Spatiotemporal evolution of lung injury during ventilator-induced lung injury

呼吸机所致肺损伤期间肺损伤的时空演变

• 批准号: 10058766
• 负责人: Courtney Mattson
• 金额: $ 4.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058766
• 关键词: Acute respiratory failure; Adult Respiratory Distress Syndrome; Algorithms; Alveolar; Anatomy; Area; Biophysical Process; Cells; Computational Technique; Computer Models; Computer Simulation; Computer software; Conflict (Psychology); Critical Illness; Custom; Data; Detection; Development; Disease Progression; Distal; Edema; Elements; Equilibrium; Evolution; Feedback; Floods; Formulation; Functional disorder; Future; Gases; Goals; Gravitation; Heterogeneity; Image Analysis; Incidence; Inflammation; Injury; Knowledge; Laboratories; Lead; Legal patent; Location; Lung; Maps; Mathematics; Measurement; Mechanical ventilation; Mechanics; Mentors; Methods; Modeling; Mus; Outcome; Pathway interactions; Pattern; Periodicity; Persons; Population; Positioning Attribute; Postdoctoral Fellow; Probability; Research; Research Personnel; Risk; Spatial Distribution; Statistical Models; Stress; Structure; Syndrome; Techniques; Testing; Time; Tissues; Training; Validation; Ventilator; Ventilator-induced lung injury; Woman; base; career; cell injury; improved; injured; insight; lung injury; mechanical force; mortality; network models; novel; pressure; prevent; severe injury; simulation; skills; spatiotemporal; surfactant; theories; tool; ventilation; whole slide imaging

Project Summary Severe injury and illness may lead to Acute Respiratory Distress Syndrome (ARDS), a high mortality acute respiratory failure that has an incidence of up to 80 cases per 100,000 person/years and a mortality rate of approximately 40%. The syndrome is associated with surfactant dysfunction and airspace edema that lead to alveolar collapse (derecruitment). Because of the degeneration of lung structure and function, mechanical ventilation is required to manage ARDS and maintain adequate gas exchange. However, mechanical ventilation induces ventilator-induced lung injury (VILI) which exacerbates the effects of ARDS through tissue overdistension and the cyclic collapse and reopening of alveoli and distal airways. Great strides have been made in understanding the basic mechanisms of VILI so that ventilation may be prescribed to reduce VILI while maintaining gas exchange. However, these two demands are frequently in conflict and identifying optimal mechanical ventilation parameters remains a challenging task for even the most skilled clinician. Determining the mechanisms of injury, and thus protective ventilation patterns, is complicated by the spatiotemporal heterogeneity of ARDS and VILI. It is thought that this heterogeneity may contribute to the progression of these diseases through the physical interconnectivity of the delicate alveoli. In this scenario, reduced distensibility of a flooded or collapsed alveoli will increase the strain in adjacent patent regions. This proposal will therefore test the overall hypothesis that edema and cellular injury will start in high stress locations; these initially injured areas will create stress foci, which make the proximal areas highly susceptible to further injury. To test this hypothesis, we will use a combination of experimental and computational techniques to illustrate the existence of injury heterogeneity and its progression, quantify the influence of injured regions on new damage, and predict the mechanisms that cause injury to spread. Novel image analysis techniques and custom-built computer software will quantify the micro- and macro- scale distribution of cellular injury in mouse VILI. These measurements will, for the first time, quantify the spatial distribution of cellular-scale injury. To interpret these data, we will implement a new type of statistical model to determine the range and strength of interdependence between existing and new cellular injury. These simulations will allow interpretation of my experimental measurements and, in future studies, facilitate the identification of ventilation regimes that prevent the spread of injury to reduce ARDS mortality. Finally, novel formulations of a finite element alveolar network will be used to determine if the clustering of cell injury may be attributed increased mechanical strain caused by the physical interconnectivity of the alveoli. In addition to these scientific goals, this proposal will support the development of a promising young pulmonary researcher through didactic and mentored training in laboratory techniques, mathematics, and professional skills.

项目摘要 严重的创伤和疾病可导致急性呼吸窘迫综合征(ARDS)，是一种高死亡率的急性呼吸窘迫综合征 呼吸衰竭的发病率高达每10万人/年80例，死亡率为# 大约40%。该综合征与肺表面活性物质功能障碍和肺泡水肿有关，从而导致 肺泡塌陷(脱屑)。由于肺结构和功能的退行性改变，机械 需要通风来管理ARDS和维持足够的气体交换。然而，机械通风 诱导呼吸机诱导的肺损伤(VILI)，通过组织加重ARDS的影响 肺泡和远端气道过度扩张、周期性塌陷和重新开放。已经取得了长足的进步 了解VILI的基本机制，以便在减少VILI的同时 维持气体交换。然而，这两个需求经常是冲突的，并确定最优 即使对于最熟练的临床医生来说，机械通气参数仍然是一项具有挑战性的任务。确定 损伤的机制，从而保护性的通风模式，是复杂的时空 ARDS和VILI的异质性。人们认为，这种异质性可能有助于这些疾病的发展。 通过纤细的肺泡的物理连接而产生的疾病。在此方案中，降低了 淹没或塌陷的肺泡会增加邻近未闭区域的张力。因此，这项提议将考验 认为水肿和细胞损伤将从高应力部位开始的总体假设；这些最初是受伤的 这些区域会产生应力焦点，使近端区域非常容易受到进一步的伤害。为了测试这一点 假设，我们将使用实验和计算技术的组合来说明存在 损伤异质性及其进展，量化损伤区域对新损伤的影响， 并预测导致伤害扩散的机制。新颖的图像分析技术和定制 计算机软件将量化小鼠VILI细胞损伤的微观和宏观分布。这些 测量将首次量化细胞规模损伤的空间分布。为了解释这些 数据，我们将实施一种新型的统计模型来确定相互依赖的范围和强度 在现有的和新的细胞损伤之间。这些模拟将允许解释我的实验 测量，并在未来的研究中，促进确定防止传播的通风制度 损伤以降低ARDS死亡率。最后，将使用有限元肺泡网络的新公式来 确定细胞的聚集性损伤是否可能归因于物理引起的机械应变增加 肺泡的相互连接。除了这些科学目标外，这项提案还将支持 一位有前途的年轻肺部研究人员，通过实验室技术的教学和指导培训， 数学和专业技能。