Neutrophil Decision Making in Confined Environments in Health and Disease

描述（由申请人提供）：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面对细菌和真菌的持续攻击存活几天。中性粒细胞在许多条件下完美发挥作用的巨大选择压力使中性粒细胞成为最有效和最显著的细胞之一，就迁移速度和到达远距离目标的能力而言。然而，在某些情况下，中性粒细胞的活动可能产生更多的损害而不是益处。虽然中性粒细胞在轻微创伤后激活具有保护作用，但在严重损伤后过度活跃的中性粒细胞具有全身有害作用，即使在没有感染的情况下也可以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，都可能因活跃的中性粒细胞而加剧。其他时候，中性粒细胞变得无反应，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部的信号分子和途径的理解取得了巨大的进步，但我们对疾病过程中中性粒细胞变化的理解是有限的，因此，或调节中性粒细胞在健康和疾病中的活动的能力，仅限于很少的选择。我们相信，在了解中性粒细胞活性方面的进展不仅可以来自分子生物学研究，还可以来自新工具的开发，这些工具将使中性粒细胞在与体内情况相关的条件下的行为得以发现。最近，我们展示了中性粒细胞在比细胞更小的微通道中运动时令人惊讶的均匀运动性。利用简单的通道网络，我们观察到中性粒细胞具有惊人的能力，能够找到通往化学引诱剂来源的最短路径。我们将进一步开发这些复杂的设备，以回答组织内、健康和疾病中中性粒细胞决策的机械和化学需求问题，以及中性粒细胞生物学中这些因素之间的相互作用，并发现控制烧伤和其他危重患者炎症的新治疗策略。

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.