Optimal hemoglobin level in gut barrier function of sepsis-Roles of heme oxygenase-1

我们检验了这样一个假设，即在血红素加氧酶-1（HO-1）被诱导的条件下，输血导致的血红素负荷对宿主防御系统（如肠道屏障功能）有害。本实验采用内毒素血症大鼠模型，首先研究了血红蛋白水平（13- 16 g/dl）与低血红蛋白水平（7-9 g/dl）对肠屏障通透性的影响，发现高血红蛋白水平较低血红蛋白水平时肠屏障通透性增加。为了验证HO-1在这一发现中的参与，我们随后检查了HO-1诱导的大鼠中血红蛋白水平的相同作用。然而，输血和血液稀释处理的大鼠腹腔注射氯化血红素诱导HO-1导致所有死亡在16小时内。高、低血红蛋白大鼠肠粘膜HO-1免疫组化染色均未见增强。总之，NO-1不太可能促进内毒素血症中高血红蛋白诱导的肠粘膜通透性升高的发展。应用活体显微镜观察肠道微循环，发现高血红蛋白组大鼠肠道微循环减慢，毛细血管密度降低。此外，高血红蛋白组大鼠的往复运动增强，而低血红蛋白组大鼠的往复运动无明显变化。用NO供体灌流改善了粘膜微循环，而用L-NAME抑制NO合酶则使微循环恶化，与血红蛋白水平无关。鉴于这些数据，NO是内毒素血症中肠粘膜通透性的重要调节剂，重点是高血红蛋白水平的影响。

We tested the hypothesis that heme loading by blood transfusion was harmful for the host defense system like gut barrier function under the conditions where heme oxygenase-1 (HO-1) was induced. Using endotoxemic rat model, we first examined the effects of hemoglobin level, high (13-16g/dl) versus low (7-9 g/dl) by isovolemic transfusion or hemodilution, respectively, on the permeability of gut barrier, and found that high level of hemoglobin augmented the increased permeability of gut in endotoxemic rats compared with low-hemoglobin. To text the involvement of HO-1 in this finding, we then examined the same effects of hemoglobin level in HO-1 induced rats. However, both blood transfusion and hemodilution in rats treated with intraperitoneal hemin injection to induce HO-1 caused all death within 16 hours. Besides, immunohistochemistry of HO-1 on gut mucosa showed no augmentation in both high and low hemoglobin rats. Taken together, NO-1 is unlikely to contribute to the development of high-hemoglobin-induced, the elevation of gut mucosal permeability, in endotoxemia. Using an intravital microscopy to observe gut mucosal microcirculation, we then found that intramucosal microcirculation was retarded and capillary density was reduced in the high hemoglobin group in healthy rats. In addition, high-hemoglobin augmented to-and-fro phenomenon observed in endotoxemic rats whereas no significant changes were observed in low-hemoglobin group. Superfusion with NO donor ameliorated the mucosal microcirculation and inhibition of NO synthase with L-NAME deteriorated the microcirculation irrespectively of hemoglobin level. Given these data, NO is a significant regulator of gut mucosal permeability in endotoxemia with focus on the effects high hemoglobin level.