Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome.
Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome.
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DOI：
10.1136/thoraxjnl-2017-210030
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发表时间：
2017-10
期刊：
影响因子：
10
通讯作者：
Rossi AG
中科院分区：
文献类型：
--
作者：
Dorward DA;Lucas CD;Doherty MK;Chapman GB;Scholefield EJ;Conway Morris A;Felton JM;Kipari T;Humphries DC;Robb CT;Simpson AJ;Whitfield PD;Haslett C;Dhaliwal K;Rossi AG
急性呼吸窘迫综合征(ARDS)是一种以中性粒细胞为主的肺部疾病。尽管受到多种促炎介质的影响，但确定合适的候选治疗方案仍然难以捉摸。我们的目的是描述线粒体甲酰化多肽在ARDS中的存在，并表征甲酰肽受体1(FPR1)信号在无菌肺部炎症中的功能重要性。用高效液相色谱-串联质谱法测定了ARDS患者支气管肺泡灌洗液(BALF)和血清中线粒体甲酰化肽的含量。体外用线粒体甲酰化多肽刺激人中性粒细胞，用流式细胞仪和趋化试验评价其作用。用线粒体甲酰化多肽或盐酸诱导小鼠肺损伤。骨髓嵌合体决定了髓系和实质FPR1在无菌肺部炎症中的作用。ARDS患者BALF和血清中线粒体甲酰化多肽水平升高。这些多肽在体外和体内通过依赖FPR1的机制来驱动中性粒细胞的激活和趋化。在小鼠肺损伤中，fpr1−/−小鼠的炎症被减轻，即使在损伤开始后给药，药理上的fpr1拮抗剂也能概括这一效果。FPR1在肺泡上皮细胞和嵌合体小鼠中均有表达，表明髓系和实质系FPR1均参与了肺部炎症。我们提供了线粒体甲酰化肽在人类疾病中的第一个确凿证据，并证明它们在ARDS中升高，在小鼠肺损伤模型中很重要。这项工作揭示了线粒体甲酰化肽FPR1信号是无菌急性肺损伤的关键驱动因素，也是ARDS的潜在治疗靶点。
Acute respiratory distress syndrome (ARDS) is an often fatal neutrophil-dominant lung disease. Although influenced by multiple proinflammatory mediators, identification of suitable therapeutic candidates remains elusive. We aimed to delineate the presence of mitochondrial formylated peptides in ARDS and characterise the functional importance of formyl peptide receptor 1 (FPR1) signalling in sterile lung inflammation. Mitochondrial formylated peptides were identified in bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS by liquid chromatography–tandem mass spectrometry. In vitro, human neutrophils were stimulated with mitochondrial formylated peptides and their effects assessed by flow cytometry and chemotaxis assay. Mouse lung injury was induced by mitochondrial formylated peptides or hydrochloric acid. Bone marrow chimeras determined the contribution of myeloid and parenchymal FPR1 to sterile lung inflammation. Mitochondrial formylated peptides were elevated in BALF and serum from patients with ARDS. These peptides drove neutrophil activation and chemotaxis through FPR1-dependent mechanisms in vitro and in vivo. In mouse lung injury, inflammation was attenuated in Fpr1−/− mice, effects recapitulated by a pharmacological FPR1 antagonist even when administered after the onset of injury. FPR1 expression was present in alveolar epithelium and chimeric mice demonstrated that both myeloid and parenchymal FPR1 contributed to lung inflammation. We provide the first definitive evidence of mitochondrial formylated peptides in human disease and demonstrate them to be elevated in ARDS and important in a mouse model of lung injury. This work reveals mitochondrial formylated peptide FPR1 signalling as a key driver of sterile acute lung injury and a potential therapeutic target in ARDS.
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影响因子：
5.5
作者：
Dorward DA;Lucas CD;Alessandri AL;Marwick JA;Rossi F;Dransfield I;Haslett C;Dhaliwal K;Rossi AG
通讯作者：
Rossi AG
影响因子：
7.4
作者：
Kung CT;Hsiao SY;Tsai TC;Su CM;Chang WN;Huang CR;Wang HC;Lin WC;Chang HW;Lin YJ;Cheng BC;Su BY;Tsai NW;Lu CH
通讯作者：
Lu CH
DOI：
10.1164/rccm.200812-1928oc
发表时间：
2009-07-01
影响因子：
24.7
作者：
Conway Morris A;Kefala K;Wilkinson TS;Dhaliwal K;Farrell L;Walsh T;Mackenzie SJ;Reid H;Davidson DJ;Haslett C;Rossi AG;Sallenave JM;Simpson AJ
通讯作者：
Simpson AJ
影响因子：
5.4
作者：
Rabiet, MJ;Huet, E;Boulay, F
通讯作者：
Boulay, F
DOI：
10.1183/09031936.00093911
发表时间：
2012-05
期刊：
The European respiratory journal
影响因子：
--
作者：
Patel BV;Wilson MR;Takata M
通讯作者：
Takata M