Additional Heterogeneities

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The flow diverting effectiveness ofHPV may depend not only on some of the factors indicated above, but also on the cause of the poor ventilation. For example, in pneumonia, both the host and pathogen mediated inflammatory response would be expected to affect local HPV and/or its modulation (6, 41, 91). In addition, the extent to which the arteries serving the region are mechanically influenced by the alteration in local lung mechanics responsible for the local hypoventilation may have an effect as a consequence ofway the vessels are imbedded within the lung parenchyma. Pulmonary vessels have been categorized as alveolar and extra-alveolar vessels. The designation is based on how they are affected by lung inflation. Due to interdependence between the vessel walls and surrounding parenchyma, lung inflation distends extra-alveolar vessels, which include the larger intrapulmonary arteries. Thus, an increase in lung volume would oppose extra-alveolar vessel HPV (15). The alveolar vessels include the capillaries within the alveolar septa that stretch and narrow as the alveolar wall circumference increases with inflation. Thus, an increase in volume would augment alveolar vessel HPV. The small hypoxia responsive arteries are located close to or within the transition region between the larger extra-alveolar arteries and the smaller alveolar capillaries. The extent to which these vessels behave more like extra-alveolar or alveolar vessels may determine the extent to which local distortions ofthe lung parenchyma will augment or oppose the HPV (15), and there are species variations, with hypoxia responsive vessels being mainly extra-alveolar in the dog (15), rat (7), and ferret (15, 86), but more alveolar in the sheep and pig (15, 86). In the rat at least, the growth of vascular smooth muscle into smaller vessels, that occurs during chronic hypoxia (50), is accompanied by a transition in the behavior of the hypoxic response from that indicative of an extra-alveolar site of action to that of an alveolar site of action (7). In addition, in any region in which the alveoli are disconnected from the flow of tracheal air, such as in a region of atelectasis or behind an obstructed airway, the vessels within the region are subject to the forces transmitted through the surrounding parenchyma in a manner similar to the interdependence affecting the extra-alveolar vessels. Thus, the extent to which the hypoxia responsive vessels are subjected to these forces will impact on the extent to which HPV is effective in reducing regional flow (15).

Between-species heterogeneities (72) in the intensity of HPV are difficult to evaluate at least in part because the modulation of the hypoxic response may vary among species depending on the preparation used in the study. For example in isolated lung experiments the dog came out as a poorly responding species (72), whereas in situ dog lungs responded well to hypoxia (62, 63), much like isolated dog lungs treated with cyclooxygenase inhibitors (3, 15). One between species heterogeneity that has a teleological rationale is the correlation between the effectiveness of the response and the extent of collateral ventilation, which holds for several species studied (33). The rationale is that the presence of collateral ventilation, which would tend to diminish the impact of small airway obstruction on local ventilation, would also decrease the importance of HPV as a means of controlling V/Q mismatch.

It may be surprising that, given the importance of HPV in the fetus, the intensity of HPV typically increases with post-natal age (24, 76). This may be at least partly because the transition from fetal to neonatal circulation, in which increased pulmonary blood flow is a key element, involves mechanisms that attenuate HPV (1, 28, 38, 51). Postnatal development also involves extension of smooth muscle into smaller arteries (67), in keeping with a transition of the hypoxic response from that providing the tone required to keep the flow to the lungs low during the globally and normally low lung oxygen levels before birth to that providing local control of blood flow in the air breathing lung. HPV has been found to be both more (22) and less intense (65) than normal in lungs from mature animals chronically exposed to hypoxia, and the functional implications are not entirely obvious either way.

These and other heterogeneities certainly add complexity to the problem of understanding the physiological and pathophysiological implications ofHPV. In so doing they help to make the pursuit of that understanding challenging and exciting, as reflected in the many ingenious approaches that have been applied to the problem, only a very few of which could be represented in the available space.

Acknowledgments

Work from our laboratory presented in this chapter was supported by the NIH (HL-19298), the Department of Veterans' Affairs and the W. M. Keck Foundation.

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The editor notes with sadness the passing of Dr. Christopher Dawson, an extraordinary mentor for young investigators and an eminent scientist in the field of pulmonary physiology, and was very grateful that this book contains one of his last works on the heterogeneity of hypoxic pulmonary vasoconstriction. His presence in the scientific community will be sorely missed.

Christopher A. Dawson, Ph.D., Professor and eminent research scientist died suddenly and unexpectedly on July 12, 2003 at his office. He is recognized as an inspirational mentor, model researcher and has had a profound influence as a teacher and faculty leader at the Medical College of Wisconsin. Dr. Dawson was born in 1942 in Long Beach, California and received his Ph.D. degree from the University of California, Santa Barbara in 1969. As a Professor of Physiology and Medicine at the Medical College of Wisconsin and at Marquette University, he was recognized as one of the world experts in the pulmonary circulation. As documented by more than 200 original research publications and 22 invited reviews and book chapters, he and his associates pioneered many novel technologies that revealed important functions of the lung that were previously unknown. He served as an Associate Editor of the major research journals in his field, Journal of Applied Physiology and American Journal of Physiology. His scholarly and multifaceted works were supported continuously since 1971 by the Department of Veterans Affairs and the National Institutes of Health. Among his many noteworthy discoveries was that the lining of the blood vessels in the lungs contribute critically to the regulation of hormones that modify pulmonary blood flow. He also was instrumental in the first studies to show that isolated small pulmonary arteries contracted and depolarized to hypoxia. His most recent studies using X-ray imaging of the pulmonary circulation have led to a new understanding of how multiple generations of the pulmonary vasculature function under normal and pathological conditions.

His quiet and humble manner, exacting scientific standards and selfless encouragement of other researchers made him a highly sought source of sound advice. Dr. Dawson collaborated closely with a number of bioengineers, physicians, and basic science investigators at Marquette University, the Medical College of Wisconsin, the Zablocki Veterans Hospital, the Froedtert Lutheran Memorial Hospital and the Children's Hospital of Southeast Wisconsin. For his internationally recognized contributions to lung research, Dr. Dawson was given the Medical Career Scientist Award by the Department of Veterans Affairs in 1999, and in the same year he received the Distinguished Service Award by the Medical College of Wisconsin.

Dr. Dawson is survived by his wife Michal Ann, his daughter Marcey Kay and her husband Keith Gulley and their son Dawson Gulley; his son Brian Christopher and wife Cecilia and their daughter Kana Rose; his mother Elvira and father Alfred and his brother Mark and wife Rebecca.

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