Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury
Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury
复制标题
DOI：
10.4049/jimmunol.174.8.5033
复制
发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Levy, BD
中科院分区：
文献类型：
--
作者：
Fukunaga, K;Kohli, P;Levy, BD
急性肺损伤 (ALI) 是一种严重疾病，死亡率极高，且无特效治疗方法。在早期渗出阶段，中性粒细胞活化并在肺部积聚，导致低氧血症、广泛的组织损伤和呼吸衰竭。在临床试验中，促炎介质的抑制尚未被证明有效。在这项研究中，我们采取了一种新的研究策略，强调促进肺损伤缓解的介质。开发了一种新的由酸吸入引起的 ALI 自发缓解实验小鼠模型，以鉴定内源性促缓解机制。 ALI 增加了小鼠肺中环氧合酶 2 (COX-2) 的表达。 COX-2 的选择性药理抑制或基因破坏可阻止 ALI 的缓解。 COX-2 衍生产品增加了促分解脂质介质脂氧素 A(4) (LXA(4)) 的水平，并且在阿司匹林存在的情况下，增加了 15-epi-LXA(4) 的水平。 LXA(4) 和 15-epi-LXA(4) 均与 LXA(4) 受体 (ALX) 相互作用以介导抗炎作用。酸损伤显着诱导 ALX 表达，并且 ALX 表达增加的转基因小鼠表现出对 ALI 的显着保护。总之，这些发现表明 COX-2 衍生介质在 ALI 中发挥保护作用，部分是通过增强脂氧素信号传导，并对这种破坏性临床疾病具有潜在的治疗意义。
Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. In its early exudative phase, neutrophil activation and accumulation in the lung lead to hypoxemia, widespread tissue damage, and respiratory failure. In clinical trials, inhibition of proinflammatory mediators has not proven effective. In this study, we pursued a new investigative strategy that emphasizes mediators promoting resolution from lung injury. A new spontaneously resolving experimental murine model of ALI from acid aspiration was developed to identify endogenous proresolving mechanisms. ALI increased cyclooxygenase 2 (COX-2) expression in murine lung. Selective pharmacologic inhibition or gene disruption of COX-2 blocked resolution of ALI. COX-2-derived products increased levels of the proresolving lipid mediators lipoxin A(4) (LXA(4)) and, in the presence of aspirin, 15-epi-LXA(4),. Both LXA(4) and 15-epi-LXA(4) interact with the LXA(4) receptor (ALX) to mediate anti-inflammatory actions. ALX expression was markedly induced by acid injury and transgenic mice with increased ALX expression displayed dramatic protection from ALI. Together, these findings indicate a protective role in ALI for COX-2-derived mediators, in part via enhanced lipoxin signaling, and carry potential therapeutic implications for this devastating clinical disorder.