Divisions of Nephrology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Internal Medicine Research Laboratory, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
PLoS One. 2020 Jul 10;15(7):e0232741. doi: 10.1371/journal.pone.0232741. eCollection 2020.
Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients.
Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms.
Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles.
The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.
炎症在慢性肾脏病（CKD）患者的动脉粥样硬化和心血管发病率和死亡率的发展中起主要作用。Toll 样受体 4（TLR4）是脂多糖（内毒素）和其他参与炎症发病机制的配体的主要受体。我们确定内毒素水平和 TLR4 多态性的存在是否与南非 CKD 患者的炎症和动脉粥样硬化标志物相关。
在 160 名参与者（120 名 CKD 患者和 40 名对照）中测量内毒素、脂多糖结合蛋白（LBP）、血清 CD14（sCD14）、白细胞介素 8（IL-8）、单核细胞趋化蛋白 1（MCP-1）和颈动脉内膜中层厚度（CIMT）。使用比值比评估 sCD14、IL-8 和 MCP-1 存在时内毒素与 CIMT 之间的关联。筛查参与者是否存在 Asp299Gly 和 Thr399Ile TLR4 多态性，并比较 TLR4 多态性患者与无 TLR4 多态性患者的 CIMT 和炎症标志物。
内毒素水平与 sCD14（r = 0.441，p<0.001）和 MCP-1（r = 0.388，p<0.001）水平相关，而增加的 CIMT 与 MCP-1（r = 0.448，p<0.001）、sCD14 水平（r = 0.476，p<0.001）、LBP（r = 0.340，p<0.001）和 IL-8（r = 0.395，p<0.001）相关。动脉粥样硬化与内毒素水平相关（比值比：4.95；95%置信区间：2.52-9.73；p<0.001），并可通过炎症标志物水平升高来预测。对携带 TLR4 多态性的患者进行分析表明，与携带野生型 TLR4 等位基因的患者相比，其血清炎症标志物水平降低，CIMT 值降低。需要进一步确认的额外发现表明，TLR4 多态性与炎症标志物和 CIMT 值降低有关。
