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: 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
• 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

 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（由适用提供）：急性呼吸窘迫综合征（ARDS）是急性呼吸衰竭的一种形式，由败血症，烟损伤和严重创伤等多种侮辱引起。 ARDS的死亡率高30-40％，每年大约死亡75,000人死亡。这超过了由于乳腺癌或前列腺癌引起的死亡率。 ARDS的处理是基于支持的机械通气，而呼吸衰竭的根本原因有望得到解决。但是，由于ARDS中肺损伤的不均匀性质施加的不均匀性，因此很难选择适当的通风参数。灵感压力必须足够低，以避免过度透露精致的副群（volutrauma），而同时到期压力必须足够高，以防止因重复崩溃（降低）和呼吸道的重新开放（招募）和ALVEOLI（ALVEOLI）（ALVEOLI）（ATELECTRECLAUMA）造成的损害。 Volutrauma和atelectrauma都可以导致呼吸机诱导的肺损伤（VILI），这表现为空间中水肿的局部积累。反过来，这会导致表面活性剂失活，增加组织应力，并在正面反馈机制中进一步导致死亡。但是，确切的维利如何在肺组织内开始，然后随着时间的流逝而发展。我们假设水肿和肺不张从高组织应激的区域开始局部开始，然后向外传播以由于流体结构相互作用而消耗其余的肺部。在机械通气期间，这会加剧，因为通气异质性放大器局部应力灶中产生的损害。我们将通过使用基于设计的立体原理来量化在ARDS小鼠模型中VILI在VILI进展过程中随时间变化的空间分布来测试这一假设。然后，这些测量结果将为Alloolar网络的计算模型的开发提供信息，该计算模型将固体和流体机械耦合，以确定不均匀的水肿如何改变微观组织的应力和募集/扩散。数值模型将用于研究潜在保护的机械通气模式，例如可变的潮汐体积通气，避免在肺组织的固定区域中持续浓缩应激，就像常规常规通气时一样倾向于发生。这些研究将促进发展 新型的ARDS保护性通风策略，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的生理学方面具有丰富的经验。形态计量分析中的互补训练将为PI提供量化肺损伤的微尺度影响所需的技能，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。该研究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能够发展为独立研究人员的职业，该研究人员将生物工程和计算方法应用于肺部疾病研究。