Integration of ventilation-perfusion matching by hypoxic pulmonary vasoconstriction

项目摘要 气流(通风)和血流(灌流)的空间重叠是气体交换的关键决定因素。 肺部的效率。血管闭塞疾病，如肺血栓，其特征是呼吸- 血流(V/Q)不匹配，经常导致继发性低氧血症。尽管生理学上 V/Q匹配的重要性，我们对维持的调节机制的了解存在空白 在病理和正常情况下有足够的气体交换。在三个目标中，我们建议研究 缺氧性肺血管收缩(HPV)在调节V/Q匹配中的分子和整合作用人乳头瘤病毒是 在局部肺泡缺氧时被激活，在那里上游小动脉收缩，将血流重定向到 肺部供氧较多的区域。目前，该领域还没有就 控制这一生理现象的分子途径。此外，人们还不能理解 HPV的综合作用影响整个器官水平的血管/组织力学和氧转运。一个 对HPV的综合理解将使我们能够更好地理解发生V/Q错配的病理 并开发更有效的治疗干预措施。我们假设(1)人乳头瘤病毒是由一种 传导血管反应，其中肺泡缺氧使肺泡-毛细血管边界去极化，然后 去极化波以与血流方向相反的方向穿过内皮壁；和(2) 人乳头瘤病毒使局部血流均质化将使局部肺泡-毛细血管氧流量均质化 从而最大限度地吸收血液中的氧气。通过理论和实验的结合，我们将 开发、验证和做出功能预测，以用多尺度多物理来测试这些假设 V/Q匹配的计算模型。这一计算模型考虑了肺组织的结构 血管网络，血液-组织相互作用的机械耦合，气体交换，血红蛋白生物化学， 和血管调节机制；并最终提供一个电子环境，用于假设检验和 精致。我们的模型将用于预测局部肺泡-毛细血管氧通量是如何增加的。 对缺氧和急性血管闭塞的反应。这些预测将被比较和仔细审查 在我们自己的老鼠实验中，我们通过输液测量肺血流分布，并 用血气想象荧光标记的微球(15微米)和全身动脉血氧 分析器。一些实验将涉及注入500微米玻璃微球以产生大的V/Q 不匹配，和/或包括给药以抑制推定的 控制HPV的途径。对我们的假设的支持或反驳以及必要的改进将基于 我们的V/Q匹配计算模型同时解释测量系统的能力/能力 动脉血氧和血流量分布。

Project Summary The spatial overlap of airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Vaso-occlusive diseases such as pulmonary emboli are characterized by ventilation- perfusion (V/Q) mismatching which frequently results in secondary hypoxemia. Despite the physiological importance of V/Q matching, there are gaps in our knowledge of the regulatory mechanisms that maintain adequate gas exchange under pathological and normal conditions. In three aims, we propose to study the molecular and integrative role of hypoxic pulmonary vasoconstriction (HPV) in regulating V/Q matching. HPV is activated in response to local alveolar hypoxia, where upstream arterioles constrict to redirect blood flow to areas of the lung with greater oxygen supply. There is currently no consensus in the field regarding the governing molecular pathways of this physiological phenomenon. Moreover, it is not understood how the integrated action of HPV affects vascular/tissue mechanics and oxygen transport at the whole-organ level. An integrated understanding of HPV will allow us to better understand pathologies where V/Q mismatching occurs and develop more efficacious therapeutic interventions. We hypothesize that (1) HPV is mediated by a conducted vascular response in which alveolar hypoxia depolarizes the alveolar-capillary boundary and then a wave of depolarization propagates through the endothelial wall in the opposite direction of blood flow; and (2) homogenization of regional blood flow by HPV will homogenize the regional alveolar-capillary oxygen flux which maximizes the uptake of oxygen into the bloodstream. By integrating theory and experiments we will develop, validate, and make functional predictions to test these hypotheses with a multi-scale multi-physics computational model of V/Q matching. This computational model accounts for the structure of pulmonary vascular networks, mechanical coupling of blood-tissue interactions, gas exchange, hemoglobin biochemistry, and vasoregulatory mechanisms; and ultimately provides an in silico environment for hypothesis testing and refinement. Our model will be used to predict how regional alveolar-capillary oxygen flux is augmented in response to hypoxia and acute vascular occlusions. These predictions will be compared to and scrutinized against our own rat experiments where we measure pulmonary blood flow distribution via the infusion and imagining of fluorescently labeled microspheres (15 µm), and systemic arterial blood oxygen by a blood gas analyzer. Some experiments will involve the infusion of 500 µm glass microspheres to generate large V/Q mismatches, and/or include the administration of pharmacological agents to inhibit key players in the putative pathway that governs HPV. Support or disproof and necessary refinements of our hypotheses will be based on the ability/inability of our computational model of V/Q matching to simultaneously explain measured systemic arterial oxygen and blood flow distributions.