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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

基本信息

批准号：
10227204
负责人：
Courtney Mattson
金额：
$ 4.12万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10227204
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

项目摘要

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.

项目概要严重伤害和疾病可能导致急性呼吸窘迫综合征 (ARDS)，这是一种高死亡率的急性疾病呼吸衰竭的发病率高达每 10 万人/年 80 例，死亡率为大约40%。该综合征与表面活性剂功能障碍和空腔水肿有关，从而导致肺泡塌陷（复张）。由于肺结构和功能的退化，机械性需要通气来控制 ARDS 并保持足够的气体交换。然而，机械通气诱发呼吸机相关性肺损伤 (VILI)，从而通过组织加剧 ARDS 的影响过度膨胀以及肺泡和远端气道的周期性塌陷和重新打开。已经取得了巨大的进步了解 VILI 的基本机制，以便可以通过通气来减少 VILI，同时维持气体交换。然而，这两个要求经常发生冲突，需要确定最佳的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。确定损伤机制以及保护性通气模式因时空变化而变得复杂 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进展通过脆弱肺泡的物理互连来治疗疾病。在这种情况下，降低了肺泡被淹没或塌陷会增加邻近专利区域的压力。因此，该提案将测试水肿和细胞损伤将在高压力位置开始的总体假设；这些最初受伤的区域会产生应力集中，使邻近区域极易受到进一步伤害。为了测试这个假设，我们将结合实验和计算技术来说明存在性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尺度损伤的空间分布。来解读这些数据，我们将实施一种新型统计模型来确定相互依赖的范围和强度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，有助于确定防止传播的通风制度损伤以降低 ARDS 死亡率。最后，有限元肺泡网络的新颖公式将用于确定细胞损伤的聚集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性。除了这些科学目标外，该提案还将支持以下领域的发展：通过实验室技术的教学和指导培训，成为一名有前途的年轻肺部研究人员，数学、专业技能。