Spatiotemporal evolution of lung injury during ventilator-induced lung injury

项目摘要 严重的损伤和疾病可导致急性呼吸窘迫综合征（ARDS），这是一种高死亡率的急性呼吸道疾病。 呼吸衰竭的发病率高达80例/100，000人/年，死亡率为 大约40%。该综合征与表面活性物质功能障碍和空气水肿有关， 肺泡萎陷（去募集）。由于肺结构和功能的退化， 需要通气来管理ARDS并保持足够的气体交换。然而，机械通气 诱导呼吸机诱导的肺损伤（VILI），其通过组织加重ARDS的作用 过度膨胀以及肺泡和远端气道的周期性塌陷和重新开放。方面取得了很大的进步 了解VILI的基本机制，以便可以规定通气以减少VILI， 保持气体交换。然而，这两种需求经常发生冲突， 机械通气参数对于即使是最熟练的临床医生来说仍然是一项具有挑战性的任务。确定 损伤的机制以及保护性通气模式因时空因素而复杂化， ARDS和VILI的异质性。据认为，这种异质性可能有助于这些疾病的进展。 疾病通过微妙的肺泡的物理互连。在这种情况下， 淹没或塌陷的肺泡将增加相邻患者区域的应变。因此，该提案将测试 总的假设是水肿和细胞损伤将在高应力位置开始;这些最初受伤的 区域将产生应力集中，这使得近端区域非常容易受到进一步的损伤。为了验证这一 假设，我们将使用实验和计算技术相结合，以说明存在 损伤异质性及其进展，量化损伤区域对新损伤的影响， 并预测导致损伤扩散的机制。新颖的图像分析技术和定制的 计算机软件将量化小鼠VILI中细胞损伤的微观和宏观尺度分布。这些 测量将首次量化细胞尺度损伤的空间分布。解释这些 数据，我们将实施一种新型的统计模型，以确定相互依存的范围和强度 现有和新的细胞损伤之间的联系这些模拟将允许解释我的实验 测量，并在未来的研究中，促进识别通风制度，防止蔓延的 降低ARDS死亡率。最后，将使用有限元肺泡网络的新公式来 确定细胞损伤的聚集是否可归因于由物理损伤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，该提案还将支持开发 通过实验室技术的教学和指导培训， 数学和专业技能。

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.