Lidocaine pretreatment attenuates inflammatory response and protects against sepsis-induced acute lung injury via inhibiting potassium efflux-dependent NLRP3 activation.

OBJECTIVE: Sepsis may often result in acute lung injury (ALI), with a high mortality and morbidity. Available evidence indicates that activation of NLRP3 inflammasome to induce macrophage inflammation plays a crucial role in the inflammation progression of ALI and lidocaine can attenuate inflammatory responses. We hypothesized that lidocaine may attenuate inflammatory response and sepsis-induced ALI by inhibiting potassium efflux-dependent NLRP3 activation. METHODS: C57BL/6N mice were randomized and divided into six groups (n = 6) receiving different treatments. Lung vascular permeability and histological changes in the lungs were evaluated by Evans blue dye, bronchoalveolar lavage analysis and hematoxylin and eosin staining. J774A.1 macrophages were divided into 12 groups receiving different treatments. The expression of both NLRP3 inflammasome activation-related protein and P2X7 in the macrophages was measured by immunofluorescence staining and Western blots. The whole cell currents were determined by a voltage-patch clamp technique. RESULTS: Challenge with LPS led to ALI in mice with an increased lung injury score (0.54 ± 0.09), which was significantly attenuated by lidocaine pretreatment (0.20 ± 0.08, P < 0.0001). Lidocaine pretreatment significantly decreased the NLRP3 activation and IL-1ß release in the macrophages. Furthermore, lidocaine pretreatment down-regulated the expression of P2X7 receptors, inhibited LPS- and ATP-induced sodium (Na+) inward flow, and maintained the intracellular K+ level in the macrophages. In addition, activation of Na+ influx did not eliminate anti-inflammatory effect of lidocaine. The activation of NLRP3 could be suppressed by extracellular K+ level in a dose-dependent model. However, lidocaine pretreatment eliminated NLRP3 activation and IL-1ß release induced by K+ efflux, and decreased outward K+ current and extracellular K+ level in the macrophages challenged by LPS/ATP. CONCLUSIONS: Lidocaine pretreatment can attenuate the sepsis-induced ALI by an anti-inflammatory mechanism of inhibiting K+ efflux-dependent NLRP3 activation.

Trimethylamine N-oxide is associated with coronary atherosclerotic burden in non-ST-segment myocardial infarction patients: SZ-NSTEMI prospective cohort study.

Trimethylamine N-oxide (TMAO) is reported to accelerate atherosclerosis and the development of adverse cardiac outcomes. Relationship between coronary atherosclerotic burden and TMAO has been examined in stable coronary artery disease and ST-segment elevation myocardial infarction, but not in non-ST-segment elevation myocardial infarction (NSTEMI). We examined the association between TMAO and coronary atherosclerotic burden in NSTEMI. In this prospective cohort study, two groups including NSTEMI (n = 73) and age-sex matched Healthy (n = 35) individuals were enrolled between 2019 and 2020. Coronary atherosclerotic burden was stratified based on the number of diseased coronary vessels and clinical risk scores including SYNTAX and GENSINI. Fasting plasma TMAO was measured by isotope dilution high-performance liquid chromatography. The median plasma TMAO levels were significantly higher in the NSTEMI group than in the Healthy group, respectively (0.59 µM; interquartile range [IQR]: 0.43-0.78 versus 0.42 µM; IQR: 0.33-0.64; P = 0.006). Within the NSTEMI group, higher TMAO levels were observed in the multivessel disease (MVD) versus single vessel disease (P = 0.002), and intermediate-high risk (score ≥ 23) versus low risk (score < 23) of SYNTAX (P = 0.003) and GENSINI (P = 0.005). TMAO level remained an independent predictor of MVD (odds ratio [OR]: 5.94, P = 0.005), intermediate-high risk SYNTAX (OR: 3.61, P = 0.013) and GENSINI scores (OR: 4.60, P = 0.008) following adjustment for traditional risk factors. Receiver operating characteristic curve (AUC) analysis for TMAO predicted MVD (AUC: 0.73, 95% confidence interval [Cl]: 0.60-0.86, P = 0.002), intermediate-high SYNTAX score (AUC: 0.70, 95% Cl: 0.58-0.82, P = 0.003) and GENSINI score (AUC: 0.70, 95% Cl: 0.57-0.83, P = 0.005). In all, TMAO levels are independently associated with high coronary atherosclerotic burden in NSTEMI.

Association of total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol with atherosclerotic cardiovascular disease and cancer in a Chinese male population.

This prospective study included 68,759 Chinese male adults from Kailuan cohort of China who had a standardized medical examination between 2006 and 2007 and were followed up for approximately 8 years until occurrence of ASCVD, cancer or death or until December 31, 2014. Subjects were divided into four categories based on the quartiles of TC, LDL-C and non-HDL-C. Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). During follow-up, 2,916 males developed ASCVD and 1,884 developed cancer. Compared with the lowest quartile, the upper-most quartiles of TC, LDL-C and non-HDL-C were all associated with increased ASCVD risk (HR 1.53; HR 1.16; HR 1.55); however, the upper-most quartiles of TC, LDL-C and non-HDL-C were all negatively associated with cancer (HR0.84; HR 0.82; HR 0.80) and these associations were present after exclusion of incident cancers during the first 4 years of follow-up. In a word, we report that high TC, LDL-C and non-HDL-C concentrations increased ASCVD incidence in a male population and that these lipid profiles were inversely associated with total cancer and several individual cancers.