Hill G E, Springall D R, Robbins R A
Department of Anesthesiology, University of Nebraska Medical Center, Omaha 68198-4455, USA.
Surgery. 1997 Apr;121(4):449-55. doi: 10.1016/s0039-6060(97)90316-0.
Cardiopulmonary bypass (CPB) is associated with an increase in airway nitric oxide (NO), plasma levels of tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta. Cytokine induction of the inducible form of nitric oxide synthase (iNOS) has been implicated in organ injury. In addition, serine protease inhibitors reduce cytokine-induced iNOS expression. Aprotinin, a serine protease inhibitor, has been demonstrated to exhibit significant antiinflammatory effects. We hypothesized that aprotinin administration during CPB would significantly reduce endogenous airway NO production.
Airway NO was measured during CPB in 10 patients receiving aprotinin and in 10 control subjects. In vitro, aprotinin was added to cultures of a murine lung epithelial cell line and was stimulated with cytomix, a combination of TNF, interleukin-1, and interferon-gamma.
Airway NO concentration was increased after 50 minutes of CPB duration compared with that measured at 5 minutes in control subjects (53 +/- 5 versus 19 +/- 3 parts per billion, p < 0.05) but not in the aprotinin group (21 +/- 6 versus 15 +/- 3 parts per billion). Aprotinin reduced nitrite concentrations in the cell culture supernatant fluids after 24 hours (cytomix, 21.5 +/- 2.1 mumol/L; cytomix plus aprotinin, 2.7 +/- 0.6 mumol/L, p < 0.05). Immunohistochemistry showed a reduction in cytokine-induced iNOS expression and Northern blot analysis showed a decrease in iNOS mRNA.
These data demonstrate that aprotinin reduces NO production in vivo and reduces cytokine-induced iNOS expression in vitro.
体外循环（CPB）与气道一氧化氮（NO）增加、肿瘤坏死因子-α（TNF-α）血浆水平升高以及白细胞介素-1β升高有关。细胞因子诱导的诱导型一氧化氮合酶（iNOS）与器官损伤有关。此外，丝氨酸蛋白酶抑制剂可降低细胞因子诱导的iNOS表达。抑肽酶是一种丝氨酸蛋白酶抑制剂，已被证明具有显著的抗炎作用。我们假设在CPB期间给予抑肽酶可显著降低内源性气道NO生成。
在CPB期间，对10例接受抑肽酶治疗的患者和10例对照受试者测量气道NO。在体外，将抑肽酶添加到小鼠肺上皮细胞系培养物中，并用细胞混合液（TNF、白细胞介素-1和干扰素-γ的组合）进行刺激。
与对照组5分钟时测量的气道NO浓度相比，CPB持续50分钟后气道NO浓度升高（53±5 vs 19±3十亿分之一，p<0.05），但抑肽酶组未升高（21±6 vs 15±3十亿分之一）。24小时后，抑肽酶降低了细胞培养上清液中的亚硝酸盐浓度（细胞混合液，21.5±2.1μmol/L；细胞混合液加抑肽酶，2.7±0.6μmol/L，p<0.05）。免疫组织化学显示细胞因子诱导的iNOS表达减少，Northern印迹分析显示iNOS mRNA减少。
这些数据表明，抑肽酶可降低体内NO生成，并在体外降低细胞因子诱导的iNOS表达。
