Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model
Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model
复制标题
DOI：
10.1152/ajpregu.00148.2003
复制
发表时间：
2003-08-01
影响因子：
2.8
通讯作者：
Traber, D
中科院分区：
文献类型：
--
作者：
Enkhbaatar, P;Murakami, K;Traber, D
一氧化氮 (NO) 已被证明在吸入烟雾后的急性肺损伤 (ALI) 中发挥着重要作用。在本研究中，我们开发了一种绵羊败血症模型，该模型通过让绵羊吸入烟雾，然后将细菌滴入气道中来模拟人类败血症和肺炎。我们假设神经元一氧化氮合酶 (nNOS) 的抑制可能有益于治疗与该模型相关的 ALI。雌性绵羊（n = 26）经过手术准备以进行研究并进行气管切开术。随后向每只动物的气道吹入 48 口棉花烟雾（40 摄氏度），然后将活的铜绿假单胞菌 [5 x 10(11) 菌落形成单位 (CFU)] 注入每只羊的肺部。所有绵羊均使用 100% O-2 进行机械通气。损伤后1小时开始连续输注7-硝基吲唑（7-NI）（一种nNOS抑制剂）、N-G-单甲基-L-精氨酸（L-NMMA）（一种非特异性NOS抑制剂）或氨基胍（AG）（一种诱导型NOS抑制剂）。施用 7-NI 改善了肺气体交换（PaO2/FIO2；其中 PaO2 是动脉 PO2，FIO2 是吸入氧浓度分数）和肺分流分数，并减弱了未治疗绵羊中观察到的肺湿干重比的增加。从组织学角度来看，7-NI 可以预防气道阻塞。 7-NI 显着抑制未治疗组损伤后气道血流量的增加。 7-NI 也抑制血浆硝酸盐和亚硝酸盐 (NOx) 浓度的增加。 L-NMMA 后处理改善了肺气体交换，但 AG 没有。本研究结果表明，nNOS 可能参与烟雾吸入损伤后气道细菌滴入后发生 ALI 的发病机制。
Nitric oxide ( NO) has been shown to play a major role in acute lung injury (ALI) after smoke inhalation. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that mimics human sepsis and pneumonia. We hypothesized that the inhibition of neuronal NO synthase ( nNOS) might be beneficial in treating ALI associated with this model. Female sheep (n = 26) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke ( 40 degreesC) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa [5 x 10(11) colony forming units (CFU)] into each sheep's lung. All sheep were mechanically ventilated using 100% O-2. Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, N-G-monomethyl-L-arginine (L-NMMA), a nonspecific NOS inhibitor, or aminoguanidine (AG), an inducible NOS inhibitor, was started 1 h after insult. The administration of 7-NI improved pulmonary gas exchange (PaO2/FIO2; where PaO2 is arterial PO2 and FIO2 is fractional inspired oxygen concentration) and pulmonary shunt fraction and attenuated the increase in lung wet-to-dry weight ratio seen in the nontreated sheep. Histologically, 7-NI prevented airway obstruction. The increase in airway blood flow after injury in the nontreated group was significantly inhibited by 7-NI. The increase in plasma concentration of nitrate and nitrite ( NOx) was inhibited by 7-NI as well. Posttreatment with L-NMMA improved the pulmonary gas exchange, but AG did not. The results of the present study show that nNOS may be involved in the pathogenesis of ALI after smoke inhalation injury followed by bacterial instillation in the airway.