Enkhbaatar Perenlei, Lange Matthias, Nakano Yoshimitsu, Hamahata Atsumori, Jonkam Collette, Wang Jianpu, Jaroch Stefan, Traber Lillian, Herndon David, Traber Daniel
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Shock. 2009 Sep;32(3):253-7. doi: 10.1097/SHK.0b013e318193e2ba.
Smoke inhalation injury is often complicated with pneumonia, which frequently leads to subsequent development of sepsis. Excessive NO has been shown to mediate many sepsis-related pathological responses. In the present study, we used our well-established ovine smoke inhalation and pneumonia/sepsis model to examine the hypothesis that neuronal NO synthase (NOS) may be primarily responsible for these pathological alterations. We report the beneficial effects of the specific neuronal NOS (nNOS) inhibitor ZK234238. Adult female sheep were surgically prepared for the study. After 5 to 7 days' recovery, sheep were anesthetized and given double injury: insufflation of 48 breaths of cotton smoke (<40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa (5 x 10(11) colony-forming units) into each sheep's lung via tracheostomy tube. All sheep were mechanically ventilated and fluid resuscitated by lactated Ringer's solution. Sheep were randomly allocated into groups: control (injured not treated, n = 6) and treated (injured, but treated with ZK234238, n = 4). Continuous infusion of ZK234238 (100 microg x kg(-1) x h(-1)) was started 1 h after insult. ZK234238 attenuated the hypotension (at 18 and 24 h) and fall in systemic vascular resistance (at 24 h) seen in control animals. ZK234238 significantly inhibited increased fluid accumulation as well as increased plasma nitrate/nitrite 24 h after injury. Neuronal NOS inhibition significantly reduced lung water content and attenuated inflammatory indices such as lung tissue myeloperoxidase activity, IL-6 mRNA, and reactive nitrogen species. The above results suggest that the nNOS-derived NO may be involved in the pathophysiology of sepsis-related multiorgan dysfunction.
烟雾吸入性损伤常并发肺炎，进而频繁导致随后的脓毒症发生。已表明过量的一氧化氮（NO）介导许多与脓毒症相关的病理反应。在本研究中，我们使用我们成熟的绵羊烟雾吸入和肺炎/脓毒症模型来检验神经元型一氧化氮合酶（NOS）可能是这些病理改变主要原因的假说。我们报告了特异性神经元型NOS（nNOS）抑制剂ZK234238的有益作用。成年雌性绵羊经手术准备用于该研究。在恢复5至7天后，绵羊被麻醉并接受双重损伤：向每只动物气道内吹入48次棉烟（<40摄氏度），随后通过气管造口管向每只绵羊肺内注入活的铜绿假单胞菌（5×10¹¹菌落形成单位）。所有绵羊均接受机械通气并用乳酸林格氏液进行液体复苏。绵羊被随机分为两组：对照组（受伤但未治疗，n = 6）和治疗组（受伤但用ZK234238治疗，n = 4）。在损伤后1小时开始持续输注ZK234238（100微克×千克⁻¹×小时⁻¹）。ZK234238减轻了对照组动物出现的低血压（在18和24小时）和全身血管阻力下降（在24小时）。ZK234238在损伤后24小时显著抑制了液体蓄积增加以及血浆硝酸盐/亚硝酸盐增加。抑制神经元型NOS显著降低了肺含水量，并减轻了炎症指标，如肺组织髓过氧化物酶活性、白细胞介素-6 mRNA和活性氮物质。上述结果表明，nNOS衍生的NO可能参与了脓毒症相关多器官功能障碍的病理生理学过程。
