euk-134 and Pulmonary-Fibrosis

Topics: Aging; Alveolar Epithelial Cells; Animals; Apoptosis; Asbestos; Catalase; Cell Line; DNA Damage; DNA, Mitochondrial; Female; Gene Expression Regulation; Glucuronidase; Klotho Proteins; Male; Mice; Mitochondria; Organometallic Compounds; Oxidants; Oxidative Stress; Protective Agents; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Receptor, IGF Type 1; Receptors, Fibroblast Growth Factor; RNA, Messenger; Salicylates; Signal Transduction

Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of lung fibrosis. Our group has shown that in the asbestos exposed lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for lung fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced lung.. To determine whether transgenic mice that express mitochondrial-targeted catalase (MCAT) have reduced lung fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis.. Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary fibrosis as measured by lung collagen levels and lung fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced.. Our finding that MCAT mice have reduced pulmonary fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role for AEC mitochondrial H

Topics: Administration, Inhalation; Animals; Asbestos; Bleomycin; Caspase 3; Catalase; Collagen; DNA, Mitochondrial; Epithelial Cells; Gene Expression; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Intubation, Intratracheal; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Proteins; Organometallic Compounds; Peptides; Pulmonary Alveoli; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein C; Reactive Oxygen Species; Salicylates; Transgenes