Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Catalonia, Spain.
Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G726-34. doi: 10.1152/ajpgi.00162.2009. Epub 2009 Jul 23.
Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen alpha1(I) and alpha1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.
血管紧张素 II 通过刺激非吞噬性 NADPH 氧化酶 (NOX) 诱导的氧化应激促进肝纤维化。血管紧张素 II 型 1 (AT1) 受体阻滞剂可减轻实验性肝纤维化，但它们在人类肝纤维化中的作用尚不清楚。我们研究了氯沙坦对慢性丙型肝炎 (CHC) 患者肝纤维化形成、炎症和 NOX 基因表达的影响。14 例 CHC 合并肝纤维化患者接受口服氯沙坦 (50 mg/天) 治疗 18 个月。在基线和治疗后进行肝活检。通过组织学分析 (METAVIR) 评估炎症和纤维化程度。通过天狼星红染色的形态计量学定量测量胶原含量。整个系列的总体胶原含量和纤维化分期保持稳定，但在 7 例患者中纤维化分期下降。7 例患者的炎症活性改善。通过定量 PCR 评估氯沙坦对 31 个促纤维化和炎症基因以及 NOX 复合物成分在肝内表达的影响。氯沙坦治疗与几种促纤维化和 NOX 基因的表达显著降低相关，包括前胶原 α1(I) 和 α1(IV)、尿激酶型纤溶酶原激活物、金属蛋白酶 2、NOX 激活物 1 (NOXA-1) 和组织者 1 (NOXO-1) 和 Rac-1。所有患者均耐受良好，氯沙坦可有效减轻全身肾素-血管紧张素系统的活性。未观察到对血清肝试验或病毒载量的影响。我们的结论是，长期给予氯沙坦，一种口服 AT1 受体阻滞剂，与 CHC 患者的 NOX 成分和纤维化基因的下调相关。需要进行对照研究来评估 AT1 受体阻滞剂在慢性肝损伤中的作用。
