Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice.
Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice.
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DOI：
10.1097/aln.0b013e31826a4ae3
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发表时间：
2012-10
期刊：
影响因子：
8.8
通讯作者：
Hellman J
中科院分区：
文献类型：
--
作者：
Prakash A;Mesa KR;Wilhelmsen K;Xu F;Dodd-o JM;Hellman J
缺血再灌注（I/R）损伤涉及无菌性炎症，通常与多种临床情况相关，如复苏后出血、短暂性栓塞事件和器官移植。I/R损伤可诱导肺功能障碍，无论I/R发生在肺本身还是远处器官。最近，有证据表明先天免疫系统的受体和途径参与识别无菌炎症，并与参与识别和应答病原体的受体和途径相当重叠。我们使用了一个暂时性单侧左肺动脉闭塞而不涉及支气管的小鼠手术模型来创建通气性肺I/R损伤。此外，我们通过暂时剥夺细胞的所有营养物质来模拟体外营养性I/R损伤。与假手术小鼠相比，接受通气肺I/R损伤的小鼠上调了IL-1β、IL-6和CXCL 1和2的炎性介质信使RNA的表达，肺中性粒细胞募集的组织学证据证实了这一点，并且IL-1β、IL-6和HMGB 1蛋白的血浆水平升高。这种对I/R的炎症反应需要Toll样受体-4。此外，我们证明了体外巨噬细胞和内皮细胞之间的协同性和相互作用，导致对I/R的炎症反应增强。值得注意的是，我们发现肺泡巨噬细胞的选择性耗竭使小鼠对通气肺I/R损伤具有抵抗力。我们的数据表明，肺泡巨噬细胞和模式识别受体，Toll样受体-4所需的肺I/R损伤的早期炎症反应的产生。
Ischemia reperfusion (I/R) injury involves sterile inflammation and is commonly associated with diverse clinical situations such as hemorrhage followed by resuscitation, transient embolic events, and organ transplantation. I/R injury can induce lung dysfunction whether the I/R occurs in the lung itself or in a remote organ. Recently, evidence has emerged that receptors and pathways of the innate immune system are involved in recognizing sterile inflammation and overlap considerably with those involved in recognition and response to pathogens. We used a mouse surgical model of transient unilateral left pulmonary artery occlusion without bronchial involvement to create ventilated lung I/R injury. Additionally, we mimicked nutritional I/R injury in vitro by transiently depriving cells of all nutrients. Compared with sham-operated mice, mice subjected to ventilated lung I/R injury had upregulated lung expression of inflammatory mediator messenger RNA for IL-1β, IL-6, and CXCL1 and 2, paralleled by histologic evidence of lung neutrophil recruitment, and increased plasma levels of IL-1β, IL-6 and HMGB1 proteins. This inflammatory response to I/R required toll-like receptor-4. Furthermore, we demonstrated in vitro cooperativity and cross-talk between macrophages and endothelial cells, resulting in augmented inflammatory responses to I/R. Remarkably, we found that selective depletion of alveolar macrophages rendered mice resistant to ventilated lung I/R injury. Our data reveal that alveolar macrophages and the pattern recognition receptor, toll-like receptor-4 are required for the generation of the early inflammatory response to lung I/R injury.