Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

COMPREHENSIVE THERAPEUTIC EFFICACY ANALYSIS OF INTRAVENOUS IMMUNOGLOBULIN IN TREATING SEPSIS-INDUCED COAGULOPATHY: A SINGLE-CENTER, RETROSPECTIVE OBSERVATIONAL STUDY.

ABSTRACT: Objective : The aim of the study is to investigate the efficacy of intravenous immunoglobulin (IVIg) in treating sepsis-induced coagulopathy ( SIC ). Methods : A retrospective controlled analysis was conducted on 230 patients with SIC at Ganzhou People's Hospital from January 2016 to December 2022. All patients were screened using propensity score matching and treated according to the SSC2016 guidelines. Compared with the control group (n = 115), patients in the test group (n = 115) received IVIg (200 mg/kg.d) for 3 consecutive days after admission. The rating scales, coagulation function, survival, and treatment duration were evaluated. Results : On day 3 of treatment, both groups exhibited reduced platelet and thromboelastogram (TEG) maximum amplitude (MA) levels, with the control group showing a more significant decrease ( P < 0.05). By the fifth day, these levels had recovered in both groups. However, the test group experienced a significant increase by day 7 ( P < 0.05). Coagulation factors II and X began to increase on day 3, and normalization was significantly faster in the test group on day 5 ( P < 0.05). The levels of prothrombin time, international normalized ratio, activated partial thromboplastin time, d -dimer, fibrinogen, fibrin degradation products, TEG-R, and TEG-K exhibited a notable decline on day 3 and demonstrated significantly faster recovery on day 5 in the test group ( P < 0.05). In addition, both groups showed a reduction in Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, disseminated intravascular coagulation, and lactate (LAC) levels on day 3, but the test group's scores decreased significantly more by day 7 ( P < 0.05). Within the test group, white blood cell count, C-reactive protein, procalcitonin, IL-6, and Tmax levels were lower ( P < 0.05). Furthermore, the test group demonstrated shorter duration for intensive care unit stay, mechanical ventilation, and continuous renal replacement therapy ( P < 0.05). No significant differences were observed in the duration of fever or vasoactive drug use between the groups. However, the log-rank method indicated a higher 28-day survival rate in the test group ( P < 0.05). Conclusion : IVIg can successfully increase platelet count and coagulation factors, correct coagulation disorders, enhance organ function, and reduce 28-day mortality in patients with SIC .

Organism type of infection is associated with prognosis in sepsis: an analysis from the MIMIC-IV database.

BACKGROUND: Sepsis has a high mortality rate, which is expensive to treat, and is a major drain on healthcare resources; it seriously impacts the quality of human life. The clinical features of positive or non-positive blood cultures have been reported, but the clinical features of sepsis with different microbial infections and how they contribute to clinical outcomes have not been adequately described. METHODS: We extracted clinical data of septic patients with a single pathogen from the online Medical Information Mart for Intensive Care(MIMIC)-IV database. Based on microbial cultures, patients were classified into Gram-negative, Gram-positive, and fungal groups. Then, we analyzed the clinical characteristics of sepsis patients with Gram-negative, Gram-positive, and fungal infections. The primary outcome was 28-day mortality. The secondary outcomes were in-hospital mortality, the length of hospital stay, the length of ICU stay, and the ventilation duration. In addition, Kaplan-Meier analysis was used for the 28-day cumulative survival rate of patients with sepsis. Finally, we performed further univariate and multivariate regression analyses for 28-day mortality and created a nomogram for predicting 28-day mortality. RESULTS: The analysis showed that bloodstream infections showed a statistically significant difference in survival between Gram-positive and fungal organisms; drug resistance only reached statistical significance for Gram-positive bacteria. Through univariate and multivariate analysis, it was found that both the Gram-negative bacteria and fungi were independent risk factors for the short-term prognosis of sepsis patients. The multivariate regression model showed good discrimination, with a C-index of 0.788. We developed and validated a nomogram for the individualized prediction of 28-day mortality in patients with sepsis. Application of the nomogram still gave good calibration. CONCLUSIONS: Organism type of infection is associated with mortality of sepsis, and early identification of the microbiological type of a patient with sepsis will provide an understanding of the patient's condition and guide treatment.

Sacubitril/valsartan alleviates sepsis-induced acute lung injury via inhibiting GSDMD-dependent macrophage pyroptosis in mice.

Sepsis-induced acute lung injury (ALI) is a life-threatening disorder with intricate pathogenesis. Macrophage pyroptosis reportedly plays a vital role in ALI. Although it has been established that angiotensin receptor blockers (ARBs) can reduce sepsis-induced organ injury, the efficacy of sacubitril/valsartan (SV) for sepsis has been largely understudied. Here, we aimed to investigate the role of SV in sepsis-induced ALI. Caecal ligation and puncture (CLP) were used to induce polymicrobial sepsis and related ALI. The therapeutic effects of SV in CLP mice were subsequently assessed. Gasdermin D (GSDMD)-/- mice were used to validate the signalling pathways affected by SV. In vitro, mouse bone marrow-derived macrophages (BMDMs) and Raw264.7 cells were treated with SV following exposure to lipopolysaccharide and adenosine triphosphate. Finally, the serum obtained from 42 septic patients was used for biochemical analysis. Compared to the other ARBs, SV yielded more pronounced anti-inflammatory effects on macrophages. In vivo, SV decreased mortality rates, significantly reduced lung damage and prevented the inflammatory response in CLP mice. In addition, SV suppressed GSDMD-mediated macrophage pyroptosis in mice. In BMDMs and Raw264.7 cells, the anti-inflammatory and anti-pyroptosis properties of SV were verified. SV treatment effectively inhibited NLRP3 inflammasome activation and prevented macrophage pyroptosis in a GSDMD-dependent manner. Furthermore, we found that septic individuals had considerably higher serum angiotensin II levels. Overall, we found that SV might prevent ALI in CLP mice by inhibiting GSDMD-mediated pyroptosis of macrophages. Thus, SV might be a viable drug for sepsis-induced ALI.

Macrophagic Extracellular Vesicle CXCL2 Recruits and Activates the Neutrophil CXCR2/PKC/NOX4 Axis in Sepsis.

Sepsis is a life-threatening organ dysfunction caused by a dysfunctional host response to infection. Neutrophils play a protective role by releasing antibacterial proteins or by phagocytizing bacteria. However, excess neutrophils can induce tissue damage. Recently, a novel intercellular communication pathway involving extracellular vesicles (EVs) has garnered considerable attention. However, whether EVs secreted by macrophages mediate neutrophil recruitment to infected sites has yet to be studied. In this study, we assessed the chemotactic effect of EVs isolated from mouse Raw264.7 macrophages on mouse neutrophils and found that CXCL2 was highly expressed in these EVs. By regulating CXCL2 in Raw264.7 macrophages, we found that CXCL2 on macrophage EVs recruited neutrophils in vitro and in vivo. The CXCL2 EVs activated the CXCR2/PKC/NOX4 pathway and induced tissue damage. This study provides information regarding the mechanisms underlying neutrophil recruitment to tissues and proposes innovative strategies and targets for the treatment of sepsis.

Chronic remote ischemic preconditioning-induced increase of circulating hSDF-1α level and its relation with reduction of blood pressure and protection endothelial function in hypertension.

Although previous data showed that remote ischemic preconditioning (RIPC) has beneficial effect on blood pressure (BP) reduction, the efficacy of RIPC-induced decline in BP and the favorable humoral factors in hypertension is elusive. This present study is performed to evaluate whether RIPC reduces BP, improves microvascular endothelial function and increases circulating hSDF-1α generation in hypertension. Fifteen hypertensive patients received 3 periods of 5-min inflation/deflation of the forearm with a cuff on the upper arm daily for 30 days. Clinic and 24-h ambulatory blood pressure monitoring (ABPM) were examined before and after the end of this procedure. Microvascular endothelial function was measured by finger reactive hyperemia index (RHI) using the Endo-PAT 2000 device. The circulating hSDF-1α level was tested by ELISA. RIPC significantly decreased systolic BP (139.13 ± 6.68 versus 131.45 ± 7.45 mmHg) and diastolic BP (89.67 ± 4.98 versus 83.83 ± 6.65 mmHg), meanwhile 24-h ambulatory systolic and diastolic BP dropped from 136.33 ± 9.10 mmHg to 131.33 ± 7.12 mmHg and 87.60 ± 6.22 mmHg to 82.47 ± 4.47 mmHg respectively. RHI was improved (1.95 ± 0.34 versus 2.47 ± 0.44). Plasma hSDF-1α level was markedly increased after RIPC (1585.86 ± 167.17 versus 1719.54 ± 211.17 pg/ml). The increase in hSDF-1α level was associated with the fall in clinic and 24-h ABPM and rise in RHI. The present data suggests that RIPC may be a novel alternative or complementary intervention means to treat hypertension and protect endothelial function.