ALI(acute lung injury) is a severe respiratory dysfunction caused by various intrapulmonary and extrapulmonary factors. It is primarily characterized by oxidative stress and affects the integrity of the pulmonary barrier. In severe cases, ALI can progress to ARDS(acute respiratory distress syndrome), a condition that poses a serious threat to the lives of affected patients. To date, the etiological mechanisms underlying ALI remain elusive, and available therapeutic options are quite limited. AMPK(AMP-activated protein kinase), an essential serine/threonine protein kinase, performs a pivotal function in the regulation of cellular energy levels and cellular regulatory mechanisms, including the detection of redox signals and mitigating oxidative stress. Meanwhile, Nrf2(nuclear factor erythroid 2-related factor 2), a critical transcription factor, alleviates inflammation and oxidative responses by interacting with multiple signaling pathways and contributing to the modulation of oxidative enzymes associated with inflammation and programmed cell death. Indeed, AMPK induces the dissociation of Nrf2 from Keap1(kelch-like ECH-associated protein-1) and facilitates its translocation into the nucleus to trigger the transcription of downstream antioxidant genes, ultimately suppressing the expression of inflammatory cells in the lungs. Given their roles, AMPK and Nrf2 hold promise as novel treatment targets for ALI. This study aimed to summarise the current status of research on the AMPK/Nrf2 signaling pathway in ALI, encompassing recently reported natural compounds and drugs that can activate the AMPK/Nrf2 signaling pathway to alleviate lung injury, and provide a theoretical reference for early intervention in lung injury and future research on lung protection.

In intensive care units, acute lung injury (ALI) is a syndrome that is frequently encountered. It is associated with a high rate of morbidity and mortality. Despite the extensive research conducted by the medical community on its treatment, no specific effective drugs have been identified. Quercetin is a natural flavonoid with many biological activities and pharmacological effects. Research indicates that Quercetin can modulate various targets and signaling pathways, inhibiting oxidative stress, inflammatory responses, ferroptosis, apoptosis, fibrosis, and bacterial and viral infections in ALI. This regulation suggests its potential therapeutic application for the condition. Currently, there is no comprehensive review addressing the application of Quercetin in the treatment of ALI. This paper begins with a classification of ALI, followed by a detailed summary of the mechanisms through which Quercetin may treat ALI to evaluate its potential as a novel therapeutic option.

Inhibiting apoptosis of type II alveolar epithelial cells (AEC II) is an effective way to decrease hyperoxic acute lung injury (HALI); however, the specific underlying molecular mechanisms have not yet been fully elucidated. Although miRNA‑21‑5p has previously been reported to decrease H2O2‑induced AEC II apoptosis by targeting PTEN in vitro, whether miR‑21‑5p can decrease HALI in vivo and the downstream molecular mechanisms remain unclear. In the present study, rats were endotracheally administered with an miR‑21‑5p‑encoding (AAV‑6‑miR‑21‑5p) or a negative control adenovirus vector, and then a HALI model was established by exposure to hyperoxia. At 3 weeks following the administration of AAV‑6‑miR‑21‑5p, the severity of HALI was decreased, as evidenced by the improved outcome of the oxygenation index, respiratory index, wet/dry weight ratio and pathological scores of the HALI lungs. To further investigate the underlying mechanisms, AEC II cells were isolated from the lungs of the experimental rats and cultured. The expression levels of miR‑21‑5p and its target gene, PTEN, were detected, as well as the levels of phosphorylated and total AKT. In addition, the apoptosis rate of AEC II was detected by flow cytometry. The results demonstrated that AAV‑6‑miR‑21‑5p administration increased the miR‑21‑5p levels in primary AEC II cells, while it decreased the expression levels of PTEN. miR‑21‑5p overexpression also increased AKT phosphorylation in AEC II cells from the HALI lungs compared with that of the HALI alone group and the control virus group. The present study indicated that miR‑21‑5p ameliorated HALI in vivo, which may have resulted from the inhibition of PTEN/AKT‑induced apoptosis of AEC II cells. These findings suggest that miR‑21‑5p and PTEN/AKT signaling might serve as potential targets for HALI treatment.

Background: Oxygen therapy usually exposes patients to hyperoxia, which induces injuries in the lung, the heart, and the brain. The gut and its microbiome play key roles in critical illnesses, but the impact of hyperoxia on the gut and its microbiome remains not very clear. We clarified the time- and dose-dependent effects of hyperoxia on the gut and investigated oxygen-induced gut dysbiosis and explored the underlying mechanism of gut injury by transcriptome analysis.Methods: The C57BL/6 mice were randomly divided into the control group and nine different oxygen groups exposed to hyperoxia with an inspired O₂ fraction (FiO₂) of 40, 60, and 80% for 24, 72, and 168 h (7 days), respectively. Intestinal histopathological and biochemical analyses were performed to explore the oxygen-induced gut injury and inflammatory response. Another experiment was performed to explore the impact of hyperoxia on the gut microbiome by exposing the mice to hyperoxia (FiO₂ 80%) for 7 days, with the 16S rRNA sequencing method. We prolonged the exposure (up to 14 days) of the mice to hyperoxia (FiO₂ 80%), and gut transcriptome analysis and western blotting were carried out to obtain differentially expressed genes (DEGs) and signaling pathways related to innate immunity and cell death.Results: Inhaled oxygen induced time- and dose-dependent gut histopathological impairment characterized by mucosal atrophy (e.g., villus shortening: 80% of FiO₂ for 24 h: P = 0.008) and enterocyte death (e.g., apoptosis: 40% of FiO₂ for 7 days: P = 0.01). Administered time- and dose-dependent oxygen led to intestinal barrier dysfunction (e.g., endotoxemia: 80% of FiO₂ for 72 h: P = 0.002) and potentiated gut inflammation by increasing proinflammatory cytokines [e.g., tumor necrosis factor alpha (TNF-α): 40% of FiO₂ for 24 h: P = 0.003)] and reducing anti-inflammatory cytokines [Interleukin 10 (IL-10): 80% of FiO₂ for 72 h: P < 0.0001]. Hyperoxia induced gut dysbiosis with an expansion of oxygen-tolerant bacteria (e.g., Enterobacteriaceae). Gut transcriptome analysis identified 1,747 DEGs and 171 signaling pathways and immunoblotting verified TLR-4, NOD-like receptor, and apoptosis signaling pathways were activated in oxygen-induced gut injury.Conclusions: Acute hyperoxia rapidly provokes gut injury in a time- and dose-dependent manner and induces gut dysbiosis, and an innate immune response is involved in an oxygen-induced gut injury.