Hepatic Unit and Clinical Pharmacology Service, Hospital General Universitario de Alicante, Universidad Miguel Hernández, Elche, Alicante, Spain.
Hepatology. 2011 Mar;53(3):935-44. doi: 10.1002/hep.24102.
Patients with cirrhosis receiving norfloxacin show a restored inflammatory balance that likely prevents clinical complications derived from an excessive proinflammatory response to bacterial product challenges. This study sought to investigate associated inflammatory control mechanisms established in patients with cirrhosis receiving norfloxacin. A total of 62 patients with cirrhosis and ascites in different clinical conditions were considered. Blood samples were collected and intracellular and serum norfloxacin were measured. Inflammatory mediators were evaluated at messenger RNA and protein levels. Neutrophils from all patients were cultured with lipopolysaccharide (LPS) and anti-interleukin-10 (anti-IL-10) monoclonal antibody in different conditions. IL-10 and heme oxygenase-1 (HO-1) were up-regulated in patients receiving norfloxacin and correlated with norfloxacin in a concentration-dependent manner, whereas proinflammatory inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-κB behaved inversely. Higher IL-10 levels correlated with lower white blood cell count and higher mean arterial pressure. No correlations were found between IL-10 and disease clinical scores or liver function markers in blood. Neutrophilic in vitro assays showed that the effect of LPS on proinflammatory mediator levels in the presence of norfloxacin was abrogated by significantly increasing IL-10 and HO-1 expression. After stimulation with LPS plus anti-IL-10, proinflammatory mediators were dramatically increased in patients receiving norfloxacin, and increasing intracellular norfloxacin concentrations did not decrease the expression levels of these proinflammatory molecules. Unblocking IL-10 restored proinflammatory mediator and HO-1 expression to previously observed levels in response to LPS stimulation.
Although the described association does not necessarily mean causality, an IL-10-mediated HO-1-induced anti-inflammatory mechanism is present in patients with cirrhosis receiving norfloxacin, that is directly associated with cell-modulating events in these patients.
接受诺氟沙星治疗的肝硬化患者表现出炎症平衡的恢复，这可能防止了因细菌产物刺激引起的过度炎症反应而导致的临床并发症。本研究旨在探讨接受诺氟沙星治疗的肝硬化患者中建立的相关炎症控制机制。共纳入 62 例不同临床状况的肝硬化伴腹水患者。采集血样，检测细胞内和血清中的诺氟沙星。在信使 RNA 和蛋白质水平评估炎症介质。在不同条件下，用脂多糖（LPS）和抗白细胞介素-10（抗-IL-10）单克隆抗体培养所有患者的中性粒细胞。接受诺氟沙星治疗的患者中 IL-10 和血红素加氧酶-1（HO-1）上调，并呈浓度依赖性与诺氟沙星相关，而诱导型一氧化氮合酶、环氧化酶-2 和核因子-κB 呈相反变化。较高的 IL-10 水平与较低的白细胞计数和较高的平均动脉压相关。在血液中，未发现 IL-10 与疾病临床评分或肝功能标志物之间存在相关性。中性粒细胞体外实验表明，在存在诺氟沙星的情况下，LPS 对促炎介质水平的影响被显著增加的 IL-10 和 HO-1 表达所阻断。在 LPS 加抗-IL-10 刺激下，接受诺氟沙星治疗的患者中促炎介质显著增加，增加细胞内诺氟沙星浓度并不能降低这些促炎分子的表达水平。阻断 IL-10 可恢复 LPS 刺激下观察到的促炎介质和 HO-1 表达水平。
尽管所描述的关联不一定意味着因果关系，但在接受诺氟沙星治疗的肝硬化患者中存在 IL-10 介导的 HO-1 诱导的抗炎机制，这与这些患者的细胞调节事件直接相关。
