Sevoflurane-induced inflammation development: involvement of cholinergic anti-inflammatory pathway.

Chronic inflammation plays an important role in the mechanisms underpinning the development of anesthesia-induced cognitive dysfunction. However, less is known about how anesthesia causes inflammation. One possibility is that the inflammation is related to alteration of the activity of the alpha 7 nicotinic acetylcholine receptor cholinergic anti-inflammatory pathway. This study analyzed the effect of sevoflurane administration on the cognitive function by using a novel object recognition test and Y-maze test, and on acetylcholinesterase activity and expression in hippocampal tissue by using an acetylcholinesterase assay kit and quantitative real-time PCR. This study also evaluated the effect of alpha 7 nicotinic acetylcholine receptor agonist PNU-282987 and antagonist methyllycaconitine on cognitive function and the level of hippocampal tumor necrosis factor-α in aged rats exposed to sevoflurane anesthesia. We found that 3% sevoflurane significantly impaired cognitive function and increased acetylcholinesterase activity by upregulating its expression in hippocampal tissue. Sevoflurane-induced impairment of cognitive function was significantly rescued by PNU-282987 but aggravated by methyllycaconitine. In addition to impairment of cognitive function, sevoflurane also significantly increased tumor necrosis factor-α level in plasma and hippocampal tissue. Similarly, this sevoflurane-induced change of tumor necrosis factor-α level in rats was antagonized by PNU-282987 but amplified by methyllycaconitine. In conclusion, our data show that the development of inflammation in sevoflurane-induced cognitive decline is associated with the downregulation of alpha 7 nicotinic acetylcholine receptor cholinergic anti-inflammatory pathway in aged rats.

Joint analysis of D-dimer, N-terminal pro b-type natriuretic peptide, and cardiac troponin I on predicting acute pulmonary embolism relapse and mortality.

Previous studies on the adverse events of acute pulmonary embolism (APE) were mostly limited to single marker, and short follow-up duration, from hospitalization to up to 30 days. We aimed to predict the long-term prognosis of patients with APE by joint assessment of D-dimer, N-Terminal Pro-Brain Natriuretic Peptide (NT-ProBNP), and troponin I (cTnI). Newly diagnosed patients of APE from January 2011 to December 2015 were recruited from three hospitals. Medical information of the patients was collected retrospectively by reviewing medical records. Adverse events (APE recurrence and all-cause mortality) of all enrolled patients were followed up via telephone. D-dimer > 0.50 mg/L, NT-ProBNP > 500 pg/mL, and cTnI > 0.40 ng/mL were defined as the abnormal. Kaplan-Meier curve was used to compare the cumulative survival rate between patients with different numbers of abnormal markers. Cox proportional hazard regression model was used to further test the association between numbers of abnormal markers and long-term prognosis of patients with APE after adjusting for potential confounding. During follow-up, APE recurrence and all-cause mortality happened in 78 (30.1%) patients. The proportion of APE recurrence and death in one abnormal marker, two abnormal markers, and three abnormal markers groups were 7.69%, 28.21%, and 64.10% respectively. Patients with three abnormal markers had the lowest survival rate than those with one or two abnormal markers (Log-rank test, P < 0.001). After adjustment, patients with two or three abnormal markers had a significantly higher risk of the total adverse event compared to those with one abnormal marker. The hazard ratios (95% confidence interval) were 6.27 (3.24, 12.12) and 10.7 (4.1, 28.0), respectively. Separate analyses for APE recurrence and all-cause death found similar results. A joint test of abnormal D-dimer, NT-ProBNP, and cTnI in APE patients could better predict the long-term risk of APE recurrence and all-cause mortality.

[Knockout of TLR2 gene attenuates insulin resistance and promotes M2 polarization of macrophages in mice].

Objective To study the effect of deletion of Toll-like receptor 2 (TLR2) gene on insulin resistance and polarization of macrophages in mice. Methods The wild-type (WT) and TLR2 knockout (TLR2-/-) C57BL/6 male mice, aged 28 days, were selected, with 12 mice in each group. The genotype of each mouse was identified by PCR. After mice were fed with basic diet for 3 months, the glucose tolerance test (GTT) and insulin resistance test (ITT) were performed. The mononuclear cells isolated from peripheral blood were stimulated with GM-CSF/IFN-γ and M-CSF/IL-4/IL-13, respectively, to induce differentiation to M1-like and M2-like macrophages. The CD11b, F4/80, CD11c, CD206 and early growth response 2 (EGR2) were detected by flow cytometry to determine the phenotype of macrophages. The levels of TNF-α, IL-6 and IL-10 in the culture supernatant of macrophages were detected using ELISA. Results The result of PCR identification was consistent with the genotype of mice. Compared to WT mice, TLR2-/- mice exhibited the significantly improved glycemic control at 30 min during GTT and the significantly increased insulin sensitivity at 15 minutes during ITT. The flow cytometry showed that M1 markers decreased and M2 macrophages increased in the TLR2-/- mice. ELISA showed that the levels of IL-6 and TNF-α significantly decreased in the culture supernatant of M1 macrophages, while the level of IL-10 significantly increased in the culture supernatant of M2 macrophages in TLR2-/- mice compared with WT mice. Conclusion TLR2 signal has an effect on the polarization of macrophages and makes macrophages tend to switch to M1 phenotype. A higher number of pro-inflammatory factors secreted by M1 macrophages contribute to a low-grade inflammation state in the body, which leads to a decrease in glucose tolerance and insulin sensitivity.