Mesenchymal Stem Cell (MSC) regulation of pulmonary macrophage populations in Acute Respiratory Distress Syndrome (ARDS).

急性呼吸窘迫综合征(ARDS)是一种严重的临床综合征，影响所有重症监护患者的20%。不幸的是，大约30%-50%的人会死于这种疾病，幸存者的生活质量可能会因为随之而来的慢性肺部问题而严重下降。目前还没有有效的治疗方法，因此迫切需要新的药物。ARDS的特点是肺部过度和不受控制的炎症，导致免疫细胞的不适当渗透，肺充满水，无法维持其主要功能-呼吸。为了呼吸，这些患者需要机械呼吸。ARDS由多种原因引起，尽管肺炎引起的ARDS是最常见的，也是最具破坏性的。炎症是身体对感染、刺激或其他伤害的反应方式。正常情况下，炎症是机体修复和应对感染的一种方式，然而，在某些情况下，如ARDS，炎症可能会导致严重的损害和肺功能的损害。被称为巨噬细胞的免疫细胞作为炎症反应的协调者，在ARDS的发展和消退中发挥着关键作用。近年来，在ARDS研究领域工作的临床医生和基础科学家越来越关注基于细胞的治疗方法。与药物治疗相比，细胞治疗的一个关键优势是细胞可以主动响应局部微环境并发挥多种有益作用，在这个复杂的疾病过程中调节几个损伤和修复途径。ARDS基于细胞治疗的最有希望的候选细胞之一是间充质干细胞(MSC)，它代表一种成人干细胞(可以很容易地从成人患者或健康志愿者的组织中分离出来)，因此不存在与使用胚胎组织相关的伦理问题。间充质干细胞可以在实验室条件下很容易地繁殖和操纵，并具有分化为多种不同类型的身体细胞的能力。重要的是，长期的研究已经证明了它们在发生肿瘤方面的安全性。我们小组以及其他研究人员进行的多项临床前动物研究表明，MSC作为ARDS的治疗药物确实具有保护作用。在许多有益的作用中，它们的使用总是与显著减轻炎症有关，然而这种现象的机制仍然不清楚，关于它们与肺免疫细胞相互作用的数据仍然不充分和有争议。为了将MSC转化为临床实践，我们必须对其作用机制有更准确的了解。在拟议的研究中，我们热衷于解决的主要问题是：MSC治疗如何影响肺巨噬细胞？根据我们的初步数据和其他研究的结果，我们有理由假设MSC将促进巨噬细胞的极化，使其向抑制炎症的状态转变，并促进ARDS的分解--所谓的“交替激活的巨噬细胞”或M2巨噬细胞。来自这项研究的机制数据将使MSC基础上的新疗法的开发更接近患者。此外，它还将拓宽有关肺巨噬细胞生物学及其在解决ARDS中的作用的现有知识，这可能导致其他新的治疗方法。重要的是，这项拟议研究的结果也可能与其他巨噬细胞依赖的炎症条件相关。

Acute Respiratory Distress Syndrome (ARDS) is a severe clinical syndrom that affects 20% of all critically ill patients in intensive care. Unfortunately, around 30-50% of these people will die from the condition and the quality of life of the survivers can be seriously reduced due to the consequent chronic lung problems.There is no effective treatments for this condition at this time and therefore new medicines are urgently needed. ARDS is characterised by an excessive and disregulated inflammation in the lung that leads to inappropriate infiltration of immune cells, lungs fill with water and fail to maintain its main function - breathing. In order to breath these patients require mechanical ventilation.ARDS results from multiple causes, although pneumonia induced ARDS is the most common and the most devastating. Inflammation is the way in which the body reacts to infection, irritation or other injury. Normally, inflammation is one way the body heals and copes with the infection, however, when disregulated in certain condition such as ARDS it can lead to severe damages and impair of the the lung function. Immune cells called macrophages have increasingly been recognized to play a key role in the development and resolution of ARDS functioning as a coordinators of inflammatory responses. Recently more and more attention of clinicians and basic scientists working in the field of ARDS research is drawn to cell-based therapies. A key advantage of cell based therapy compared to pharmacologic treatment is that cells can actively respond to the local microenvironment and exert multiple beneficial effects, modulating several injurious and reparative pathways in this complex disease process.One of the most promising candidate for a cell based therapy for ARDS are cells termed Mesenchymal Stem Cells (MSC), which represent one kind of adult stem cells (can be easily isolated from tissues of adult patients or healthy volunteers), because of this there is no ethical issues that are related to use of embryonic tissues. MSC could easily be propagated and manipulated under laboratory conditions and have capacity to differentiate into multiple different cell types of the body. Importantly, long term research has shown their safety in terms of developing tumors.Multiple preclinical animal studies conducted by our group as well as by other investigators showed that MSC indeed have protective effect when administered as a treatment for ARDS. Among several beneficial effects, their administration always is associated with drastically reduced inflammation, however the mechanisms of this phenomenon are still unclear and data on their interaction with the immune cells of the lung remain unsufficient and controversial. To translate MSC into the clinical practice it is essential that we have more precise understanding of their mechanism of action. The main question we are keen to address in the proposed research is: how MSC treatment influence the lung macrophages? What alterations do MSC induce in their functions and what molecular mechanisms mediate those changes.Based on our preliminary data and results from other studies we have reasons to hypothesize that MSC will promote polarization of macrophages towards the state in which they will supress the inflammation and promote the resolution of ARDS- so called "alternatively activated macrophages" or M2 macrophages.The mechanistic data from this study will bring development of new therapy on the MSC basis closer to the patients. Additionally, it will broaden the existing knowledge of lung macrophage biology and their role in the resolution of ARDS which could lead to other new treatments. Importantly, findings from the proposed study may also have relevance for other macrophage dependent inflammatory conditions.