IL1RAP Exacerbates Sepsis-Induced Pulmonary and Spleen Injury Through Regulating CD4+ T Lymphocyte Differentiation.

BACKGROUND: Complex pathophysiological the specific mechanism of sepsis on CD4+ T-cell responses is less well understood. IL1 receptor accessory protein (IL1RAP) was found to be involved in activating host immune responses. METHOD: Cecum ligation and puncture (CLP) was utilized to build a mouse sepsis model. The experiment was randomly divided into four groups: Sham, CLP, CLP + shNC, and CLP + shIL1RAP group. RESULTS: qRT-PCR suggested mRNA levels of IL1RAP were decreased when IL1RAP was knocked down with the mRNA levels of IL-1ß, NF-κB, and p38 decreased. Histopathology showed severe pathological damage with alveolar integrity lost, red blood cells in the alveoli, massive inflammatory cell infiltration, and the alveolar wall was thickening in the CLP group. The inflammatory cytokine levels of TNF-α, IL-1ß, and IFN-γ were elevated in CLP mice by ELISA. The counts of CD4+ T cells were decreased in sepsis mice in peripheral blood, spleen, and BALF by flow cytometry. However, the above was blocked down when using shIL1RAP. Western blot suggested sh IL1RAP inhibited IL-1ß, NF-κB, and p38 protein expressions. CONCLUSIONS: We defined IL1RAP as a new target gene through NF-κB/MAPK pathways regulating CD4+ T lymphocyte differentiation mediated the progression of sepsis, which is potentially exploitable for immunotherapy.

Screening of Important Factors in the Early Sepsis Stage Based on the Evaluation of ssGSEA Algorithm and ceRNA Regulatory Network.

BACKGROUND: Sepsis is a dysregulated host response to pathogens. Delay in sepsis diagnosis has become a primary cause of patient death. This study determines some factors to prevent septic shock in its early stage, contributing to the early treatment of sepsis. METHODS: The sequencing data (RNA- and miRNA-sequencing) of patients with septic shock were obtained from the NCBI GEO database. After re-annotation, we obtained lncRNAs, miRNA, and mRNA information. Then, we evaluated the immune characteristics of the sample based on the ssGSEA algorithm. We used the WGCNA algorithm to obtain genes significantly related to immunity and screen for important related factors by constructing a ceRNA regulatory network. RESULT: After re-annotation, we obtained 1708 lncRNAs, 129 miRNAs, and 17 326 mRNAs. Also, through the ssGSEA algorithm, we obtained 5 important immune cells. Finally, we constructed a ceRNA regulation network associated with SS pathways. CONCLUSION: We identified 5 immune cells with significant changes in the early stage of septic shock. We also constructed a ceRNA network, which will help us explore the pathogenesis of septic shock.

Diallyl Disulfide (DADS) Ameliorates Intestinal Candida albicans Infection by Modulating the Gut microbiota and Metabolites and Providing Intestinal Protection in Mice.

Diallyl disulfide (DADS), a garlic extract also known as allicin, has been reported to have numerous biological activities, including anticancer, antifungal, and inflammation-inhibiting activities, among others. Although many studies have assessed whether DADS can treat Candida albicans infection in vitro, its in vivo function and the underlying mechanism are still not clear. Accumulated evidence has implicated the gut microbiota as an important factor in the colonization and invasion of C. albicans. Thus, this study aimed to identify the mechanism by which DADS ameliorates dextran sulfate (DSS)-induced intestinal C. albicans infection based on the systematic analysis of the gut microbiota and metabolomics in mice. Here, we determined the body weight, survival, colon length, histological score, and inflammatory cytokine levels in the serum and intestines of experimental mice. Fecal samples were collected for gut microbiota and metabolite analysis by 16S rRNA gene sequencing and LC-MS metabolomics, respectively. DADS significantly alleviated DSS-induced intestinal C. albicans infection and altered the gut microbial community structure and metabolic profile in the mice. The abundances of some pathogenic bacteria, such as Proteobacteria, Escherichia-Shigella, and Streptococcus, were notably decreased after treatment with DADS. In contrast, SCFA-producing bacteria, namely, Ruminiclostridium, Oscillibacter, and Ruminococcaceae_UCG-013, greatly increased in number. The perturbance of metabolites in infectious mice was improved by DADS, with increases in secondary bile acids, arachidonic acid, indoles and their derivatives, which were highly related to the multiple differentially altered metabolic pathways, namely, bile secretion, arachidonic acid metabolism, and tryptophan metabolism. This study indicated that DADS could modulate gut microbiota and metabolites and protect the gut barrier to alleviate DSS-induced intestinal C. albicans infection in mice. Moreover, this work might also provide novel insight into the treatment of C. albicans infection using DADS.

Antibiotics De-Escalation in the Treatment of Ventilator-Associated Pneumonia in Trauma Patients: A Retrospective Study on Propensity Score Matching Method.

BACKGROUND: Antimicrobial de-escalation refers to starting the antimicrobial treatment with broad-spectrum antibiotics, followed by narrowing the drug spectrum according to culture results. The present study evaluated the effect of de-escalation on ventilator-associated pneumonia (VAP) in trauma patients. METHODS: This retrospective study was conducted on trauma patients with VAP, who received de-escalation therapy (de-escalation group) or non-de-escalation therapy (non-de-escalation group). Propensity score matching method was used to balance the baseline characteristics between both groups. The 28-day mortality, length of hospitalization and Intensive Care Unit stay, and expense of antibiotics and hospitalization between both groups were compared. Multivariable analysis explored the factors that influenced the 28-day mortality and implementation of de-escalation. RESULTS: Among the 156 patients, 62 patients received de-escalation therapy and 94 patients received non-de-escalation therapy. No significant difference was observed in 28-day mortality between both groups (28.6% vs. 23.8%, P = 0.620). The duration of antibiotics treatment in the de-escalation group was shorter than that in the non-de-escalation group (11 [8-13] vs. 14 [8-19] days, P = 0.045). The expenses of antibiotics and hospitalization in de-escalation group were significantly lower than that in the non-de-escalation group (6430 ± 2730 vs. 7618 ± 2568 RMB Yuan, P = 0.043 and 19,173 ± 16,861 vs. 24,184 ± 12,039 RMB Yuan, P = 0.024, respectively). Multivariate analysis showed that high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, high injury severity score, multi-drug resistant (MDR) infection, and inappropriate initial antibiotics were associated with patients' 28-day mortality, while high APACHE II score, MDR infection and inappropriate initial antibiotics were independent factors that prevented the implementation of de-escalation. CONCLUSIONS: De-escalation strategy in the treatment of trauma patients with VAP could reduce the duration of antibiotics treatments and expense of hospitalization, without increasing the 28-day mortality and MDR infection.