5-lipoxygenase deficiency prevents respiratory failure during ventilator-induced lung injury
5-lipoxygenase deficiency prevents respiratory failure during ventilator-induced lung injury
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DOI：
10.1164/rccm.200501-034oc
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发表时间：
2005-08-01
影响因子：
24.7
通讯作者：
Zapol, WM
中科院分区：
文献类型：
--
作者：
Caironi, P;Ichinose, F;Zapol, WM
原理：高VT（HVT）机械通气会逐渐导致肺损伤和气体交换效率降低。低通气性肺血管收缩（HPV）将血流导向通气良好的肺区域，在肺损伤期间保持全身氧合。最近的实验研究表明，5-脂氧合酶（5LO）生物合成白三烯（LT）在内毒素损伤HPV中起重要作用。目的：探讨人乳头状瘤病毒（HPV）的损伤是否与HVT相关的低氧血症有关，并评价LT在呼吸机相关肺损伤中的作用。方法：我们研究了野生型和5LO缺陷小鼠通气长达10小时与低VT（LVT）或HVT。结果如下：在野生型小鼠中，HVT而不是LVT增加肺血管通透性和水肿形成，损害全身氧合，并降低存活率。左主支气管阻塞引起的左肺血管阻力增加反映了HPV在HVT通气的动物中明显受损。HVT通气增加了支气管肺泡灌洗的LT和中性粒细胞水平。在5LO缺陷小鼠中，HVT诱导的肺血管通透性增加和呼吸力学恶化明显减弱，全身氧合得到保留，存活率增加。此外，在5LO缺陷小鼠中，HVT通气并不损害左主支气管闭塞增加左肺血管阻力的能力。给予MK 886（一种5LO活性抑制剂）或MK 571（一种选择性半胱氨酰-LT 1受体拮抗剂），在很大程度上预防了呼吸机诱导的肺损伤。结论：这些结果表明LT在HVT通气引起的肺损伤和氧合受损中起着重要作用。
Rationale: Mechanical ventilation with high VT (HVT) progressively leads to lung injury and decreased efficiency of gas exchange. Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to well-ventilated lung regions, preserving systemic oxygenation during pulmonary injury. Recent experimental studies have revealed an important role for leukotriene (LT) biosynthesis by 5-lipoxygenase (5LO) in the impairment of HPV by endotoxin. Objectives:To investigate whether or not impairment of HPV contributes to the hypoxemia associated with HVT and to evaluate the role of LTs in ventilator-induced lung injury. Methods: We studied wild-type and 5LO-deficient mice ventilated for up to 10 hours with low VT (LVT) or HVT. Results: In wild-type mice, HVT, but not LVT, increased pulmonary vascular permeability and edema formation, impaired systemic oxygenation, and reduced survival. HPV, as reflected by the increase in left pulmonary vascular resistance induced by left mainstem bronchus occlusion, was markedly impaired in animals ventilated with HVT. HVT ventilation increased bronchoalveolar lavage levels of LTs and neutrophils. In 5LO-deficient mice, the HVT-induced increase of pulmonary vascular permeability and worsening of respiratory mechanics were markedly attenuated, systemic oxygenation was preserved, and survival increased. Moreover, in 5LO-deficient mice, HVT ventilation did not impair the ability of left mainstem bronchus occlusion to increase left pulmonary vascular resistance. Administration of MK886, a 5LO-activity inhibitor, or MK571, a selective cysteinyl-LT1 receptor antagonist, largely prevented ventilator-induced lung injury. Conclusions: These results indicate that LTs play a central role in the lung injury and impaired oxygenation induced by HVT ventilation.