Asbestos causes asbestosis (pulmonary fibrosis secondary to asbestos) and malignancies (bronchogenic carcinoma and mesothelioma) 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 (ETC) 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 specific p53-dependent transcriptional molecule, Noxa, as well as a novel mechanism by which mitochondrial human 8-oxoguanine-DNA glycosylase 1 (mt-hOgg1) prevents oxidant-induced intrinsic AEC apoptosis by preserving mitochondrial aconitase. Although Bcl-2 family members are crucial for regulating apoptosis, it is unclear how specific Bcl-2 proteins modulate asbestos-induced AEC apoptosis and whether downstream proapoptotic Bax/Bak activation is essential for mediating asbestosis. In this renewal, we investigate the molecular mechanisms underlying asbestos-induced AEC intrinsic apoptosis. Our HYPOTHESIS is that mitochondrial hOgg1 and aconitase are important for attenuating asbestos- induced AEC mtDNA damage resulting from mitochondrial ROS production that leads to p53 (Noxa) activation, Bax/Bak intrinsic AEC apoptosis and pulmonary fibrosis. Our SPECIFIC OBJECTIVES that will be examined over the next 4 years include: (1) To determine whether mitochondrial hOgg1 preservation of aconitase is important in attenuating asbestos- induced AEC mtDNA damage that results in p53 (Noxa) activation and intrinsic apoptosis. We will also assess whether Ogg1-/- mice are more susceptible to asbestosis. (2) To determine whether asbestos-induced ROS from AEC mitochondria activate p53 (Noxa)-dependent transcription that causes mitochondria (Bax/Bak)-regulated apoptosis. We will also determine whether mitochondrial ROS are crucial for mediating pulmonary fibrosis following asbestos exposure. (3) To determine whether asbestos-induced AEC p53 (Noxa) activation results in the loss of Mcl-1 leading to Bax/Bak-mediated apoptosis. We will determine whether mice with conditional loss of Bax/Bak at the alveolar epithelium are protected against asbestosis. There are several immediate and long-range benefits from these studies. First, they should provide insight into the mechanisms underlying asbestos-induced AEC DNA damage, p53 activation, mitochondrial dysfunction, and apoptosis as well as how these events cause pulmonary fibrosis. Second, these studies will characterize the role of mitochondrial hOgg1 preservation of aconitase in preventing asbestos-induced AEC mitochondrial dysfunction, p53 activation, and intrinsic apoptosis. Finally, and perhaps most importantly, our findings may provide new information about the pathophysiologic events of other chronic lung diseases that will identify novel management approaches. Strategies aimed at reducing mitochondrial ROS production and preserving mitochondrial DNA integrity may prove useful in preventing pulmonary fibrosis and/or lung cancer from exposure to various pulmonary toxins (e.g. asbestos, cigarette smoke, air-borne particulate matter etc).
Asbestos-related lung diseases (asbestosis, bronchogenic lung cancer and mesothelioma) continue to pose serious health concerns worldwide, including in the veteran population. The pathogenesis of asbestos-induced lung diseases 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. Specifically, we investigate the role of AEC mitochondria-derived ROS, p53 (Noxa) activation and down-stream Bax activation. These studies will also characterize the role of mitochondrial DNA repair enzyme (hOgg1) and aconitase in preventing asbestos- induced AEC apoptosis. Notably, the asbestos paradigm should provide insights into the pathogenesis of other more common diseases, such as lung cancer and idiopathic pulmonary fibrosis, which are frequently present in the veteran population and for which more effective management strategies are clearly needed.
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