The Importance of Inhomogeneity in the Pathogenesis of Lung Injury

不均匀性在肺损伤发病机制中的重要性

基本信息

批准号：
8949132
负责人：
Bradford J Smith
金额：
$ 11.18万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8949132
关键词：
Acute respiratory failure Adult Respiratory Distress Syndrome Affect Alveolar Alveolus Animal Experimentation Atelectasis Biomedical Engineering Cessation of life Collection Computer Simulation Computing Methodologies Conflict (Psychology)Couples Critical Illness Development Edema Environment Environmental air flow Equilibrium Feedback Goals Heterogeneity Injury Lead Link Liquid substance Location Lung Lung diseases Malignant neoplasm of prostate Measurement Mechanical ventilation Mechanics Medicine Modeling Mus Nature Organ Outcome Pathogenesis Pathway interactions Patients Physiology Production Research Research Personnel Respiratory Failure Respiratory physiology Rest Role Sepsis Solid Spatial Distribution Stress Structure Structure of parenchyma of lung Testing Tidal Volume Time Tissues Training Trauma United States Universities Variant Ventilator-induced lung injury Vermont Volutrauma atelectrauma base career college design experience improved injured lung injury malignant breast neoplasm mortality mouse model novel pressure prevent programs research study skills smoke inhalation spatiotemporal surfactant treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Acute respiratory distress syndrome (ARDS) is a form of acute respiratory failure resulting from a variety of insults including sepsis, smoke inhalation and severe trauma. ARDS has a high mortality rate of 30-40%, which results in approximately 75,000 deaths per year. This exceeds the mortality due to breast or prostate cancer. Treatment of ARDS is based on supportive mechanical ventilation that is applied while the underlying cause of respiratory failure hopefully resolves. However, selecting appropriate ventilation parameters is difficult because of the conflicting requirements imposed by the inhomogeneous nature of lung injury in ARDS. Inspiratory pressures must be sufficiently low to avoid over-distention of the delicate parenchyma (volutrauma) while at the same time expiratory pressures must be high enough to prevent damage caused by the repetitive collapse (derecruitment) and reopening (recruitment) of airways and alveoli (atelectrauma). Volutrauma and atelectrauma can both lead to ventilator-induced lung injury (VILI) which is manifest as local accumulation of edema in the airspaces. This, in turn, leads to surfactant inactivation, increased tissue stress, and further VILI in a positive feedback mechanism that often leads to death. However, exactly how VILI begins within the lung tissue, and then develops over time, remains poorly understood. We hypothesize that edema and atelectasis begin locally in regions of high tissue stress and then propagate outward to consume the rest of the lung as a result of fluid-structure interactions. This is exacerbated during mechanical ventilation because ventilation heterogeneity amplifies the damage generated in local stress foci. We will test this hypothesis by using design- based stereology to quantify how the spatial distributions of edema and atelectasis change with time during the progression of VILI in mouse models of ARDS. These measurements will then inform the development of a computational model of an alveolar network that couples solid and fluid mechanics to determine how inhomogeneous edema alters microscale tissue stress and recruitment/derecruitment. The numerical model will be used to investigate potentially protective modes of mechanical ventilation, such as variable tidal volume ventilation, that avoid persistently concentrating stress in fixed regions of the lung tissue, as tends to occur with conventional regular ventilation. These studies will facilitate the development of novel protective ventilation strategies for ARDS and thereby help reduce mortality. The PI of this proposal has extensive experience with numerical modeling, animal experimentation, and organ-scale physiology. Complementary training in morphometric analysis will provide the PI with the skills necessary to quantify the micro-scale effects of lung injury, and to link these structural changes to lung function and injury progression using computational models. This program of study and research, together with the world-class research environment provided by the University of Vermont College of Medicine, will enable the PI to develop a career as an independent investigator applying bioengineering and computational methods to the study of lung disease.

描述（由综合征申请人提供）：急性呼吸窘迫 (ARDS) 是一种由脓毒症、烟雾吸入和严重创伤等多种损伤引起的急性呼吸衰竭，其死亡率高达 30-40%。每年约有 75,000 例死亡，这超过了乳腺癌或前列腺癌导致的死亡率。ARDS 的治疗基于支持性机械通气，而呼吸衰竭的根本原因有望得到解决。由于 ARDS 肺损伤的不均匀性所带来的相互矛盾的要求，适当的通气参数很困难。吸气压力必须足够低，以避免脆弱的肺实质过度扩张（体积伤），同时呼气压力必须足够高。防止气道和肺泡反复塌陷（复张）和重新打开（复张）造成的损伤（肺不张伤和肺不张伤）。呼吸机引起的肺损伤（VILI），表现为气腔局部水肿积聚，这反过来又导致表面活性剂失活、组织应激增加，并进一步导致 VILI 的正反馈机制，通常导致死亡。 VILI 到底是如何在肺组织内开始并随着时间的推移而发展的，我们仍然知之甚少，我们发现水肿和肺不张是在组织高应力区域局部开始的，然后向外传播以消耗肺部的其余部分。这种情况在机械通气期间会加剧，因为通气不均匀性会放大局部应力灶产生的损伤，我们将通过使用基于设计的体视学来量化水肿和肺不张的空间分布如何随时间变化来检验这一假设。这些测量结果将为肺泡网络计算模型的开发提供信息，该模型将固体和流体力学耦合起来，以确定不均匀水肿如何改变微观组织应力和数值模型将用于研究机械通气的潜在保护模式，例如可变潮气量通气，避免压力持续集中在肺组织的固定区域，而这些研究往往会发生这种情况。将有利于发展该提案的 PI 在数值建模、动物实验和器官规模生理学方面拥有丰富的经验，形态测量分析方面的补充培训将为 PI 提供量化所需的技能。该研究计划以及佛蒙特大学医学院提供的世界一流的研究环境将研究肺损伤的微观影响，并利用计算模型将这些结构变化与肺功能和损伤进展联系起来。使 PI 能够开发作为一名独立研究者，应用生物工程和计算方法来研究肺部疾病。