1Department of Anaesthesiology and Critical Care Medicine, University Medical Center Freiburg, Freiburg, Germany.2Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY.
Crit Care Med. 2017 Aug;45(8):e849-e857. doi: 10.1097/CCM.0000000000002440.
Hydrogen sulfide reduces ventilator-induced lung injury in mice. Here, we have examined the underlying mechanisms of hydrogen sulfide-mediated lung protection and determined the involvement of cyclooxygenase 2, 15-deoxy Δ-prostaglandin J2, and peroxisome proliferator-activated receptor gamma in this response.
Randomized, experimental study.
University medical center research laboratory.
C57BL/6 mice and in vitro cell catheters.
The effects of hydrogen sulfide were analyzed in a mouse ventilator-induced lung injury model in vivo as well as in a cell stretch model in vitro in the absence or presence of hydrogen sulfide. The physiologic relevance of our findings was confirmed using pharmacologic inhibitors of cyclooxygenase 2 and peroxisome proliferator-activated receptor gamma.
Mechanical ventilation caused significant lung inflammation and injury that was prevented in the presence of hydrogen sulfide. Hydrogen sulfide-mediated protection was associated with induction of cyclooxygenase 2 and increases of its product 15-deoxy Δ-prostaglandin J2 as well as cyclooxygenase 2/15-deoxy Δ-prostaglandin J2-dependent activation of peroxisome proliferator-activated receptor gamma. Hydrogen sulfide-dependent effects were mainly observed in macrophages. Applied mechanical stretch to RAW 264.7 macrophages resulted in increased expression of interleukin receptor 1 messenger RNA and release of macrophage inflammatory protein-2. In contrast, incubation of stretched macrophages with sodium hydrosulfide prevented the inflammatory response dependent on peroxisome proliferator-activated receptor gamma activity. Finally, application of a specific peroxisome proliferator-activated receptor gamma inhibitor abolished hydrogen sulfide-mediated protection in ventilated animals.
One hydrogen sulfide-triggered mechanism in the protection against ventilator-induced lung injury involves cyclooxygenase 2/15-deoxy Δ-prostaglandin J2-dependent activation of peroxisome proliferator-activated receptor gamma and macrophage activity.
硫化氢可减轻小鼠呼吸机所致肺损伤。在此，我们研究了硫化氢介导肺保护的潜在机制，并确定了环氧合酶 2、15-脱氧 Δ-前列腺素 J2 和过氧化物酶体增殖物激活受体 γ 在该反应中的作用。
随机、实验性研究。
大学医学中心研究实验室。
C57BL/6 小鼠和体外细胞导管。
在体内小鼠呼吸机所致肺损伤模型和体外细胞拉伸模型中分析硫化氢的作用，同时分析在有无硫化氢存在的情况下这些作用。使用环氧合酶 2 和过氧化物酶体增殖物激活受体 γ 的药理学抑制剂来验证我们发现的生理相关性。
机械通气导致明显的肺炎症和损伤，而在硫化氢存在下则可预防这种损伤。硫化氢介导的保护与环氧合酶 2 的诱导及其产物 15-脱氧 Δ-前列腺素 J2 的增加以及环氧合酶 2/15-脱氧 Δ-前列腺素 J2 依赖性过氧化物酶体增殖物激活受体 γ 的激活有关。在巨噬细胞中主要观察到硫化氢依赖性作用。将 RAW 264.7 巨噬细胞施加机械拉伸会导致白细胞介素受体 1 信使 RNA 的表达增加和巨噬细胞炎症蛋白-2 的释放。相反，将拉伸的巨噬细胞与硫氢化钠孵育可防止依赖过氧化物酶体增殖物激活受体 γ 活性的炎症反应。最后，应用特异性过氧化物酶体增殖物激活受体 γ 抑制剂可消除通气动物中硫化氢介导的保护作用。
针对呼吸机所致肺损伤的保护作用的一个硫化氢触发机制涉及环氧合酶 2/15-脱氧 Δ-前列腺素 J2 依赖性过氧化物酶体增殖物激活受体 γ 激活和巨噬细胞活性。
