Astaxanthin inhibits apoptosis in alveolar epithelial cells type II in vivo and in vitro through the ROS‐dependent mitochondrial signalling pathway

Abstract

Oxidative stress is an important molecular mechanism underlying lung fibrosis. The mitochondrion is a major organelle for oxidative stress in cells. Therefore, blocking the mitochondrial signalling pathway may be the best therapeutic manoeuver to ameliorate lung fibrosis. Astaxanthin (AST) is an excellent antioxidant, but no study has addressed the pathway of AST against pulmonary oxidative stress and free radicals by the mitochondrion-mediated signalling pathway. In this study, we investigated the antioxidative effects of AST against H2O2- or bleomycin (BLM)-induced mitochondrial dysfunction and reactive oxygen species (ROS) production in alveolar epithelial cells type II (AECs-II) in vivo and in vitro. Our data show that AST blocks H2O2- or BLM-induced ROS generation and dose-dependent apoptosis in AECs-II, as characterized by changes in cell and mitochondria morphology, translocation of apoptotic proteins, inhibition of cytochrome c (Cyt c) release, and the activation of caspase-9, caspase-3, Nrf-2 and other cytoprotective genes. These data suggest that AST inhibits apoptosis in AECs-II cells through the ROS-dependent mitochondrial signalling pathway and may be of potential therapeutic value in lung fibrosis treatment.

Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander?

“…Taken together, these data may suggest that mitochondrial protein turnover within the alveolus occurs at a higher rate than in other lung cells raising the possibility that the alveolus is particularly sensitive to mitochondrial perturbations. In accord with this notion, the hypoxic environment at the alveolar level that ensues following acute lung injury has been shown to trigger enhanced mitochondrial ROS generation by alveolar cells, which plays a key role in modulating TGFβ signaling and onset of fibrosis (Zhou, et al, 2009, Na, et al, 2010, Panduri, Weitzman, Chandel, & Kamp, 2004, Chandel, et al, 2000and Song, et al, 2014. Similar observations have been made in animals treated with bleomycin (Song, et al, 2014), asbestos (Song, et al, 2014), asbestos (Cheresh, et al, 2015 andPanduri, et al, 2009) or particulate matter air pollution .…”

“…In accord with this notion, the hypoxic environment at the alveolar level that ensues following acute lung injury has been shown to trigger enhanced mitochondrial ROS generation by alveolar cells, which plays a key role in modulating TGFβ signaling and onset of fibrosis (Zhou, et al, 2009, Na, et al, 2010, Panduri, Weitzman, Chandel, & Kamp, 2004, Chandel, et al, 2000and Song, et al, 2014. Similar observations have been made in animals treated with bleomycin (Song, et al, 2014), asbestos (Song, et al, 2014), asbestos (Cheresh, et al, 2015 andPanduri, et al, 2009) or particulate matter air pollution . Consistent with this idea, lung tissue from IPF patients display elevated lactate levels, which synergizes with TGF-beta to induce myofibroblast differentiation under hypoxic conditions providing a direct link between perturbed glycolysis and modulation of a key pathway implicated in lung remodeling (Kottmann, et al, 2012).…”

Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis

“…Specifically, the apoptotic pathway is regulated by early translocation of anti-apoptotic (Bcl-xl) and pro-apoptotic (Bak and Bax) proteins to or from the mitochondria [25]. Therefore, we assessed the protein levels of BCL-XL, BAK, and BAX during apoptosis in c-kit-positive cells after TBI.…”

Systemic sclerosis-associated fibrosis

“…It was recently demonstrated that in bleomycin-induced pulmonary fibrosis in Wistar rats, there is acquisition of mtDNA deletions, respiratory chain dysfunction and mtROS production during the development of pulmonary fibrosis *(44). Similarly, Song et al *(45) demonstrated that inhibition of H 2 O 2 or bleomycin-induced mtROS production by astaxanthin (AST) prevents AECII apoptosis, which may mitigate fibrotic responses.…”