Sepsis presents as a severe infectious disease frequently documented in clinical settings. Characterized by its systemic inflammatory response syndrome, sepsis has the potential to trigger multi-organ dysfunction and can escalate to becoming life-threatening. A common fallout from sepsis is acute lung injury (ALI), which often progresses to acute respiratory distress syndrome (ARDS). Macrophages, due to their significant role in the immune system, are receiving increased attention in clinical studies. Macrophage polarization is a process that hinges on an intricate regulatory network influenced by a myriad of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. In this review, our primary focus is on the classically activated macrophages (M1-like) and alternatively activated macrophages (M2-like) as the two paramount phenotypes instrumental in sepsis’ host immune response. An imbalance between M1-like and M2-like macrophages can precipitate the onset and exacerbate the progression of sepsis. This review provides a comprehensive understanding of the interplay between macrophage polarization and sepsis-induced acute lung injury (SALI) and elaborates on the intervention strategy that centers around the crucial process of macrophage polarization.

In 2016, the SOFA score was proposed as the main evaluation system for diagnosis in the definition of sepsis 3.0, and the SOFA score has become a new research focus in sepsis. Some people are skeptical about diagnosing sepsis using the SOFA score. Experts and scholars from different regions have proposed different, modified versions of SOFA score to make up for the related problems with the use of the SOFA score in the diagnosis of sepsis. While synthesizing the different improved versions of SOFA proposed by experts and scholars in various regions, this paper also summarizes the relevant definitions of sepsis put forward in recent years to build a clear, improved application framework of SOFA score. In addition, the comparison between machine learning and SOFA scores related to sepsis is described and discussed in the article. Taken together, by summarizing the application of the improved SOFA score proposed in recent years in the related definition of sepsis, we believe that the SOFA score is still an effective means of diagnosing sepsis, but in the process of the continuous refinement and development of sepsis in the future, the SOFA score needs to be further refined and improved to provide more accurate coping strategies for different patient populations or application directions regarding sepsis. Against the big data background, machine learning has immeasurable value and significance, but its future applications should add more humanistic references and assistance.

Purpose: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections have been increasingly reported worldwide. We aimed to identify the risk factors for nosocomial CRKP infections and assess the clinical outcomes. Patients and Methods: We conducted a case-control study with data collected from January 2016 to December 2018 in China. Controls were selected at a ratio of 1:1 from patients with nosocomial carbapenem-susceptible Klebsiella pneumonia (CSKP) infections. Risk factors for nosocomial CRKP infections and clinical outcomes were assessed with univariate and multivariate analyses. Results: A total of one hundred forty-two patients with CRKP infections and one hundred forty-two patients with CSKP infections were enrolled in this study. Multivariate analysis showed that exposure to antibiotics within 3 months prior to admission (odds ratio OR, 2.585; 95% confidence interval [CI], 1.425– 4.691; P=0.002), exposure to carbapenems (OR, 2.532; 95% CI, 1.376– 4.660; P=0.003), exposure to fluoroquinolones (OR, 3.309; 95% CI, 1.326– 8.257; P=0.010), and the presence of a nasogastric tube (OR, 2.796; 95% CI, 1.369– 5.712; P=0.005) were independent risk factors for CRKP infections. The 30-day mortality rate in the CRKP group was 19.7%, while the in-hospital mortality rate was 28.9%. In the CRKP group, a higher creatinine level (OR, 1.009; 95% CI, 1.002– 1.016; P = 0.013), being in shock at the time of a positive culture (OR, 4.454; 95% CI, 1.374– 14.443; P = 0.013), and co-infection with other resistant bacteria (OR, 4.799; 95% CI, 1.229– 18.740; P = 0.024) were independent predictors of in-hospital mortality in patients with CRKP infections. Kaplan–Meier curves showed that the CRKP group had a shorter survival time than the CSKP group. Conclusion: Nosocomial CRKP infection was associated with exposure to carbapenems and fluoroquinolones within 3 months prior to hospitalization and the presence of a nasogastric tube. Patients infected with CRKP had higher 30-day and in-hospital mortality rates. A higher creatinine level, shock and co-infection with other resistant bacteria were independent predictors of in-hospital mortality in patients with CRKP infections.

(1) Background: Both sepsis acute lung injury (SALI) and non-small-cell lung cancer (NSCLC) are life-threatening diseases caused by immune response disorders and inflammation, but the underlining linking mechanisms are still not clear. This study aimed to detect the shared gene signature and potential molecular process between SALI and NSCLC. (2) Methods: RNA sequences and patient information on sepsis and NSCLC were acquired from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was used to build a co-expression network associated with sepsis and NSCLC. Protein–protein interaction (PPI) analysis of shared genes was intuitively performed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The involvement of EZH2 in the tumor immune microenvironment (TIME) and sepsis immune microenvironment (IME) was assessed by R software. Western blot, flow cytometry, and other in vitro assays were performed to further confirm the function and mechanism of EZH2 in NSCLC and SALI. (3) Results: WGCNA recognized three major modules for sepsis and two major modules for NSCLC, and there were seven shared genes identified for the two diseases. Additionally, the hub gene EZH2 was screened out. It was shown that EZH2 was closely related to the IME in the two diseases. In the validation assay, our data showed that EZH2 was expressed at a higher level in peripheral blood mononuclear cells (PBMCs) of septic patients than those of healthy donors (HDs), and EZH2 was also expressed at a higher level in lipopolysaccharide (LPS)-induced PBMCs and non-small cell lung cancer (A549) cells. EZH2 inhibitor (GSK343) downregulated the proliferation ability of A549 cells in a concentration-dependent manner, parallel with the decreased expression level of PD-L1. Similarly, GSK343 inhibited PD-L1 protein expression and downregulated the level of proinflammatory factors in LPS-induced PBMCs. In the co-culture system of PBMCs and human type II alveolar epithelial cells (ATIIs), the addition of GSK343 to PBMCs significantly downregulated the apoptosis of LPS-induced ATIIs. (4) Conclusions: This study illustrated that EZH2 inhibition could ameliorate A549 cell proliferation and LPS-induced ATII apoptosis in parallel with downregulation of PD-L1 protein expression, which provided new insights into molecular signaling networks involved in the pathogenetics of SALI and NSCLC.

Introduction: Sepsis-induced acute lung injury (SALI) is a critical illness with high mortality, and pulmonary microvascular endothelial cells (PMECs) barrier dysfunction is a well-documented pathogenesis of SALI. The current study aimed to investigate the underlying mechanism of Reduning (RDN) in the treatment of SALI.Methods: Network pharmacology and molecular dynamics simulation (MDS) were used to confirm the possibility of key active components of RDN combining with AKT1. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to investigate the effect of RDN in vivo. Immunofluorescence (IF) and co-immunoprecipitation (CoIP) were used to investigate the relationship between mammalian target of rapamycin (mTOR) and Bax in PMECs. ELISA was used to test the level of TNF-α. Flow cytometry was used to detect apoptosis. JC-1 and electron microscopy were used to evaluate mitochondrial damage. The results showed that RDN likely alleviated SALI via targeting AKT1.Results: In vivo, RDN could evidently decrease the expression levels of apoptosis-related proteins, alleviate mitochondrial damage, reduce lung tissue edema, down-regulate the level of TNF-α in the serum, and improve the mortality of sepsis in mice. In vitro, RDN had a significant effect on reducing the level of apoptosis-related proteins and cell apoptosis rate, while also mitigated mitochondrial damage. Furthermore, RDN could effectively lower the level of Bax in PMECs and increase the level of mTOR both in vivo and in vitro. Notably, mTOR has the ability to directly bind to Bax, and RDN can enhance this binding capability.Discussion: RDN could attenuate SALI through reducing apoptosis of PMECs, which is a promising therapeutic strategy for SALI prevention.

Purpose: AKT1 is an important target in sepsis acute lung injury (SALI). The current study was aim to construct a high-throughput screening (HTS) system based on the ChemDiv database (https://www.chemdiv.com/complete-list/) and use the system to screen for AKT1 activation agents, which may provide clues for the research and development of new drugs to treat SALI.Methods: Based on the existing X-ray structure of AKT1 and known AKT activators, a large-scale virtual HTS was performed on the ChemDiv database of small molecules by the cascade docking method and demonstrated both accuracy and screening efficiency. Molecular docking and molecular dynamics simulations were used to assess the stability and binding characteristics of the identified small-molecule compounds. The protective effect of the new highly selective compound on SALI were verified both in vitro and in vivo experiments.Results: The small-molecule compound 7460-0250 was screened out as a specific activator of AKT1. Molecular validation experiments confirmed that compound 7460-0250 specifically promoted the phosphorylation of AKT1 and down-regulated the LPS-induced apoptosis of human umbilical vein endothelial cells (HUVECs) by activating the AKT-mTOR pathway. Up-regulated mTOR was detected to directly interact with Bax to reduce apoptosis. In vivo, compound 7460-0250 could improved survival rate and alleviated lung injury of sepsis mice induced by cecum ligation and puncture (CLP), parallel with the activation of the AKT-mTOR pathway.Conclusion: Small-molecule compound 7460-0250 was successfully screened and confirmed as a highly selective AKT1 activator, which is a critical target in the development of new therapeutics for SALI.