Asbestos causes asbestosis and malignancies by mechanisms that are not fully elucidated. The extent of alveolar epithelial cell (AEC) injury and repair are critical determinants of the fibrogenic potential of toxic agents such as asbestos. Previous studies, including ones from our group, have identified some of the important factors contributing to the adverse effects of asbestos as well as strategies that are protective. We have shown that iron-derived reactive oxygen species (ROS) from the mitochondria electron transport chain mediate asbestos-induced AEC DNA damage and apoptosis by a p53- and mitochondria-regulated (intrinsic) death pathway. Our more recent data implicate an important role for a novel mechanism by which mitochondrial human 8-oxoguanine-DNA glycosylase 1 (mt-hOgg1) prevents oxidant-induced intrinsic AEC apoptosis by preserving mitochondrial aconitase (Aco2). Bcl-2 family members are crucial for regulating apoptosis yet it is unclear how specific Bcl-2 proteins modulate asbestos-induced AEC apoptosis and whether this is essential for mediating asbestosis. Our HYPOTHESIS is that mitochondrial hOgg1 preservation of mitochondrial aconitase is important for attenuating asbestos-induced AEC mitochondrial (mt)DNA damage resulting from mitochondrial ROS production that leads to Bax/Bak intrinsic AEC apoptosis and pulmonary fibrosis.
Our SPECIFIC AIMS that will be examined over the next 5 years include: (1) To determine whether mt-hOgg1 preservation of Aco2 is important in attenuating asbestos (crocidolite and Libby amphibole)-induced AEC mtDNA damage that results in intrinsic apoptosis. We will also utilize Ogg1-/- and Ogg1 overexpressing mice to genetically assess the relationship between Ogg1 preservation of AEC Aco2 levels, apoptosis and asbestosis. (2) To assess whether a small molecule (e.g. Euk-134 or Ogg1 cleaved molecule) protects Aco2. We will also utilize a murine model of asbestosis to determine whether Euk-134 attenuates AEC mitochondrial ROS production, reductions in Aco2 and apoptosis as well as pulmonary fibrosis. (3) To determine whether TFAMfl/fl mice, incapable of AEC mitochondrial ROS production, are protected against asbestos-induced AEC apoptosis and fibrosis. We will also assess whether mice with conditional loss of Bax/Bak at the alveolar epithelium are protected against asbestosis. These studies should provide insight into the mechanisms underlying asbestos-induced AEC mtDNA damage and mitochondria-regulated apoptosis that can cause pulmonary fibrosis. Importantly, the asbestos paradigm may provide new information about the pathophysiologic events of other lung diseases that will identify novel management approaches that may prove useful in preventing pulmonary fibrosis and/or lung cancer following exposure to various pulmonary toxins (e.g. asbestos, cigarette smoke, particulate matter etc).
Asbestos-related lung diseases (asbestosis, bronchogenic lung cancer and mesothelioma) continue to pose serious health concerns worldwide, yet the pathogenesis is incompletely understood. The proposed studies should provide insight into the molecular mechanisms underlying asbestos-induced alveolar epithelial cell (AEC) cell death (apoptosis), which is an important initial event leading to fibrosis and carcinogenesis following asbestos exposure as well as in other more common diseases, such as idiopathic pulmonary fibrosis and lung cancer for which more effective management strategies are clearly needed. Specifically, we investigate the role of mitochondrial DNA repair enzyme (hOgg1) and aconitase in preventing asbestos (crocidolite and Libby amphibole)-induced AEC apoptosis as well as the role of AEC mitochondria-derived ROS and down-stream Bax activation.
|Cheresh, Paul; Morales-Nebreda, Luisa; Kim, Seok-Jo et al. (2015) Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice. Am J Respir Cell Mol Biol 52:25-36|
|Lin, Ziying; Liu, Tie; Kamp, David W et al. (2014) AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy. Free Radic Biol Med 72:296-307|
|Kim, Seok-Jo; Cheresh, Paul; Williams, David et al. (2014) Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells. J Biol Chem 289:6165-76|
|Cheresh, Paul; Kim, Seok-Jo; Tulasiram, Sandhya et al. (2013) Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta 1832:1028-40|
|Liu, Gang; Cheresh, Paul; Kamp, David W (2013) Molecular basis of asbestos-induced lung disease. Annu Rev Pathol 8:161-87|
|Kamp, David W; Liu, Gang; Cheresh, Paul et al. (2013) Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response. Am J Respir Cell Mol Biol 49:892-901|