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

• 批准号: 9377181
• 负责人: Bradford J Smith
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9377181
• 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; Interruption; 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; Recruitment Activity; 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; skills; smoke inhalation; spatiotemporal; surfactant; treatment strategy

 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（由申请人提供）：急性呼吸窘迫综合征（ARDS）是一种急性呼吸衰竭，由多种损伤引起，包括败血症、烟雾吸入和严重创伤。ARDS具有30- 40%的高死亡率，这导致每年约75，000人死亡。这超过了乳腺癌或前列腺癌的死亡率。ARDS的治疗是基于支持性机械通气，当呼吸衰竭的根本原因有望解决时应用。然而，选择合适的通气参数是困难的，因为在ARDS肺损伤的不均匀性所施加的相互冲突的要求。吸气压力必须足够低，以避免脆弱的软组织过度膨胀（体积创伤），同时呼气压力必须足够高，以防止气道和肺泡的反复塌陷（去复张）和重新开放（复张）（肺不张）造成的损害。体积创伤和肺不张创伤都可以导致呼吸机诱导的肺损伤（VILI），其表现为局部水肿积聚在气隙中。这反过来又导致表面活性剂失活，增加组织应力，并在正反馈机制中进一步导致VILI，这通常导致死亡。然而，VILI如何在肺组织内开始，然后随着时间的推移发展，仍然知之甚少。我们假设水肿和肺不张开始于局部高组织应力区域，然后由于流体-结构相互作用而向外传播以消耗肺的其余部分。这在机械通气期间加剧，因为通气异质性放大了局部应力集中产生的损伤。我们将通过使用基于设计的体视学来量化在ARDS小鼠模型中VILI进展期间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。然后，这些测量结果将为肺泡网络的计算模型的开发提供信息，该计算模型将固体力学和流体力学结合起来，以确定不均匀水肿如何改变微尺度组织应力和募集/去募集。数值模型将用于研究机械通气的潜在保护模式，如可变潮气量通气，避免在肺组织的固定区域持续集中应力，这往往会发生与传统的定期通气。这些研究将促进发展 新的保护性通气策略，从而有助于降低死亡率。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。形态学分析的补充培训将为PI提供量化肺损伤的微观效应所需的技能，并使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。该学习和研究计划，以及佛蒙特大学医学院提供的世界一流的研究环境，将使PI能够发展成为一名独立的研究人员，将生物工程和计算方法应用于肺部疾病的研究。