High-Mobility Group Box 1 (HMGB1) and Autophagy in Acute Lung Injury (ALI): A Review.

Acute lung injury (ALI) is a life-threatening clinical syndrome in critically ill patients. The identification of novel biological markers for the early diagnosis of ALI and the development of more effective treatments are topics of current research. High mobility group box-1 protein (HMGB1) is a late inflammatory mediator associated with sepsis, malignancy, and immune disease. Levels of HMGB1 may reflect the severity of inflammation and tissue damage, indicating a potential role for HMGB1 as a prognostic biomarker in ALI, and a potential target for blocking inflammatory pathways. Several studies have shown that HMGB1 regulates autophagy. Autophagy, or type II programmed cell death, is an essential biological process that maintains cellular homeostasis. Studies have shown that HMGB1 and autophagy are involved in the pathogenesis of many lung diseases including ALI but the specific mechanisms underlying this association remain to be determined. This review aims to provide an update on the current status of the role of HMBG1 and autophagy in ALI.

Glycyrrhizic Acid Alleviates Lipopolysaccharide (LPS)-Induced Acute Lung Injury by Regulating Angiotensin-Converting Enzyme-2 (ACE2) and Caveolin-1 Signaling Pathway.

Acute lung injury (ALI) is mainly caused by severe infection, shock, trauma, and burn, which causes the extensive release of inflammatory factors and other mediators. As a major bioactive constituent of traditional Chinese herb licorice, glycyrrhizic acid (GA) plays an important effect on inflammatory regulation. Nevertheless, the exact mechanism of this effect remains unclear. The present study aims to explore the potential protective effect of GA on LPS-induced ALI. Our results showed that GA significantly attenuated LPS-induced ALI and decreased the production of inflammatory factors, including IL-1ß, MCP-1, COX2, HMGB1, and adhesion molecules, such as E-selectin, VCAM-1, and modulated expression of angiotensin-converting enzyme 2 (ACE2). Moreover, treatment of ACE2 inhibitor (MLN-4760) reversed the effects of GA on the secretion of pro-inflammatory factors in ALI. Additionally, GA exerts its protective effect by regulating the ACE2 and caveolin-1/NF-κB signaling pathway. In conclusion, this study showed that GA alleviated LPS-induced ALI by upregulating ACE2 and inhibiting the caveolin-1/NF-κB signaling pathway.

Caveolin-1 identified as a key mediator of acute lung injury using bioinformatics and functional research.

Acute lung injury (ALI) is a potentially life-threatening, devastating disease with an extremely high rate of mortality. The underlying mechanism of ALI is currently unclear. In this study, we aimed to confirm the hub genes associated with ALI and explore their functions and molecular mechanisms using bioinformatics methods. Five microarray datasets available in GEO were used to perform Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs) and the key genes were identified via the protein-protein interaction (PPI) network. Lipopolysaccharide intraperitoneal injection was administered to establish an ALI model. Overall, 40 robust DEGs, which are mainly involved in the inflammatory response, protein catabolic process, and NF-κB signaling pathway were identified. Among these DEGs, we identified two genes associated with ALI, of which the CAV-1/NF-κB axis was significantly upregulated in ALI, and was identified as one of the most effective targets for ALI prevention. Subsequently, the expression of CAV-1 was knocked down using AAV-shCAV-1 or CAV-1-siRNA to study its effect on the pathogenesis of ALI in vivo and in vitro. The results of this study indicated that CAV-1/NF-κB axis levels were elevated in vivo and in vitro, accompanied by an increase in lung inflammation and autophagy. The knockdown of CAV-1 may improve ALI. Mechanistically, inflammation was reduced mainly by decreasing the expression levels of CD3 and F4/80, and activating autophagy by inhibiting AKT/mTOR and promoting the AMPK signaling pathway. Taken together, this study provides crucial evidence that CAV-1 knockdown inhibits the occurrence of ALI, suggesting that the CAV-1/NF-κB axis may be a promising therapeutic target for ALI treatment.

Glycyrrhizic acid ameliorates LPS-induced acute lung injury by regulating autophagy through the PI3K/AKT/mTOR pathway.

Acute lung injury (ALI) is a major pathological issue characterized by serious inflammatory response, and a major clinically critical illness with high morbidity and mortality. Glycyrrhizic acid (GA) is a major bioactive constituent isolated from traditional Chinese herb licorice, which has been reported to have positive effects on inflammation. Nevertheless, the effects of GA on lipopolysaccharide (LPS)-treated ALI in mice have not been reported. The purpose of our study is to investigate the inhibitory effects of GA on ALI treated by LPS and to elucidate its possible mechanisms. We found that GA significantly attenuated lung injury and decreased the production of inflammatory factors TNF-α, IL-1ß, and HMGB1 with LPS treatment. GA induced autophagy which was showed by enhanced number of autophagosomes through upregulating the protein levels of LC3-II/I and Beclin-1 and downregulating SQSTM1/P62. Moreover, pre-treatment of 3-Methyladenine (3-MA), an autophagy inhibitor, reversed the inhibiting effects of GA on the secretion of inflammatory factors in ALI. The PI3K/AKT/mTOR pathway was associated with GA-induced autophagy under ALI induced by LPS. In conclusion, this study indicated that GA inhibited the production of inflammatory factors in LPS-induced ALI by regulating the PI3K/AKT/mTOR pathway related autophagy, which may provide a novel therapeutic perspective of GA in ameliorating ALI.