Integration of ventilation-perfusion matching by hypoxic pulmonary vasoconstriction

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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.