[Role of p38 Mitogen-activated Protein Kinase Signaling Pathway in the Hippocampal Neurons Autophagy of Rats with Sepsis].

OBJECTIVE: To investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling pathway in autophagy of neurons in hippocampus of sepsis rats. METHODS: A sepsis model was established by cecal ligation and puncture (CLP). SD rats were randomly divided into sham-operated group (sham group), model group (CLP group), vehicle-treated group (CLP+Veh group) and inhibitor-treated group (CLP+SB203580 group), and each group was divided into 3, 6, 12, 24 and 48 h subgroups. CLP+Veh group and CLP+SB203580 group were injected with 1% DMSO 5 µL and 0.1 mmol/L SB203580 5 µL respectively in the lateral ventricle, and CLP was established 30 min after injection. The sham group only turned over the cecum and closed the abdomen without other treatments. The vital signs of rats were monitored, including mean arterial pressure (MAP) and heart rate (HR). Neurobehavioral score was used to investigate the brain injury in rats. Histopathological changes in hippocampus of rats were observed by HE staining. The process of neuronal autophagy in hippocampal of rats was observed under transmission electron microscope (TEM). Western blot assay was performed to detect the expression of microtubule associated protein 1 light chain 3 (LC3)Ⅱ, LC3Ⅰ, selective autophagy adaptor protein p62/sequestosome-1 (p62/SQSTM1), MAPK-activated protein kinase 2 (MK-2) and phosphorylation MK-2 (p-MK-2) in the hippocampus. The expressions of LC3 and p62/SQSTM1 in hippocampal neurons of rats were observed by immunofluorescence. RESULTS: At different time points, MAP of CLP group was lower than sham group, while HR was higher than sham group, the change was most obvious at 12 h after molding; the neurobehavioral score of CLP group was the lowest; the histopathological changes in the hippocampus were obvious; and many autophagy vacuoles were observed under transmission electron microscope; compared with CLP group, the neurobehavioral score of CLP+SB203580 group increased; the pathological changes in the hippocampus improved; the inclusions in autophagy vacuoles were degraded under transmission electron microscopy; Western blot results showed:compared with sham group, expression of-LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 increased, and p62/SQSTM1 decreased in hippocampal tissue of CLP group in rat, the former reaches its peak at 12 h, the latter bottomed out at 12 h. Compared with the other groups, at 12 h of modeling, the expression of LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 was further increased, the expression of p62/SQSTM1 decreased further in hippocampal tissue of CLP+SB203580 group in rat (P < 0.05); immunofluorescence observation showed that localization and expression of LC3 and p62/SQSTM1 in NeuN were consistent with Western blot. CONCLUSION: Inhibition of p38 MAPK signaling pathway in sepsis rats can further activate autophagy and protect neurons in the hippocampus.

SIRS, SOFA, qSOFA, and NEWS in the diagnosis of sepsis and prediction of adverse outcomes: a systematic review and meta-analysis.

BACKGROUND: We compared Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), Quick Sepsis-related Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) for sepsis diagnosis and adverse outcomes prediction. METHODS: Clinical studies that used SIRS, SOFA, qSOFA, and NEWS for sepsis diagnosis and prognosis assessment were included. Data were extracted, and meta-analysis was performed for outcome measures, including sepsis diagnosis, in-hospital mortality, 7/10/14-day mortality, 28/30-day mortality, and ICU admission. RESULTS: Fifty-seven included studies showed good overall quality. Regarding sepsis prediction, SIRS demonstrated high sensitivity (0.85) but low specificity (0.41), qSOFA showed low sensitivity (0.42) but high specificity (0.98), and NEWS exhibited high sensitivity (0.71) and specificity (0.85). For predicting in-hospital mortality, SOFA demonstrated the highest sensitivity (0.89) and specificity (0.69). In terms of predicting 7/10/14-day mortality, SIRS exhibited high sensitivity (0.87), while qSOFA had high specificity (0.75). For predicting 28/30-day mortality, SOFA showed high sensitivity (0.97) but low specificity (0.14), whereas qSOFA displayed low sensitivity (0.41) but high specificity (0.88). CONCLUSIONS: NEWS independently demonstrates good diagnostic capability for sepsis, especially in high-income countries. SOFA emerges as the optimal choice for predicting in-hospital mortality and can be employed as a screening tool for 28/30-day mortality in low-income countries.

Regulation of hippocampal neuronal apoptosis and autophagy in mice with sepsis-associated encephalopathy by immunity-related GTPase M1.

AIMS: Sepsis-associated encephalopathy (SAE) is a common complication of severe sepsis. Our goal was to investigate the role of immunity-related GTPase M1 (IRGM1) in SAE and its underlying mechanism. METHODS: A mouse sepsis model was established by cecal ligation and perforation. SAE was diagnosed by behavior, electroencephalography, and somatosensory evoked potentials. Wild-type mice with SAE were treated with SB203580 to block the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We assessed hippocampal histological changes and the expression of IRGM1, interferon-γ (IFN-γ), and p38 MAPK signaling pathway-related proteins. RESULTS: Immunity-related GTPase M1 and IFN-γ levels increased in the hippocampus, with apoptosis, autophagy, and the p38 MAPK signaling pathway activated in neurons. Administration of SB203580 to mice with SAE reduced apoptosis and autophagy. Relative to wild-type mice with SAE, the general condition of Irgm1-/- mice with SAE was worsened, the p38 MAPK signaling pathway was inhibited, and neuronal apoptosis and autophagy were reduced. The absence of IRGM1 exacerbated SAE, with higher p38 MAPK signaling pathway activity and increased apoptosis and autophagy. CONCLUSIONS: During SAE, IRGM1 can at least partially regulate apoptosis and autophagy in hippocampal neurons through the p38 MAPK signaling pathway.