LUNG CARBONIC ANHYDRASE AND VENTILATION PERFUSION MATCHI

该项目将调查时间的存在和影响， 局部肺通气和灌注的变化及其作用 肺碳酸酐酶（CA）在通气-灌注（V/Q）匹配中的作用。 正常肺中气体交换的显著效率是基于 根据由以下原因引起的通气和灌注的区域匹配， 肺的结构（解剖学）属性以及活性 调节通气和灌注分布的机制。 虽然影响血流和动脉血流的空间异质性的因素 通风已被广泛研究，但很少有人知道如何 时间变化影响整体异质性。 这项研究的假设是，在肺，1）时间 局部血流和通气确实会发生波动，2）它们 具有足以导致V/Q失配的幅度，以及3） 通过通气的快速代偿性变化（在 响应于血流变化）和灌注（响应于通气 变化）由当地CO2紧张局势的后续变化介导。 CO2具有 已知支气管扩张和肺血管收缩作用 对肺泡表面活性剂的功能性质的影响， 采取行动，以减少在面对当地波动的不匹配， 通气和灌注。 与大多数生理系统一样，二氧化碳 作为酸（即CO2 + H2O平衡H2 CO2平衡H+ + HCO（-3））; 因此，CA对这些反应的快速催化将确保这些变化 局部灌注时间变化引起的局部PCO 2 （改变CO2输送）或通风（改变CO2消除）可以 迅速改变气道和肺泡组织的pH值。 实验 方法将是在幅度和/或CO2含量上施加变化 局部灌注和通气的动力学，并测量 肺CA抑制前后的补偿性重新调整 动物和人类的各种实验方案。 此外，本发明还提供了一种方法， 局部肺灌注的自发时间变异性， 通气量和V/Q将通过正电子发射断层扫描进行量化。 这些研究将确定肺碳酸酐酶在 肺气体交换，并提供进一步的见解， 与碳酸酐酶抑制剂的临床应用相关， 特别是在那些患有潜在肺部疾病的患者中， 任何调节V/Q分布的机制的丧失都可能是有害的。

This project will investigate the presence and impact of temporal variations in regional pulmonary ventilation and perfusion and the role of lung carbonic anhydrase (CA) in ventilation-perfusion (V/Q) matching. The remarkable efficiency of gas exchange in the normal lung is based upon the regional matching of ventilation and perfusion which arise from both structural (anatomic) attributes of the lung as well as active mechanisms regulating the distribution of ventilation and perfusion. Although factors affecting spatial heterogeneity in blood flow and ventilation have been studied extensively, very little is known about how temporal variations affect overall heterogeneity. The hypotheses of this investigation are that in the lung, 1) temporal fluctuations in regional blood flow and ventilation do occur, 2) they are of sufficient magnitude to contribute to V/Q mismatch, and 3) the effect is minimized by rapid compensatory changes in ventilation (in response to blood flow changes) and perfusion (in response to ventilation changes) mediated by consequent changes in local CO2 tensions. CO2 has known bronchodilator and pulmonary vasoconstrictor effects in addition to effects on the functional properties of alveolar surfactant which will act to reduce mismatching in the face of local fluctuations in ventilation and perfusion. As in most physiological systems, CO2 acts as an acid (ie CO2 + H2O equilibrium H2CO2 equilibrium H+ + HCO(-3)); thus rapid catalysis of these reactions by CA will assure that changes in regional PCO2 brought about by temporal variations in local perfusion (varying CO2 delivery) or ventilation (varying CO2 elimination) can rapidly alter pH in airway and alveolar tissue. The experimental approach will be to impose changes in the magnitude and/or CO2 content of regional perfusion and ventilation and to measure the kinetics of compensatory readjustments before and after inhibition of lung CA in a variety of experimental protocols in animals and humans. In addition, the spontaneous temporal variability in regional lung perfusion, ventilation and V/Q will be quantified by positron emission tomography. These studies will define a new role for lung carbonic anhydrase in pulmonary gas exchange and provide further insights into the problems associated with the clinical use of carbonic anhydrase inhibitors, especially in those patients with underlying lung disease, in whom the loss of any mechanism regulating V/Q distribution may be deleterious.