TEMPORAL HETEROGENEITY OF LUNG PERFUSION AND VENTILATION

这个项目的重点是生理学的时间波动， 局部肺泡通气（VA）和灌注（Q），并将寻求显示 面对我们的新证据，局部VA/Q稳定性如何保持 局部VA和Q以1 - 2分钟间隔自发波动 我们推测碳酸酐酶的膜结合同工酶 (CA IV）在面对以下情况时维持局部VA/Q稳定性可能是重要的： 这些波动。虽然许多生物过程中的波动是 被认为是正常的健康特征，区域VA和Q 波动将导致VA/Q不稳定，除非存在机制， 快速同步波动。VA或Q的波动（通过改变CO2 输送到一个区域或从该区域消除）将改变 血管和气道平滑肌和肺泡表面活性物质， 对CO2和H+敏感，并以最小化VA/Q变化的方式响应。 我们发现CA抑制揭示了一定程度的VA/Q错配（Swenson et al. 例如，1993年a），我们提出这是由于细胞外pH值（pHe）的减缓- 依赖的VA/Q匹配机制。因为它在很大程度上是pHe 其引发由CO2、催化剂 通过细胞表面CA IV（其活性为 直接细胞外）将确保PCO2的变化所带来的 VA或Q的变化将迅速改变局部pH。两个假设将是 研究：1）VA和Q波动中的局部扰动增加到固定的空间 VA/Q异质性，和2）肺CA IV最大限度地减少了异步的影响 区域VA和Q的波动，但由于低， 限制性，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 波动的区域VA，Q和VA/Q的两种技术与高 空间和时间分辨率;正电子发射断层扫描（PET）， 荧光微球。局部VA和Q波动对 将使用PET评估VA/Q，并与多种惰性气体进行比较 排除法时间和空间VA、Q和VA/Q异质性 将在CA IV抑制后用不可渗透的膜进行研究 抑制剂以确定该同工酶是否在VA/Q匹配中起作用。的 VA/Q波动较大的地区CA IV较高 活性将通过比较正电子- 标记的CA IV抑制剂对PET的时间VA/Q变化的影响。数据将 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 CA IV与时间和空间VA/Q异质性相关， 测定这些研究可能会导致新的见解在控制 区域VA和Q，并将确定CA IV在 肺。

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.