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

在血红素加氧酶-1 （HO-1）诱导的条件下，我们验证了输血血红素负荷对肠道屏障功能等宿主防御系统的损害。利用内毒素中毒大鼠模型，我们首先检测了等容输血或血液稀释时血红蛋白水平高（13-16g/dl）和低（7- 9g /dl）对肠道屏障通透性的影响，发现与低血红蛋白相比，高血红蛋白水平增强了内毒素中毒大鼠肠道通透性的增加。为了证明HO-1在这一发现中的作用，我们在HO-1诱导的大鼠中检测了血红蛋白水平的相同影响。然而，腹腔注射血凝素诱导HO-1的大鼠输血和血液稀释均在16小时内死亡。高、低血红蛋白大鼠肠道黏膜HO-1免疫组化均未见升高。综上所述，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。采用活体显微镜观察肠道黏膜微循环，我们发现健康大鼠高血红蛋白组粘膜内微循环迟缓，毛细血管密度降低。此外，内毒素中毒大鼠出现了高血红蛋白增强的往返现象，而低血红蛋白组无明显变化。NO供体灌注改善了粘膜微循环，L-NAME抑制NO合酶使微循环恶化，与血红蛋白水平无关。综上所述，一氧化氮是内毒素血症中肠粘膜通透性的重要调节因子，其作用主要集中在高血红蛋白水平下。

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.