Program in Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Anesth Analg. 2011 Jan;112(1):143-9. doi: 10.1213/ANE.0b013e3181fe4841. Epub 2010 Nov 3.
We tested the hypothesis that inhibition of cyclooxygenase (COX) attenuates in vivo ventilator-induced lung injury (VILI) in a prospective, randomized laboratory investigation in a university-affiliated laboratory. Adult male rats were anesthetized and randomized with or without nonselective COX inhibition (ibuprofen) and were subjected to injurious mechanical ventilation (positive end-expiratory pressure = 0; peak inspiratory pressure = 21 mm Hg).
We investigated the profile of VILI (respiratory mechanics, cytokines, eicosanoids), expression of COX enzymes, and activation of nuclear factor (NF)-κB in ibuprofen- versus vehicle-treated animals. Injurious ventilation caused lung injury (i.e., decrement in compliance, tissue edema, and elevated inflammatory cytokines, eicosanoids, and COX-2).
Pretreatment with ibuprofen that effectively inhibited eicosanoid synthesis and COX-2 activity increased survival and attenuated lung edema and decrement in respiratory mechanics. Ibuprofen had no modulatory effect on ventilator-induced activation of NF-κB or inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, GRO/KC [growth-related oncogene/keratinocyte chemoattractant]). COX activity seems important in the pathogenesis of VILI in the in vivo rat. Inhibition of COX provides significant protection (i.e., survival, pulmonary function) in VILI, but without affecting levels of important mediators (tumor necrosis factor-α, IL-1β, IL-6, GRO/KC) or activation of NF-κB.
These data confirm that nonselective COX inhibition provides partial protection against VILI and that the NF-κB signaling pathway is not exclusively eicosanoid dependent. Studies of COX inhibition in ventilator-associated lung injury might benefit from multimodal targeting that includes a comprehensive focus on inflammatory cytokines and NF-κB.
我们通过一项前瞻性、随机的实验室研究来检验假说，即在一个大学附属实验室中，抑制环氧化酶（COX）可减轻呼吸机所致肺损伤（VILI）。成年雄性大鼠麻醉后，随机分为使用或不使用非选择性 COX 抑制剂（布洛芬）组，并进行机械通气（呼气末正压=0；吸气峰压=21mmHg）。
我们在布洛芬与载体处理的动物中研究了 VILI 的特征（呼吸力学、细胞因子、类二十烷酸）、COX 酶的表达和核因子（NF）-κB 的激活。损伤性通气导致肺损伤（即顺应性下降、组织水肿和炎症细胞因子、类二十烷酸和 COX-2 升高）。
有效抑制类二十烷酸合成和 COX-2 活性的布洛芬预处理可提高存活率，并减轻肺水肿和呼吸力学下降。布洛芬对 NF-κB 或炎症细胞因子（肿瘤坏死因子-α、白细胞介素[IL]-1β、IL-6、GRO/KC[生长相关癌基因/角质细胞趋化因子]）的通气诱导激活没有调节作用。COX 活性在体内大鼠 VILI 发病机制中似乎很重要。COX 抑制可显著提供 VILI 保护（即存活率、肺功能），而不影响重要介质（肿瘤坏死因子-α、IL-1β、IL-6、GRO/KC）或 NF-κB 的激活。
这些数据证实，非选择性 COX 抑制可提供部分 VILI 保护，而 NF-κB 信号通路并非完全依赖于类二十烷酸。在与呼吸机相关的肺损伤中进行 COX 抑制研究可能受益于多模式靶向治疗，包括全面关注炎症细胞因子和 NF-κB。
