Neutrophil Decision Making in Confined Environments in Health and Disease

描述(申请人提供)：中性粒细胞的完美功能对我们的健康至关重要。没有中性粒细胞，我们只能在正常环境中细菌和真菌的持续攻击下存活几天。中性粒细胞在大量条件下完美运作的巨大选择压力，使其成为迁移速度和到达远距离靶点能力方面最有效和最显着的细胞之一。然而，在几种情况下，中性粒细胞的活动可能会产生更多的损害而不是好处。虽然中性粒细胞的激活在轻微创伤后是保护性的，但严重创伤后过度活跃的中性粒细胞会产生全身性的有害影响，即使在没有感染的情况下也能有效地损害几个器官和组织。许多疾病，如慢性炎症性疾病、器官移植后的免疫反应或严重形式的哮喘，都可能因中性粒细胞活跃而恶化。其他时候，中性粒细胞变得没有反应，同时免疫系统下调，导致或促进败血症状态。尽管对中性粒细胞内作用的信号分子和通路的了解有了巨大的进步，但我们对中性粒细胞在疾病过程中的变化的了解是有限的，因此，在健康和疾病中调节中性粒细胞活动的能力仅限于很少的选择。我们认为，在低估中性粒细胞活性方面的进展不仅来自分子生物学研究，还来自新工具的开发，这些工具将能够发现与活体情况相关的条件下的中性粒细胞行为。最近，我们展示了当中性粒细胞在比细胞更小的微通道中运动时，中性粒细胞的运动速度出人意料地均匀。利用简单的通道网络，我们观察到中性粒细胞惊人的能力，可以找到通往化学诱导剂来源的最短路径。我们将进一步开发这些复杂的设备，以回答有关组织内、在健康和疾病中对中性粒细胞决策的机械和化学要求、中性粒细胞生物学中这些因素之间的相互作用的问题，并发现控制烧伤和其他危重患者炎症的新治疗策略。 与公共健康相关：中性粒细胞完美的功能对于我们的健康和保护我们免受来自我们封闭环境的许多感染源是至关重要的。。然而，有几种情况下，中性粒细胞活动可能产生比好处更大的损害，需要新的工具来更好地表征这些条件下的中性粒细胞。虽然目前研究中性粒细胞的方法完全依赖于细胞的化学刺激，但我们最近发现，中性粒细胞在小通道中的机械限制对中性粒细胞的行为至关重要。为了更好地了解烧伤后中性粒细胞活性的变化，我们将应用新的微流体工具，并量化中性粒细胞在健康和疾病条件下对机械和化学组合刺激的反应。这一认识可能会带来新的机会，为发现有效的治疗策略来控制烧伤和其他危重患者的炎症。

DESCRIPTION (provided by applicant): Neutrophil perfect functioning is essential for our well-being. Without neutrophils, we could only survive a few days the constant assault of bacteria and fungi in our normal environment. A tremendous selective pressure on neutrophils to function perfectly in a large number of conditions made neutrophils one of the most efficient and remarkable cells in terms of migration speed and ability to reach distant targets. However, there are several conditions where neutrophil activity could produce more damage than benefits. While neutrophil activation is protective after minor trauma, hyper-active neutrophils after major injuries have systemic deleterious effects and can effectively damage several organs and tissues, even in the absence of infection. Many conditions like chronic inflammatory diseases, immune reactions post-organ transplantation, or severe forms of asthma can be exacerbated by active neutrophils. Other times, neutrophils become unresponsive, simultaneously with down-regulation of the immune system, leading to, or facilitating septic states. Despite tremendous advances in the understanding of signaling molecules and pathways acting inside neutrophils, our understanding of the changes in neutrophils during disease processes is limited, and consequently, or abilities to modulate the activity of neutrophils in health and disease, restricted to very few options. We believe that advances in understating of neutrophil activity could come not only from molecular biology studies, but also from the development of new tools that would enable the discovery of neutrophil behavior in conditions relevant to in vivo situations. Recently, we demonstrated the surprisingly uniform motility of neutrophils when moving in micro-channels smaller in size than the cell. Using simple networks of channels, we have observed the surprising ability of neutrophils to find the shortest path towards a source of chemoattractant. We will further develop these complex devices to answer questions about the mechanical and chemical requirements for neutrophil decision making inside tissues, in health and disease, regarding the interplay between these in neutrophil biology, and to uncover new therapeutic strategies for controlling inflammation in burn and other critically ill patients. PUBLIC HEALTH RELEVANCE: Neutrophil perfect functioning is essential for our well-being and protection against many infectious agents from our close environment. . However, there are several conditions where neutrophil activity could produce more damage than benefits and new tools are needed to better characterize neutrophils in these conditions. While current methods for studying neutrophils relay exclusively on chemical stimulation of the cells, we have recently shown that the mechanical confinement of the neutrophils in small channels is of utmost importance for neutrophil behavior. To better understand neutrophil alterations of activity following burn injuries, we will apply new microfluidic tools and quantify the responses of neutrophils to combined mechanical and chemical stimuli, in health and disease conditions. This understanding could results in new opportunities for uncovering effective therapeutic strategies for controlling inflammation in burn and other critically ill patients.