Bartolucci Pablo, Ngo Minh-Triet, Beuzard Yves, Galactéros Frédéric, Saber Guitanouch, Rideau Dominique, Eddahibi Saadia, Maitre Bernard, Adnot Serge, Delclaux Christophe
Unité INSERM U492-Université Paris XII, Créteil, and Laboratoire de Thérapie Génique Hématopoïétique, Hôpital Saint Louis, Paris, France.
Crit Care Med. 2007 Feb;35(2):502-9. doi: 10.1097/01.CCM.0000253403.65602.EA.
Nitric oxide bioavailability may limit the occurrence or severity of acute vaso-occlusive episodes in patients with sickle cell disease. Because sepsis is frequently involved in the initiation of vaso-occlusive crisis and acute chest syndrome, we designed the present study in transgenic (SAD) sickle cell mice to investigate whether acute infectious peritonitis affects the enzymatic balance (nitric oxide synthases/arginases) that governs lung nitric oxide production.
Controlled animal study.
Research laboratory of an academic institution.
Transgenic Hbbsingle/single SAD1 (SAD) mice and nontransgenic wild-type littermates (C57/Black mice, control group).
Cecal ligation and puncture-induced peritonitis.
We found that 24 hrs after peritonitis, control littermate mice showed an increase in inducible and endothelial nitric oxide synthase messenger RNA and proteins, together with an increase in exhaled nitric oxide (shift of the balance toward nitric oxide synthesis). In contrast, SAD mice, which showed elevated inducible and endothelial nitric oxide synthase protein expression at baseline, showed a marked decrease in nitric oxide synthase proteins, lung nitric oxide end-products, and exhaled nitric oxide after peritonitis, reflecting a shift of the enzymatic balance toward inhibition of nitric oxide synthesis. Peritonitis increased messenger RNA levels of arginase I and arginase II in controls and SAD mice but with a greater increase in arginase I in SAD than in control mice. Peritonitis was associated with a higher mortality rate at 24 hrs in SAD mice. Inhalation of nitric oxide (40 ppm in air) abolished the mortality rate induced by acute peritonitis in SAD mice.
Acute peritonitis in SAD mice is associated with a defect in lung nitric oxide production and bioavailability that may participate in the acute systemic and lung vaso-occlusive complications of sickle cell disease.
一氧化氮生物利用度可能会限制镰状细胞病患者急性血管闭塞发作的发生或严重程度。由于脓毒症常参与血管闭塞危机和急性胸部综合征的起始过程，我们在转基因（SAD）镰状细胞小鼠中开展了本研究，以调查急性感染性腹膜炎是否会影响调控肺一氧化氮生成的酶平衡（一氧化氮合酶/精氨酸酶）。
对照动物研究。
一所学术机构的研究实验室。
转基因Hbbsingle/single SAD1（SAD）小鼠和非转基因野生型同窝小鼠（C57/黑鼠，对照组）。
盲肠结扎和穿刺诱导腹膜炎。
我们发现，腹膜炎发生24小时后，对照同窝小鼠的诱导型和内皮型一氧化氮合酶信使核糖核酸及蛋白增加，呼出一氧化氮也增加（平衡向一氧化氮合成方向转变）。相比之下，SAD小鼠在基线时诱导型和内皮型一氧化氮合酶蛋白表达升高，腹膜炎后一氧化氮合酶蛋白、肺一氧化氮终产物及呼出一氧化氮显著减少，这反映酶平衡向抑制一氧化氮合成方向转变。腹膜炎使对照组和SAD小鼠的精氨酸酶I和精氨酸酶II信使核糖核酸水平升高，但SAD小鼠精氨酸酶I的升高幅度大于对照小鼠。腹膜炎与SAD小鼠24小时时较高的死亡率相关。吸入一氧化氮（空气中40 ppm）可消除SAD小鼠急性腹膜炎诱导的死亡率。
SAD小鼠的急性腹膜炎与肺一氧化氮生成及生物利用度缺陷有关，这可能参与了镰状细胞病的急性全身和肺部血管闭塞并发症。
