Abstract
Acute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2−/− mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.
Highlights
Ischemia reperfusion (IR) injury is a potential surgical complication that can inadvertently release cytotoxic agents from ischemic tissues and inflammatory mediators and produce secondary vascular disease [1]
II/R-induced acute lung injury (ALI) promotes ferroptosis To explore the role of ferroptosis in the ischemia reperfusion (IIR)-induced ALI (IIR-ALI) model, we first detected the endogenous ferric and ferrous levels in the lung tissues of the IIR-ALI model
Using hematoxylin and eosin (HE) staining (Fig. 1G), we further demonstrated that IIR produced significant damage to the lung tissue (P < 0.05)
Summary
Ischemia reperfusion (IR) injury is a potential surgical complication that can inadvertently release cytotoxic agents from ischemic tissues and inflammatory mediators and produce secondary vascular disease [1]. This may result in sepsis, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome [2]. Intestinal ischemia reperfusion (IIR) can lead to acute lung injury (ALI) and can cause acute respiratory distress syndrome It carries a high mortality rate and is a major challenge to the world of critical illness research [3,4,5,6]. Our research will uncover potential therapeutic targets in the management of IIR-ALI
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