Mitochondrial DAMPs and Inflammation after injury

描述(申请人提供)：创伤是45岁以下最常见的死亡原因，并导致巨大的医疗费用和生产力损失。我们真的不明白为什么损伤会导致危重疾病，即为什么局部机械事件，如组织挤压肢体会导致肺部炎症和衰竭。我们知道，损伤会引起炎症，这种炎症在临床上与感染引起的炎症无法区分。我们知道，感染会引起炎症，因为我们的免疫系统识别细菌表面的一些分子。我们认识到的是，我们的一些细胞内机制是从细菌进化而来的。因此，我们推断，如果细胞被创伤摧毁，泄漏出来的一些细胞内内容物在我们的免疫系统看来可能就是感染的证据。在我们开创性的前期工作中，我们现在已经确凿地表明，在临床创伤中，来自细胞内结构(称为线粒体)的碎片被释放到循环中。我们的初步工作表明，这种碎片对炎症和免疫有重要的功能影响，线粒体碎片是创伤和炎症之间的一个强有力的“缺失环节”。到目前为止，我们研究的线粒体碎片的两个主要成分是线粒体蛋白质和线粒体DNA。两者都能有效地激活免疫细胞。因此，我们认为，当死亡或受伤的细胞释放出在免疫系统看来像细菌的线粒体碎片时，组织破坏会导致炎症。因此，碎片会引起看起来像感染的炎症反应。如果我们理解这个过程，我们应该能够干预它。因此，我们建议研究线粒体碎片激活创伤后免疫的途径。我们将研究1)线粒体蛋白在免疫中的作用，2)线粒体DNA在免疫中的作用，以及3)暴露在这两个‘损伤’分子中是如何相互作用导致器官损伤的。 与公共卫生相关：损伤后发炎的主要原因尚不清楚。然而，细胞内的内容物可以通过暴露通常隐藏在细胞内的分子来激活免疫反应。线粒体是曾经自由生活的细菌的细胞内结构，因此它们包含的分子基序对人类免疫系统来说可能看起来像细菌。在创伤中，细胞被摧毁。我们发现，这个过程释放了分子基序，模拟了感染，并导致免疫反应，使患者生病。我们将对这一现象进行研究，以改善创伤受害者的护理和预后。

DESCRIPTION (provided by applicant): Trauma is the most common cause of death below age 45 and leads to enormous health care costs and lost productivity. We do not really understand why injury causes critical illness, ie why a local mechanical event such as tissue crushing a limb leads to lung inflammation and failure. We do know that injury can cause inflammation that such inflammation is clinically indistinguishable from that caused by infection. We know that infections cause inflammation because some of the molecules on the surface of bacteria are recognized by our immune system. What we recognized was that some of our intra-cellular machinery is evolutionary derived from bacteria. Thus we reasoned that if cells were destroyed by trauma some of the intra-cellular contents that leaked out might look to our immune system like evidence of infection. In our ground-breaking preliminary work, we have now shown conclusively that debris from intracellular structures called mitochondria is released into the circulation in clinical trauma. Our preliminary work showed this debris has important functional effects on inflammation and immunity and that mitochondrial debris is a potent 'missing link' between trauma and inflammation. The two major components of mitochondrial debris we have examined so far are mitochondrial proteins and mitochondrial DNA. Both potently activate immune cells. So we believe that tissue destruction causes inflammation when dead or injured cells release mitochondrial debris that looks like bacteria to the immune system. Thus the debris causes inflammatory responses that look like infection. If we understand this process we should be able to intervene in it. So we propose to study the pathways by which mitochondrial debris activates immunity after trauma. We will study 1) the role of mitochondrial proteins in immunity, 2) the role of mitochondrial DNA in immunity and 3) how exposure to these two 'damage' molecules interacts to cause organ injury. PUBLIC HEALTH RELEVANCE: The primary causes of inflammation after injury are unknown. Intracellular contents however, can activate immune responses by exposing molecules that are normally hidden within cells. Mitochondria are intracellular structures that were once free-living bacteria, So they contain molecular motifs that can look like bacteria to the human immune system. In trauma cells are destroyed. We found this process releases molecular motifs, simulates infection and causes immune responses that make patients ill. We will study this phenomenon in order to improve the care and outcomes of trauma victims.