The Evaluation of TLT-1 as treatment for ALI/ARDS

项目摘要 急性肺损伤尤其是急性呼吸窘迫综合征（acute respiratory distress syndrome，ARDS）已被确定为生命的重要组成部分 与高死亡率相关的威胁性疾病。尽管过去取得了进步 几十年来，在对肺部疾病的了解中，ARDS继续夺去超过40%的人的生命， 它的受害者。医疗保健相关费用的增加对经济产生重大影响， 由于对这种疾病的不完全了解， 控制病理表现的机制。血小板、中性粒细胞和内皮细胞 细胞已被确定为ALI/ARDS进展中的关键组分。而且我们 在过去的几年里，对血小板功能的理解已经从简单的止血工具转变为 免疫反应的动态调节剂。目前血小板的研究范式旨在揭示 使这些细胞成为炎症主要指挥官的分子机制。先前 报道已经证明血小板的缺乏导致内皮损伤的增加， 异常的中性粒细胞功能和炎症期间的出血。此外，这些影响已经 显示出在活化过程中受血小板颗粒释放的控制。迄今为止， 血小板颗粒分子或参与其中的分子仍有待阐明，代表GAB。 我们的知识因此，本研究旨在确定调节血小板功能的关键血小板成分， 炎症过程中通过调节嗜中性粒细胞-内皮细胞串扰的全身反应 和相关机制。为了剖析这个问题，我们将评估一种已知的血小板颗粒产品， 作为TLT-1在调节中性粒细胞-内皮细胞信号传导机制中的作用 炎症期间的串扰。选择TLT-1作为潜在靶点的依据出现了 先前的研究表明，TLT-1敲除小鼠表现出水肿增加， 出血以及中性粒细胞在炎症期间的显著功能障碍， Schwartzman反应引起的血管炎。此外，我们还评估了TLT-1在其他 炎症模型，包括使用LPS鼻内接种的ALI小鼠模型。我们 初步数据显示，TLT-1可预防炎症相关出血， 中性粒细胞在肺中的迁移导致内皮损伤的减少。所以基于 根据这些先前的观察，我们假设TLT-1介导了 调节中性粒细胞迁移到炎症部位的能力，并调节中性粒细胞- 炎症过程中的内皮细胞相互作用，从而控制免疫反应。我们 为了回答这个问题，我们制定了两个具体的目标。目标如下：（一）确定以下方面的作用： 炎症过程中血小板-中性粒细胞-内皮细胞相互作用中的TLT-1和（ii）阐明 TLT-1对ALI/ARDS的治疗作用。这两个目标将有助于实现我们目前的目标。 了解血小板在炎症中的生物学功能。通过以下方式获得的答案： 这项研究工作的实现将使我们的知识能够开发新的替代品， 针对控制对炎症的全身反应的治疗。

Project Summary Acute Lung injury especially acute respiratory distress syndrome (ARDS) have been identified as life threatening conditions associated with significant mortality rate. Despite advances in the past decades in the knowledge on lung diseases, ARDS continues to claim the lives of more than 40% of its victims. The increase in health care associated costs has a major economic impact, while major clinical efforts to manage this disease are insufficient due to an uncomplete understanding of the mechanisms that control the pathology manifestations. Blood platelets, neutrophils and endothelial cells have been identified as the key components in the progression of ALI/ARDS. Moreover, our understanding of platelets function has shifted over the past years from a simple hemostatic tool to dynamic modulators of the immune response. The current paradigm of platelets intents to uncover the molecular mechanisms that make these cells major orchestrators of inflammation. Previous reports have demonstrated that the absence of platelets leads to increase endothelial damage, aberrant neutrophil function and hemorrhage during inflammation. Moreover, these effects have been shown to be controlled by the release of platelet granules during activation. To date, the identity of the platelet granule molecule or molecules involved in this remains to be elucidated representing gab in our knowledge. Accordingly, this study seeks to identify key platelet components that modulate systemic response during inflammation through the modulation of neutrophil-endothelial cell crosstalk and mechanisms involved. To dissect that question we will evaluate a platelet granule product known as TLT-1 in the mediation of the signaling mechanisms that modulates neutrophil -endothelial cell cross-talk during inflammation. The basis for the selection of TLT-1 as a potential target emerges from previous studies that demonstrated that TLT-1 knockout mice exhibited increased edema and hemorrhage together with a marked dysfunction of neutrophils during inflammation elicited by the Schwartzman reaction derived vasculitis. Moreover, we have evaluated TLT-1 functions in other models of inflammation including a mouse model of ALI using intranasal inoculation of LPS. Our preliminary data shows that TLT-1 prevents inflammatory associated hemorrhage while facilitate neutrophils transmigration in lung leading to decrease endothelial damage. Therefore, based on these previous observations we hypothesize that TLT-1 mediates the signaling mechanisms that regulate neutrophil capacity to transmigrate to the inflammatory site and modulate neutrophil- endothelial cell interactions during inflammation and therefore controlling the immune response. We developed two specific aims to answer that question. The aims are as follows: (i) Define a role for TLT-1 in platelet-neutrophill-endothelial cell interactions during inflammation and (ii) Elucidate the therapeutic effects of TLT-1 on ALI/ARDS. This two aims will help to fulfill our current understanding of platelet biological functions in inflammation. The answers obtained through the realization of this research work will empower our knowledge to be able to develop new alternative treatments directed to control systemic response to inflammation.