LUNG CARBONIC ANHYDRASE & VENTILATION PERFUSION MATCHING

该项目将调查时间的存在和影响 肺局部通气量和灌注量的变化及其作用 肺碳酸酐酶(CA)在V/Q匹配中的变化。 正常肺内气体交换的显著效率是基于 基于区域匹配的通气量和灌注量 肺的结构(解剖)属性以及活动属性 调节通风和灌流分布的机制。 尽管影响血液流动空间异质性的因素和 通风已经得到了广泛的研究，但对如何通风知之甚少。 时间变化会影响整体的异质性。 这项研究的假设是，在肺中，1)时间 区域血流量和通气量的波动确实会发生，2)它们 具有足够的大小以导致V/Q失配，以及3) 通过通风的快速代偿性改变将影响降至最低(在 对血流变化的反应)和灌流(对通风的反应 变化)是由当地二氧化碳紧张局势的相应变化所调节的。二氧化碳有 已知的支气管扩张剂和肺血管收缩药另外的作用 对肺泡表面活性物质功能性质的影响 采取行动减少错配，以应对局部波动 通风和灌流。正如在大多数生理系统中一样，二氧化碳起作用 作为酸(即CO_2+H_2O平衡H_2CO_2平衡H~++HCO(-3))； 因此，CA对这些反应的快速催化将确保 局部血流灌注的时间变化所带来的区域性二氧化碳分压 (不同的二氧化碳输送)或通风(不同的二氧化碳消除)可以 迅速改变呼吸道和肺泡组织的pH值。实验性的 方法将是强制改变量值和/或二氧化碳含量 并测量局部血流和通气量的动力学。 肺CA抑制前后的代偿性再调节 在动物和人类身上的各种实验方案。此外, 区域肺血流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，并提供对问题的进一步见解 与碳酸酐酶抑制剂的临床应用有关， 尤其是在那些患有潜在肺部疾病的患者中， 任何调节V/Q分布的机制的损失都可能是有害的。

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.