Recently, numerous evidence has revealed that excessive reactive oxygen species (ROS) production and mitochondrial disruption during acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) will aggravate the inflammatory process. To identify whether antioxidation can be one of the treatment strategies during this progress, we chose mitoQ, a mitochondria-targeted antioxidant that was proved to be effective in reducing ROS generated in mitochondria, as a ROS scavenger to investigate the role of antioxidation in ALI. We demonstrated that overoxidation occurred during the process of ALI, which could be reduced by mitoQ. In the meantime, apoptosis of endothelial cells of ALI mice, accompanied by hyperpermeability of pulmonary vascular and impaired pulmonary function, was partially reversed following an intraperitoneal injection of mitoQ. Moreover, in in vitro study, lipopolysaccharides (LPS) induced excessive ROS production, mitochondrial dysfunction and apoptosis in human pulmonary microvascular endothelial cells (HPMECs), which were rectified by mitoQ. To explore underlying mechanisms, we proceeded RNA-sequencing and found significantly upregulated expression of musculoaponeurotic fibrosarcoma F (MafF) in mitoQ treated group. Additionally, mitoQ inhibited the degradation and increased nuclear translocation of NF-E2-related factor 2 (Nrf2) and upregulated its downstream antioxidant response elements (AREs), such as heme oxygenase (HO)-1 and NAD(P)H:quinone oxidoreductase (NQO)-1. This effect was abolished by transfecting HPMECs with Nrf2 or Maff siRNA. In Nrf2 deficient mice, the protective effects of mitoQ on LPS model of ALI were largely vanished. Taken together, these results provide insights into how antioxidation exerts beneficial effects on ALI via maintaining mitochondrial hemostasis, inhibiting endothelial cells apoptosis, attenuating the endothelial disruption and regulating lung inflammation via Nrf2-MafF/ARE pathway.

Acute lung injury (ALI) is associated with excessive inflammatory response, leading to acute respiratory distress syndrome (ARDS) without timely treatment. A fewer effective drugs are available currently to treat the ALI/ARDS. Herein, a therapeutic nanoplatform with reactive oxygen species (ROS)-responsiveness was developed for the regulation of inflammation. Dexamethasone acetate (Dex) was encapsulated into poly(thioketal) polymers to form polymeric nanoparticles (NPs) (PTKNPs@Dex). The NPs were composed of poly(1,4-phenyleneacetonedimethylene thioketal) (PPADT) and polythioketal urethane (PTKU), in which the thioketal bonds could be cleaved by the high level of ROS at the ALI site. The PTKNPs@Dex could accumulate in the pulmonary inflammatory sites and release the encapsulated payloads rapidly, leading to the decreased ROS level, less generation of pro-inflammatory cytokines, and reduced lung injury and mortality of mice. RNA sequencing (RNA-seq) analysis showed that the therapeutic efficacy of the NPs was associated with the modulation of many immune and inflammation-linked pathways. These findings provide a newly developed nanoplatform for the efficient treatment of ALI/ARDS.