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Background/Aim. We aimed to identify the differentially expressing metabolites (DEMs) in the muscles of the mouse model of sepsis-induced acquired weakness (sepsis-AW) using liquid chromatography-mass spectrometry (LC-MS). Materials and Methods. Sepsis by cecal ligation puncture (CLP) with lower limb immobilization was used to produce a sepsis-AW model. After this, the grip strength of the C57BL/6 male mice was investigated. The transmission electron microscopy was utilized to determine the pathological model. LC-MS was used to detect the metabolic profiles within the mouse muscles. Additionally, a statistically diversified analysis was carried out. Results. Compared to the sepsis group, 30 DEMs, including 17 upregulated and 13 down-regulated metabolites, were found in the sepsis-AW group. The enriched metabolic pathways including purine metabolism, valine/leucine/isoleucine biosynthesis, cGMP-PKG pathway, mTOR pathway, FoxO pathway, and PI3K-Akt pathway were found to differ between the two groups. The targeted metabolomics analysis explored significant differences between four amino acid metabolites (leucine, cysteine, tyrosine, and serine) and two energy metabolites (AMP and cAMP) in the muscles of the sepsis-AW experimental model group, which was comparable to the sepsis group. Conclusion. The present work identified DEMs and metabolism-related pathways within the muscles of the sepsis-AW mice, which offered valuable experimental data for diagnosis and identification of the pathogenic mechanism underlying sepsis-AW. [ABSTRACT FROM AUTHOR]

Background. Sepsis-associated encephalopathy (SAE) is a transient and reversible brain dysfunction, that occurs when the source of sepsis is located outside of the central nervous system; SAE affects nearly 30% of septic patients at admission and is a risk factor for mortality. In our study, we sought to determine whether metabolite changes in plasma could be a potential biomarker for the early diagnosis and/or the prediction of the prognosis of sepsis. Method. A total of 31 SAE patients and 28 healthy controls matched by age, gender, and body mass index (BMI) participated in our study. SAE patients were divided into four groups according to the Glasgow Coma Score (GCS). Plasma samples were collected and used to detect metabolism changes by gas chromatography-mass spectrometry (GC-MS). Analysis of variance was used to determine which metabolites significantly differed between the control and SAE groups. Results. We identified a total of 63 metabolites that showed significant differences among the SAE and control groups. In particular, the 4 common metabolites in the four groups were 4-hydroxyphenylacetic acid; carbostyril, 3-ethyl-4,7-dimethoxy (35.8%); malic acid peak 1; and oxalic acid. The concentration of 4-hydroxyphenylacetic acid in sepsis patients decreased with a decrease of the GCS. Conclusions. According to recent research on SAE, metabolic disturbances in tissue and cells may be the main pathophysiology of this condition. In our study, we found a correlation between the concentration of 4-hydroxyphenylacetic acid and the severity of consciousness disorders. We suggest that 4-hydroxyphenylacetic acid may be a potential biomarker for SAE and useful in predicting patient prognosis. [ABSTRACT FROM AUTHOR]

Background: Sepsis is newly defined as life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality rate and limited effective treatments. The role of interleukin 36α (IL-36α) in host response during sepsis remains unknown.Methods: An experimental sepsis model of cecal ligation and puncture was established to investigate the effects of IL-36α on host response to sepsis.Results: IL-36α production was significantly up-regulated during sepsis. IL-36α treatment reduced the mortality rate in mice with severe sepsis by cecal ligation and puncture. IL-36α-treated mice had more efficient bacterial clearance, inhibited tissue inflammation, improved organ injury, and reduced immune cell apoptosis. The therapeutic implication of these observations was also highlighted by the finding that specific blockade of IL-36α led to an increased mortality rate in mice with nonsevere sepsis. Furthermore, we found that IL-36α enhanced bacterial phagocytosis and killing by macrophages, thereby allowing local and systemic bacterial clearance. Importantly, macrophage depletion before the onset of sepsis eliminated IL-36α-mediated protection against sepsis.Conclusions: Our results demonstrate that IL-36α plays an important role in the host defense response to sepsis and suggest a potential therapeutic role for IL-36α in sepsis. [ABSTRACT FROM AUTHOR]

Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn). Although the expression and function of Metrnl, including neurotrophic, immunomodulatory, and insulin resistance functions in different tissues have been extensively studied, its role in sepsis has remained largely limited. The present work analyzed the levels of Metrnl and cytokines in the circulation, such as tumor necrosis factor (TNF-α), interleukin (IL-1)β, IL-6, IL-8, together with IL-10 among septic adult patients. Clinical information was obtained from such patients, including sofa score, procalcitonin(PCT)count, and C-reactive count (CRP) within 24 h when entering the intensive care unit (ICU). We constructed a sepsis model in Metrnl-deficient or normal wild-type mice using cecal ligation and perforation to study its functions in bacterial burden, survival, cytokine/chemokine generation, peritoneal lavage fluid neutrophils, macrophage and lymphocyte recruitment, and Treg/Th17 immune cell balance after CLP-induced sepsis. The expression of Metrnl was remarkably elevated in the early phase of sepsis clinically. Its serum content in patients dying of sepsis slightly decreased relative to that in survivors. Furthermore, the concentration of Metrnl in septic cases when entering the ICU independently predicted the 28-day mortality. For septic patients who had low serum Metrnl content (≤ 274.40 pg/mL), the death risk increased by 2.3 folds relative to those who had a high serum content. It is reported that Metrnl is probably insufficient among patients dying of sepsis. Additionally, the content of Metrnl in the serum of septic patients when entering the ICU is markedly and negatively related to the levels of TNF-α, IL-1β, IL-6, IL-8, IL-17, PCT, and Sofa score. Collectively, Metrnl could be a potential therapeutic target for sepsis. A low-lethality non-severe sepsis (NSS) model was constructed, which suggested that Metrnl insufficiency elevated the death rate and reduced bacterial clearance during sepsis. For Metrnl-deficient mice, impaired sepsis immunity defense might be related to decreased macrophage recruitment and Treg/Th17 lymphocyte imbalance. Recombinant Metrnl administered to Metrnl-deficient mice abolished the immunity defense impairment following NSS while protecting the high-lethality severe sepsis (SS) model in wild-type (WT) mice. In addition, Metrnl-induced sepsis prevention was intricately associated with the increased recruitment of peritoneal macrophages and modulation of the Treg/TH17 immune cell balance. Furthermore, CCL3 exposure in Metrnl-deficient mice reduced peritoneal bacterial loads while improving survival during sepsis partially by promoting the recruitment of peritoneal macrophages. Furthermore, Metrnl regulated the polarization of M1 macrophages through the ROS signaling pathway and promoted macrophage phagocytosis, thereby killing Escherichia coli. The present proof-of-concept work suggests that Metrnl-mediated recruitment of macrophages significantly affects sepsis defense in the host and modulates the Treg/Th17 immune cell balance. Findings in this work shed more light on the development of host-directed treatments that can be used to manipulate host immunity to treat sepsis. [ABSTRACT FROM AUTHOR]

Fractalkine, CX3CL1, is involved in the directional movement of chemokine cells, immune response, inflammatory response, tissue repair, and other processes. However, its role in sepsis is not well known. We measured circulating Fractalkine in adult patients with sepsis. Effects of Fractalkine on the survival, inflammation, tissue injury, and bacterial clearance were assessed using the WT or CX3CL−/− murine model of cecal ligation and puncture (CLP)-induced sepsis. Serum Fractalkine concentrations were significantly elevated in adult patients with sepsis compared to healthy adults. Increased Fractalkine correlated positively with the number of blood leukocytes and the level of inflammatory cytokines, including IL-6, IL-1β, IL-17A, IFN-γ, and TNF-α, and correlated negatively with IL-10 in clinical sepsis. Recombinant Fractalkine impaired survival whereas Fractalkine gene knockout or anti-Fractalkine antibody improved survival in the murine model of CLP-induced sepsis. Fractalkine administration increased inflammatory response, evident by higher levels of cytokines (TNF-α, IL-1β, IL-17A, IFN-γ, and IL-6 but not IL-10), and tissue damage (lung, liver, and kidney) in CLP-induced sepsis. Fractalkine reduced bacterial clearance in CLP-induced polymicrobial sepsis by reducing macrophage or neutrophil phagocytosis and intracellular elimination of E. coli. Fractalkine aggravates sepsis by increasing inflammation and decreasing bacterial clearance, and is a potential tool for anti-sepsis therapy. • FKN release occurred in clinical sepsis. Elevated FKN has a potential pro-inflammatory effect in in clinical sepsis. • FKN exacerbated experimental sepsis by increasing inflammatory responses and reducing the bacterial removal. • FKN weakened the ability of macrophages and neutrophils to engulf and eliminate E. coli. [ABSTRACT FROM AUTHOR]