Integration of ventilation-perfusion matching by hypoxic pulmonary vasoconstriction

通过缺氧肺血管收缩整合通气-灌注匹配

• 批准号: 10292926
• 负责人: Andrew Daniel Marquis
• 金额: $ 3.17万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292926
• 关键词: Accounting; Acute; Affect; Air Movements; Alveolar; Anatomy; Area; Asthma; Biochemistry; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Bronchoconstriction; Bronchodilation; Calcium Channel; Computer Models; Consensus; Coupling; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Disease; Embolism; Endothelium; Ensure; Environment; Exhibits; Exposure to; Gap Junctions; Gases; Glass; Goals; Health; Hemoglobin; Hypoxemia; Hypoxia; Hypoxia Pathway; Infusion procedures; Knowledge; Label; Lung; Measures; Mechanics; Mediating; Membrane; Microspheres; Modeling; Molecular; Organ; Oxygen; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Perfusion; Peripheral; Pharmacology; Physics; Physiological; Publishing; Pulmonary Circulation; Pulmonary Embolism; Pulmonary Fibrosis; Rattus; Regional Blood Flow; Regulation; Role; Signal Transduction Pathway; Smooth Muscle Myocytes; Sphingomyelinase; Sprague-Dawley Rats; Structure; System; Testing; Therapeutic Intervention; Tissues; Vascular Smooth Muscle; Vasodilation; Veno-Occlusive Disease; arteriole; base; blood gas analyzer; connexin 40; constriction; experimental study; hemodynamics; in silico; lung hypoxia; mathematical model; oxygen transport; predictive modeling; pulmonary function; response; sensor; theories; uptake; vasoconstriction; ventilation

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.

项目摘要 气流（通气）和血流（灌注）的空间重叠是气体交换的关键决定因素 肺的效率。肺栓塞等血管闭塞性疾病的特征是通气- 灌注（V/Q）不匹配，这经常导致继发性低氧血症。尽管生理上 虽然V/Q匹配的重要性，但我们对维持V/Q匹配的调节机制的认识存在差距。 在病理和正常条件下进行充分的气体交换。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。HPV是 激活响应局部肺泡缺氧，其中上游小动脉收缩以将血流重定向到 肺内氧气供应量较大的区域。目前，该领域尚未就以下问题达成共识 控制这种生理现象的分子途径。此外，人们不明白， HPV的综合作用影响整个器官水平的血管/组织力学和氧气输送。一个 对HPV的综合了解将使我们更好地了解发生V/Q不匹配的病理 并开发更有效的治疗干预措施。我们假设（1）HPV是由一种 进行血管反应，其中肺泡缺氧使肺泡-毛细血管边界去极化，然后 去极化波以与血流相反的方向通过内皮壁传播;以及（2） 通过HPV使局部血流均匀化将使局部肺泡-毛细血管氧通量均匀化 这使血液中的氧气吸收最大化。通过理论与实验相结合， 开发、验证和进行功能预测，以多尺度多物理场测试这些假设 V/Q匹配的计算模型。该计算模型考虑了肺动脉的结构， 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;并最终为假设检验和 精致。我们的模型将被用来预测如何区域肺泡毛细血管氧流量增加， 对缺氧和急性血管闭塞的反应。这些预测将被比较和审查 与我们自己的大鼠实验相比，我们通过输注测量肺血流分布， 荧光标记微球（15 µm）成像，通过血气分析系统动脉血氧 分析仪一些实验将涉及注入500 µm玻璃微球以产生大V/Q 错配，和/或包括施用药理学试剂以抑制推定的免疫缺陷中的关键参与者。 控制HPV的途径。支持或反证和必要的改进，我们的假设将基于 我们的V/Q匹配的计算模型同时解释测量的系统性的能力/不能力 动脉血氧和血流分布。