TEMPORAL HETEROGENEITY OF LUNG PERFUSION AND VENTILATION

这个项目的重点是时间波动的生理学。 局部肺泡通气量(VA)和灌注量(Q)，并将寻求显示 在我们的新证据面前，当地的VA/Q稳定性是如何保持的 该区域的VA和Q以1-2分钟的间隔自发波动 或者更少。我们推测碳酸酐酶的膜结合同工酶。 (CA IV)在以下情况下保持局部VA/Q稳定可能很重要 这些波动。尽管许多生物过程中的波动是 地区性VA和Q被认为是正常的健康特征 波动将导致VA/Q不稳定，除非存在机制来 快速同步波动。VA或Q的波动(通过改变二氧化碳 向某一区域输送或从该区域排出)会改变二氧化碳(和pH值) 血管和呼吸道平滑肌和肺泡表面活性物质，它们是 对CO2和H+敏感，并以模拟VA/Q变化的方式做出反应。 我们发现，CA抑制揭示了一定程度的VA/Q不匹配(Swenson et 等人，1993a)，我们认为这是由于细胞外pH(Phe)的减缓- 依赖的VA/Q匹配机制。因为这在很大程度上是PHE的变化 它们启动了由二氧化碳、催化作用变化产生的匹配反应 通过细胞表面CA IV(其活性是 细胞外定向)将确保由以下因素带来的二氧化碳变化 Va或Q的变化会迅速改变当地的Phe。将有两个假设 研究：1)VA和Q波动的局部异步性增加到固定的空间 VA/Q异质性，以及2)肺CA IV最小化不同步的影响 区域VA和Q的波动，但由于低和比率 限制、CA IV浓度、CA IV活性较高的区域 VA/Q波动较小。实验将量化和表征 区域VA、Q和VA/Q波动的两种高技术 空间和时间分辨率；正电子发射断层扫描(PET)和 荧光微球。局地VA和Q波动对 将用正电子发射计算机断层扫描(PET)评估Va/Q，并与多种惰性气体进行比较 淘汰技术。时间和空间的VA、Q和VA/Q的异质性 将研究后的CA IV抑制用一种不透膜 抑制剂，以确定该同工酶是否在VA/Q匹配中发挥作用。这个 VA/Q波动较大的地区将有较高的CA IV 活性将通过比较正电子的特定结合来测试- PET对暂时性VA/Q变化的标记CA IV抑制剂数据将是 分析以量化VA和Q波动(包括幅度， 频率、区域大小和与相邻单元的相关性)，以及 评估对VA/Q异质性的影响。肺的空间异质性 由于CA IV与时间和空间的VA/Q异质性有关，因此 下定决心。这些研究可能会为控制艾滋病带来新的见解 区域VA和Q，并将定义CA IV在 阿龙。

This project focuses on the physiology of temporal fluctuations in regional alveolar ventilation (VA) and perfusion (Q) and will seek to show how local VA/Q stability is maintained in the face of our new evidence that regional VA and Q fluctuate spontaneously in intervals of 1-2 minutes or less. We hypothesize the membrane-bound isozyme of carbonic anhydrase (CA IV) may be important m maintaining local VA/Q stability in the face of these fluctuations. Although fluctuations in many biological processes are recognized as a normal healthy characteristic, regional VA and Q fluctuations will generate instability in VA/Q unless mechanisms exist to synchronize fluctuations rapidly. Fluctuations in VA or Q (by altering CO2 delivery into or elimination from a region) will alter PCO2 (and pH) of vascular and airway smooth muscle and alveolar surfactant, which are sensitive to CO2 and H+ and respond in a manner to miminize a VA/Q change. We showed that CA inhibition unmasks a degree of VA/Q mismatch (Swenson et al., 1993a) which we propose is due to slowing of extracellular pH (pHe)- dependent VA/Q matching mechanisms. Since it is largely changes in pHe which initiate matching responses generated by changes in CO2, catalysis of pHe changes in lung cells by cell surface CA IV (whose activity is directed extracellularly) will ensure that PCO2 changes brought about by VA or Q changes will rapidly alter local pHe. Two hypotheses will be studied: 1) local asynchrony in VA and Q fluctuations add to fixed spatial VA/Q heterogeneity, and 2) lung CA IV minimizes impact of asynchronous fluctuations in regional VA and Q but as a result of low, and rate limiting, CA IV concentrations, regions with greater CA IV activity undergo less VA/Q fluctuation. Experiments will quantify and characterize fluctuations in regional VA, Q, and VA/Q by two techniques with high spatial and temporal resolution; positron emission tomography (PET) and fluorescent microspheres. The impact of local VA and Q fluctuations on VA/Q will be assessed with PET and compared to the multiple inert gas elimination technique. Temporal and spatial VA, Q, and VA/Q heterogeneity will be studied after CA IV inhibition with a membrane impermeable inhibitor to determine if this isozyme functions in VA/Q matching. The concept that areas with more VA/Q fluctuation will have higher CA IV activity will be tested by comparing specific binding of a positron- labeled CA IV inhibitor to temporal VA/Q variation by PET. Data will be analyzed to quantify VA and Q fluctuations (including magnitudes, frequencies, region size, and correlation with neighboring units), and assess the impact on VA/Q heterogeneity. The spatial heterogeneity of lung CA IV as it relates to temporal and spatial VA/Q heterogeneity will be determined. These studies may lead to new insights in the control of regional VA and Q and will define an important new role for CA IV in the lung.