TEMPORAL HETEROGENEITY OF LUNG PERFUSION AND VENTILATION

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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.