Chen Lee-Wei, Hwang Bonnie, Wang Jyh-Seng, Chen Jin-Shyr, Hsu Ching-Mei
Department of Surgery, Kaohsiung Veterans General Hospital, National Yang-Ming Medical University, Taipei, Taiwan.
Crit Care Med. 2004 Dec;32(12):2476-84. doi: 10.1097/01.ccm.0000147831.07329.32.
To determine whether inhibition of inducible nitric oxide synthase to stabilize endothelial permeability and to retain hypertonic saline in the vascular space will ameliorate burn-induced gut barrier dysfunction.
Prospective, experimental study.
Research laboratory at a university hospital.
Thermal injury models in the rat.
In experiment 1, specific pathogen free rats underwent 3% total body surface area burn or sham burn and were given 7.5 mL/kg hypertonic saline (7.5% NaCl), 7.5 mg/kg saline, or 50 mL/kg saline (nearly equal sodium load with hypertonic saline) in the right femoral vein for 15 mins for fluid resuscitation at 0, 4, or 8 hrs after burn. In experiment 2, S-methylisothiourea (7.5 mg/kg, intraperitoneally), a specific inducible nitric oxide synthase inhibitor, was given immediately after burn to rats from different groups as in experiment 1. At 24 hrs after burn, the intestinal mucosa was assayed for myeloperoxidase activity and lipid peroxidation, the distribution of fluorescein isothiocyanate-dextran across the lumen of the small intestine was determined, and bacterial translocation to the mesenteric lymph nodes and ileum histology were also examined.
Burn induced significant increases in intestinal mucosa inducible nitric oxide synthase expression, myeloperoxidase activity, lipid peroxidation, intestinal permeability, bacterial translocation to mesenteric lymph nodes, and villi sloughing in rats. Hypertonic saline administration at 0 or 4 hrs after burn worsened intestinal mucosa lipid peroxidation, neutrophil sequestration, intestinal permeability, and villi sloughing compared with those of burn + 7.5 mg/kg saline and burn + 50 mL/kg saline rats. To the contrary, burn + S-methylisothiourea rats with hypertonic saline injection at 4 or 8 hrs after burn showed an improvement of gut barrier function compared with burn + S-methylisothiourea + 7.5 mg/kg saline and burn + S-methylisothiourea + 50 mL/kg saline rats. Administration of hypertonic saline at 8 hrs after burn and S-methylisothiourea injection also significantly attenuated the bacterial translocation to mesenteric lymph nodes and villi sloughing.
Using hypertonic saline as a resuscitation fluid in early burn shock markedly augmented the thermal injury-induced intestinal mucosa neutrophil deposition, lipid peroxidation, and intestinal hyperpermeability. Inhibition of inducible nitric oxide synthase not only significantly attenuated neutrophil deposition and mucosa lipid peroxidation but also reversed the deteriorating effects of hypertonic saline on thermal injury-induced gut barrier dysfunction and bacterial translocation.
确定抑制诱导型一氧化氮合酶以稳定内皮通透性并使高渗盐水保留在血管腔内是否能改善烧伤所致的肠道屏障功能障碍。
前瞻性实验研究。
大学医院的研究实验室。
大鼠热损伤模型。
在实验1中，无特定病原体的大鼠接受3%体表面积烧伤或假烧伤，并于烧伤后0、4或8小时经右股静脉给予7.5 mL/kg高渗盐水（7.5%氯化钠）、7.5 mg/kg生理盐水或50 mL/kg生理盐水（钠负荷与高渗盐水几乎相等），持续15分钟进行液体复苏。在实验2中，将特异性诱导型一氧化氮合酶抑制剂S-甲基异硫脲（7.5 mg/kg，腹腔注射）在烧伤后立即给予与实验1中不同组的大鼠。烧伤后24小时，检测肠黏膜的髓过氧化物酶活性和脂质过氧化，测定异硫氰酸荧光素-葡聚糖在小肠腔内的分布，并检查细菌易位至肠系膜淋巴结情况及回肠组织学。
烧伤导致大鼠肠黏膜诱导型一氧化氮合酶表达、髓过氧化物酶活性、脂质过氧化、肠道通透性、细菌易位至肠系膜淋巴结以及绒毛脱落显著增加。与烧伤 + 7.5 mg/kg生理盐水和烧伤 + 50 mL/kg生理盐水的大鼠相比，烧伤后0或4小时给予高渗盐水会加重肠黏膜脂质过氧化、中性粒细胞聚集、肠道通透性和绒毛脱落。相反，烧伤后4或8小时注射高渗盐水的烧伤 + S-甲基异硫脲大鼠与烧伤 + S-甲基异硫脲 + 7.5 mg/kg生理盐水和烧伤 + S-甲基异硫脲 + 50 mL/kg生理盐水的大鼠相比，肠道屏障功能有所改善。烧伤后8小时给予高渗盐水及注射S-甲基异硫脲也显著减轻了细菌易位至肠系膜淋巴结及绒毛脱落。
在烧伤早期休克中使用高渗盐水作为复苏液会显著增加热损伤诱导的肠黏膜中性粒细胞沉积、脂质过氧化和肠道高通透性。抑制诱导型一氧化氮合酶不仅能显著减轻中性粒细胞沉积和黏膜脂质过氧化，还能逆转高渗盐水对热损伤诱导的肠道屏障功能障碍和细菌易位的恶化作用。
