Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways.
Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways.
复制标题
DOI：
10.1371/journal.pone.0059989
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Itagaki K
中科院分区：
文献类型：
--
作者：
Sun S;Sursal T;Adibnia Y;Zhao C;Zheng Y;Li H;Otterbein LE;Hauser CJ;Itagaki K
创伤和脓毒症可部分通过触发中性粒细胞（PMN）介导的内皮细胞（EC）通透性增加而引起急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）。我们已经证明，线粒体（mt）损伤相关分子模式（DAMPs）出现在损伤或休克后的血液中，并激活人PMN。因此，我们现在假设线粒体DAMP（MTD）如线粒体DNA（mtDNA）和肽可能在全身炎症期间EC通透性增加中发挥作用，并继续评估潜在机制。线粒体DNA诱导的EC渗透性的变化发生在两个阶段：一个简短的，中性粒细胞无关的“穗”的渗透性随后由一个长期的中性粒细胞依赖的增加渗透性。破碎的线粒体（MTD）引起的中性粒细胞非依赖性增加EC渗透性，被废除与蛋白酶治疗。暴露于mtDNA引起PMN-EC粘附激活表达的粘附分子表达在两种细胞类型。细胞活化表现为PMN钙流和EC MAPK磷酸化的增加。内体TLR抑制剂可减弱渗透性和PMN粘附。EC缺乏甲酰肽受体，但仍然被mt蛋白激活，表明非甲酰化mt蛋白DAMP可以激活EC。线粒体DAMP可以通过许多过程释放到循环中，导致细胞损伤并导致病理性内皮渗透性。我们在这里表明，线粒体含有多个DAMP基序，可以通过多种途径作用于EC和/或PMN。这可以增强PMN对EC的粘附，激活PMN-EC相互作用，随后增加全身内皮通透性。在炎症病理性增加内皮通透性的情况下，线粒体DAMP可能是重要的治疗靶标。
Trauma and sepsis can cause acute lung injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) in part by triggering neutrophil (PMN)-mediated increases in endothelial cell (EC) permeability. We had shown that mitochondrial (mt) damage-associated molecular patterns (DAMPs) appear in the blood after injury or shock and activate human PMN. So we now hypothesized that mitochondrial DAMPs (MTD) like mitochondrial DNA (mtDNA) and peptides might play a role in increased EC permeability during systemic inflammation and proceeded to evaluate the underlying mechanisms. MtDNA induced changes in EC permeability occurred in two phases: a brief, PMN-independent ‘spike’ in permeability was followed by a prolonged PMN-dependent increase in permeability. Fragmented mitochondria (MTD) caused PMN-independent increase in EC permeability that were abolished with protease treatment. Exposure to mtDNA caused PMN-EC adherence by activating expression of adherence molecule expression in both cell types. Cellular activation was manifested as an increase in PMN calcium flux and EC MAPK phosphorylation. Permeability and PMN adherence were attenuated by endosomal TLR inhibitors. EC lacked formyl peptide receptors but were nonetheless activated by mt-proteins, showing that non-formylated mt-protein DAMPs can activate EC. Mitochondrial DAMPs can be released into the circulation by many processes that cause cell injury and lead to pathologic endothelial permeability. We show here that mitochondria contain multiple DAMP motifs that can act on EC and/or PMN via multiple pathways. This can enhance PMN adherence to EC, activate PMN-EC interactions and subsequently increase systemic endothelial permeability. Mitochondrial DAMPs may be important therapeutic targets in conditions where inflammation pathologically increases endothelial permeability.
登录
查看更多内容
循环线粒体 DAMP 会引起对损伤的炎症反应。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Oka, Takafumi;Hikoso, Shungo;Yamaguchi, Osamu;Taneike, Manabu;Takeda, Toshihiro;Tamai, Takahito;Oyabu, Jota;Murakawa, Tomokazu;Nakayama, Hiroyuki;Nishida, Kazuhiko;Akira, Shizuo;Yamamoto, Akitsugu;Komuro, Issei;Otsu, Kinya
通讯作者：
Otsu, Kinya
DOI：
10.1097/shk.0b013e3181997173
发表时间：
2009-07
期刊：
Shock (Augusta, Ga.)
影响因子：
--
作者：
Peltz ED;Moore EE;Eckels PC;Damle SS;Tsuruta Y;Johnson JL;Sauaia A;Silliman CC;Banerjee A;Abraham E
通讯作者：
Abraham E
DOI：
10.1097/00005373-200004000-00003
发表时间：
2000-04-01
影响因子：
--
作者：
Hauser, CJ;Fekete, Z;Deitch, EA
通讯作者：
Deitch, EA
影响因子：
5.5
作者：
Hopson, Kristen Park;Truelove, Jessica;Waeber, Christian
通讯作者：
Waeber, Christian