Mitochondrial damage-associated molecular patterns from fractures suppress pulmonary immune responses via formyl peptide receptors 1 and 2.
Mitochondrial damage-associated molecular patterns from fractures suppress pulmonary immune responses via formyl peptide receptors 1 and 2.
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DOI：
10.1097/ta.0000000000000509
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Hauser CJ
中科院分区：
文献类型：
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作者：
Li H;Itagaki K;Sandler N;Gallo D;Galenkamp A;Kaczmarek E;Livingston DH;Zeng Y;Lee YT;Tang IT;Isal B;Otterbein L;Hauser CJ
组织损伤与肺炎（PNA）之间尚无已知的生物学机制。中性粒细胞（PMN）是先天性免疫细胞，其通过向化学引诱物迁移并杀死中性粒细胞胞外陷阱（NET）中的细菌而从肺中清除细菌。我们预测，组织损伤会抑制肺内PMN的抗菌功能。我们还表明，从骨中的骨衍生的损伤相关的分子模式分子可以改变PMN表型，因此假设，甲酰肽（FP）骨折易患PNA抑制PMN在lung.METHODSAnimal研究涉及以下。(1)将大鼠分为3组（每种条件10只），如下所示：（a）大腿注射生理盐水（B）股骨头内注射金黄色葡萄球菌（SA，3× 10 8），或（c）假性骨折（PsFx;大腿注射骨上清液）加股骨头内注射SA。(2)将大鼠分为4组：（a）对照组，（B）肺挫伤组（PC），（c）PsFx组，（d）PC+ PsFx组。16小时后进行支气管肺泡灌洗。临床研究涉及以下内容。(3)测定人骨上清液的FP受体（FPR）刺激。(4)实验中，（1）SA能被正常小鼠迅速清除，PsFx能显著抑制肺内细菌清除（p< 0.01）。(2a)PC可诱导PMN向肺的运输，而PsFx可减少PC诱导的PMN运输（p< 0.01）。(2b)SA可增加肺泡灌洗液中PMN的流入量，PsFx可减少PMN的流入量（P< 0.01）。在临床研究中，（3）骨上清液通过FPR-1和FPR-2激活PMN。(4)创伤使PMN CTX减少为多种趋化因子。循环中性粒细胞显示NET自发创伤后，但最大NET形成显着attenuated. CONCLUSION骨折可能会降低肺细菌清除，因为FP抑制中性粒细胞CTX通过FPR-1/2的其他化学引诱剂。创伤激活NETosis但抑制最大NETosis。骨折通过多种机制降低肺细菌清除率。骨折后PNA可能反映了损伤相关的分子模式介导的肺中性粒细胞抗菌功能的抑制。
BACKGROUNDNo known biologic mechanisms link tissue injury with pneumonia (PNA). Neutrophils (PMNs) are innate immune cells that clear bacteria from the lung by migration toward chemoattractants and killing bacteria in neutrophil extracellular traps (NETs). We predicted that tissue injury would suppress PMN antimicrobial function in the lung. We have also shown that mitochondria-derived damage-associated molecular pattern molecules from the bone can alter PMN phenotype and so hypothesized that formyl peptides (FPs) from fractures predispose to PNA by suppressing PMN activity in the lung.METHODSAnimal studies involved the following.(1) Rats were divided into three groups (10 per condition) as follows:(a) saline injection in the thigh (b) Staphylococcus aureus (SA, 3× 10 8) injected intratracheally, or (c) pseudofracture (PsFx; bone supernatant injected in the thigh) plus intratracheally injected SA.(2) Rats were divided into four groups as follows:(a) control,(b) pulmonary contusion (PC),(c) PsFx, and (d) PC+ PsFx. Bronchoalveolar lavage was performed 16 hours later. Clinical studies involved the following.(3) Human bone supernatant was assayed for its FP-receptor (FPR) stimulation.(4) Trauma patients’ PMN (n= 32; mean±SE Injury Severity Score [ISS], 27±10) were assayed for chemotaxis (CTX) or treated with Phorbol 12-myristate 13-acetate (PMA, Phorbol ester) and analyzed for NET formation.RESULTSIn the animal studies,(1) SA was rapidly cleared by the uninjured mice and PsFx markedly suppressed lung bacterial clearance (p< 0.01).(2a) PC induces PMN traffic to the lung, but PsFx decreases PC-induced PMN traffic (p< 0.01).(2b) SA increased bronchoalveolar lavage PMN, and PsFx decreased that influx (p< 0.01). In the clinical studies,(3) bone supernatant activates PMN both via FPR-1 and FPR-2.(4) Trauma decreases PMN CTX to multiple chemokines. Circulating PMNs show NETs spontaneously after trauma, but maximal NET formation is markedly attenuated.CONCLUSIONFractures may decrease lung bacterial clearance because FP suppresses PMN CTX to other chemoattractants via FPR-1/2. Trauma activates NETosis but suppresses maximal NETosis. Fractures decrease lung bacterial clearance by multiple mechanisms. PNA after fractures may reflect damage-associated molecular pattern–mediated suppression of PMN antimicrobial function in the lung.