Sordi Regina, Chiazza Fausto, Collino Massimo, Assreuy Jamil, Thiemermann Christoph
*Centre for Translational Medicine and Therapeutics, Queen Mary University of London, William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, London, UK †Department of Drug Science and Technology, University of Turin, Turin, Italy ‡Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Shock. 2016 May;45(5):525-33. doi: 10.1097/SHK.0000000000000533.
Severe hemorrhage can lead to global ischemia and hemorrhagic shock (HS), resulting in multiple organ failure (MOF) and death. Restoration of blood flow and re-oxygenation is associated with an exacerbation of tissue injury and inflammatory response. The neuronal nitric oxide synthase (nNOS) has been implicated in vascular collapse and systemic inflammation of septic shock; however, the role of nNOS in HS is poorly understood. The aim of this study was to evaluate the role of nNOS in the MOF associated with HS.Rats were subjected to HS under anesthesia. Mean arterial pressure was reduced to 30 mmHg for 90 min, followed by resuscitation with shed blood. Rats were randomly treated with two chemically distinct nNOS inhibitors [ARL 17477 (1 mg/kg) and 7-nitroindazol (5 mg/kg)] or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed.HS was associated with MOF development. Inhibition of nNOS activity at resuscitation protected rats against the MOF and vascular dysfunction. In addition, treatment of HS rats with nNOS inhibitors attenuated neutrophil infiltration into target organs and decreased the activation of NF-κB, iNOS expression, NO production, and nitrosylation of proteins. Furthermore, nNOS inhibition also reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 in HS rats.In conclusion, two distinct inhibitors of nNOS activity reduced the MOF, vascular dysfunction, and the systemic inflammation associated with HS. Thus, nNOS inhibitors may be useful as an adjunct therapy before fluids and blood administration in HS patients to avoid the MOF associated with reperfusion injury during resuscitation.
严重出血可导致全身缺血和失血性休克（HS），进而引发多器官功能衰竭（MOF）并导致死亡。血流恢复和再氧合与组织损伤和炎症反应的加剧有关。神经元型一氧化氮合酶（nNOS）与脓毒性休克的血管塌陷和全身炎症有关；然而，nNOS在HS中的作用尚不清楚。本研究的目的是评估nNOS在与HS相关的MOF中的作用。
大鼠在麻醉下接受HS。平均动脉压降至30 mmHg并维持90分钟，随后用自体失血进行复苏。复苏时，大鼠被随机用两种化学性质不同的nNOS抑制剂[ARL 17477（1 mg/kg）和7-硝基吲唑（5 mg/kg）]或溶剂处理。4小时后，评估器官损伤和功能障碍的参数。
HS与MOF的发生有关。复苏时抑制nNOS活性可保护大鼠免受MOF和血管功能障碍的影响。此外，用nNOS抑制剂治疗HS大鼠可减轻中性粒细胞向靶器官的浸润，并降低NF-κB的激活、iNOS表达、NO生成以及蛋白质的亚硝化。此外，抑制nNOS还降低了HS大鼠促炎细胞因子TNF-α和IL-6的水平。
总之，两种不同的nNOS活性抑制剂可减轻与HS相关的MOF、血管功能障碍和全身炎症。因此，nNOS抑制剂可能作为HS患者在输注液体和血液之前的辅助治疗手段，以避免复苏期间与再灌注损伤相关的MOF。
