Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress and cell death. The metabolism of iron, lipids, and amino acids and multiple signalling pathways precisely regulate the process of ferroptosis. Emerging evidence has demonstrated that ferroptosis participates in the occurrence and progression of various pathological conditions and diseases, such as infections, neurodegeneration, tissue ischaemia-reperfusion injury and immune diseases. Recent studies have also indicated that ferroptosis plays a critical role in the pathogenesis of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary infection and asthma. Herein, we summarize the latest knowledge on the regulatory mechanism of ferroptosis and its association with iron, lipid and amino acid metabolism as well as several signalling pathways. Furthermore, we review the contribution of ferroptosis to the pathogenesis of lung diseases and discuss ferroptosis as a novel therapeutic target for various lung diseases.

Exosomes derived from human mesenchymal stem cells (hMSCs) have the capacity to regulate various biological events associated with sepsis‐induced acute respiratory distress syndrome (ARDS), including cellular immunometabolism, the production of proinflammatory cytokines, allowing them to exert therapeutic effects. However, little is known about which type of hMSC‐derived exosomes (hMSC‐exo) is more effective and suitable for the treatment of sepsis‐induced ARDS. The purpose of this study is to compare the efficacy of hMSC‐derived exosomes from human adipose tissue (hADMSC‐exo), human bone marrow (hBMMSC‐exo), and human umbilical cord (hUCMSC‐exo) in the treatment of sepsis‐induced ARDS. We cocultured lipopolysaccharide‐ (LPS‐) stimulated RAW264.7 macrophage cells with the three kinds of hMSCs and found that all hMSCs reduced the glycolysis level and the content of lactic acid in macrophages. Accordingly, the expression of proinflammatory cytokines also decreased. Notably, the protective effects of hMSCs from adipose tissue were more obvious than those of bone marrow and umbilical cord hMSCs. However, this protective effect was eliminated when an exosome inhibitor, GW4869, was added. Subsequently, we extracted and cocultured hMSC‐derived exosomes with LPS‐stimulated RAW264.7 cells and found that all three kinds of exosomes exerted a similar protective effect as their parental cells, with exosomes from adipose hMSCs showing the strongest protective effect. Finally, an experimental sepsis model in mice was established, and we found that all three types of hMSCs have obvious lung‐protective effects, in reducing lung injury scores, lactic acid, and proinflammatory cytokine levels in the lung tissues and decreasing the total protein content and inflammatory cell count in the bronchoalveolar lavage fluid (BALF), and also can attenuate the systemic inflammatory response and improve the survival rate of mice. Intravenous injection of three types of hMSC‐exo, in particular those derived from adipose hADMSCs, also showed lung‐protective effects in mice. These findings revealed that exosomes derived from different sources of hMSCs can effectively downregulate sepsis‐induced glycolysis and inflammation in macrophages, ameliorate the lung pathological damage, and improve the survival rate of mice with sepsis. It is worth noting that the protective effect of hADMSC‐exo is better than that of hBMMSC‐exo and hUCMSC‐exo.

Acute respiratory distress syndrome (ARDS) is an uncontrollable, progressive pulmonary inflammatory disease, and as a common clinical critical disease, there is no effective treatment available. Electroacupuncture (EA) therapy is a type of traditional Chinese medicine physiotherapy that can alleviate the inflammatory response. However, the potential mechanism of EA in the treatment of ARDS is not yet clear. Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation. Recently, emerging evidence has shown that ferroptosis is closely related to the occurrence and development of ARDS caused by various pathological factors. Here, we further investigated whether EA-mediated inhibition of ferroptosis in lung tissue could attenuate lipopolysaccharide (LPS)-induced ARDS and explored its underlying mechanisms. In this study, mice were administered LPS intraperitoneally to establish a model of LPS-induced ARDS. We found that EA stimulation could not only reduce the exudation of inflammatory cells and proteins in the alveolar lumen but also significantly alleviate the pathological changes of lung tissue, inhibit the production of proinflammatory cytokines and improve the survival rate of mice. Concurrently, we also found that ferroptosis events occurred in the lung tissue of LPS-induced ARDS mice, manifested by elevated iron levels, ROS production and lipid peroxidation. Intriguingly, our results showed that EA stimulation at the Zusanli (ST36) acupoint activated α7 nicotinic acetylcholine receptor (α7nAchR) in lung tissue mainly through the sciatic nerve and cervical vagus nerve, thus exerting anti-ferroptosis and pulmonary protective effects. Additionally, these effects were eliminated by methyllycaconitine (MLA), a selective antagonist of α7nAchR. In vitro experiments, activation of α7nAchR protected alveolar epithelial cells from LPS-induced ferroptosis. Furthermore, our experiments showed that the pulmonary protective effects of EA stimulation were effectively reversed by erastin, a ferroptosis activator. Collectively, we demonstrated that EA stimulation could alleviate LPS-induced ARDS by activating α7nAchR to inhibit LPS-induced ferroptosis in alveolar epithelial cells. Targeting and regulating ferroptosis in alveolar epithelial cells may be a potential intervention approach for the treatment of LPS-induced ALI/ARDS in the future.

Ferroptosis is a novel form of programmed cell death which can exacerbate lung injury in septic acute respiratory distress syndrome (ARDS). Alveolar macrophages, crucial innate immune cells, play a pivotal role in the pathogenesis of ARDS. Ferritinophagy is a process of ferritin degradation mediated by nuclear receptor coactivator 4 (NCOA4) which releases large amounts of iron ions thus promoting ferroptosis. Recent evidence revealed that inhibiting macrophage ferroptosis can effectively attenuate pulmonary inflammatory injury. Melatonin (MT), an endogenous neurohormone, has antioxidant and anti-inflammatory effects and can reduce septic ARDS. However, it is not clear whether MT’s pulmonary protective effect is related to the inhibition of macrophage ferritinophagy. Our in vitro experiments demonstrated that MT decreased intracellular malondialdehyde (MDA), Fe²⁺, and lipid peroxidation levels, increased glutathione (GSH) levels and cell proliferation, and upregulated glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein levels in LPS-treated macrophages. Mechanistically, the antiferroptotic effect of MT on LPS-treated macrophages was significantly compromised by the overexpression of NCOA4. Our in vivo experiments revealed that MT alleviated the protein expression of NCOA4 and FTH1 in the alveolar macrophages of septic mice. Furthermore, MT improved lipid peroxidation and mitigated damage in alveolar macrophages and lung tissue, ultimately increasing the survival rates of septic mice. These findings indicate that MT can inhibit ferroptosis in an NCOA4-mediated ferritinophagy manner, thereby ameliorating septic ARDS.

Objective: Propofol-based sedation has been widely used for gastroscopy, but the risk of respiratory suppression in elderly patients should not be overlooked. Intravenous (IV) lidocaine during surgery can reduce the demand for propofol and the incidence of cardiopulmonary complications. We examined whether IV lidocaine reduces the dose of propofol and the occurrence of adverse events during gastroscopy in elderly patients. Methods: We conducted a prospective, single-center, double-blind randomized controlled trial in elderly patients aged ≥ 65 years with ASA I-II. Subjects were randomly assigned to the lidocaine group (Group L, n=70), who received IV 1.5 mg kg^{− 1} lidocaine followed by a continuous infusion of 4 mg kg^{− 1} h^{− 1} lidocaine, or the normal saline group (Group N, n=70), who received an equal volume of saline in the same way. Results: IV lidocaine reduced the total and maintenance propofol dose in Group L (p< 0.001), with no significant effect on the induction dose. The incidence of intraoperative hypoxia (p=0.035), emergency airway management events (p=0.005), duration of gastroscopy (p< 0.05), consciousness recovery time (p< 0.001), and postoperative pain (p=0.009) were all reduced in Group L. Patient (p=0.025) and gastroscopist (p=0.031) satisfaction was higher in Group L. Intraoperative hemodynamic parameters, the respiratory rate, the incidence of sedation-related events and anesthesiologist satisfaction were similar between the two groups. Conclusion: IV lidocaine can significantly reduce the amount of propofol, the incidence of hypoxia and postoperative pain during gastroscopy in elderly patients, with a higher patient and gastroscopist satisfaction.

Background: Mesenchymal stem cell-derived exosomes (MSC-exosomes) have been found to effectively improve the systemic inflammatory response caused by acute lung injury and acute respiratory distress syndrome (ALI/ARDS), regulate systemic immune disorders, and help injured cells repair. The purpose of this study was to take a holistic view of the current status and trends of MSC-exosomes research in ALI/ARDS. Methods: Bibliometrix, Citespace and VOSviewer software were used for bibliometric analysis of the data. We analysed the world trends, country distribution, institution contribution, most relevant journals and authors, research hotspots, and research hotspots related to Coronavirus Disease 2019 (COVID-19) based on the data collected. Results: China possessed the largest number of publications, while the USA had the highest H-index and the number of citations. Both China and the USA had a high influence in this research field. The largest number of publications in the field of MSC-exosomes and ALI/ARDS were mainly from the University of California system. Stem Cell Research & Therapy published the largest number of papers in this scope. The author with the greatest contribution was LEE JW, and ZHU YG published an article in Stem Cell with the highest local citation score. The most frequent keyword and the latest research hotspot were “NF-κB” and “Coronavirus Disease 2019”. Furthermore, our bibliometric analysis results demonstrated that MSC-exosomes intervention and treatment can effectively alleviate the inflammatory response caused by ALI/ARDS. Conclusion: Our bibliometric study suggested the USA and China have a strong influence in this field. COVID-19-induced ALI/ARDS had become a hot topic of research.