DNA Damage; DNA Repair; DNA-Activated Protein Kinase; DNA-Binding Proteins; Female; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Lung; Mesenchymal Stem Cells; Mice; Mice, SCID; Morpholines