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The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Abstract I have been fortunate to work in two areas of extreme physiology and medicine: very high altitude and the microgravity of spaceflight. My introduction to high altitude medicine was as a member of Sir Edmund Hillary's Silver Hut Expedition in 1960–1961 when a small group of physiologists spent the winter and spring at an altitude of 5,800 m just south of Mt. Everest. The physiological objective was to obtain a better understanding of the acclimatization process of lowlanders during exposure to a very high altitude for several months. As far as we knew, no one had ever spent so long at such a high altitude before. The success of this expedition prompted me to organize the 1981 American Medical Research Expedition to Everest where the scientific objective was to determine the physiological changes that allow humans to survive in the extreme hypoxia of the highest point on earth. There is good evidence that this altitude is very near the limit of human tolerance to oxygen deprivation. Much novel information was obtained including an extraordinary degree of hyperventilation which reduced the alveolar partial pressure of carbon dioxide (Pco2) to about 8 mmHg (1.1 kPa) on the summit, and this in turn allowed the alveolar partial pressure of oxygen, PO2, to be maintained at a viable level of about 35 mmHg (4.7 kPa). The low Pco2 caused a severe degree of respiratory alkalosis with an arterial pH exceeding 7.7. These were the first physiological measurements to be made on the Everest summit, and essentially, none has been made since. The second extreme environment is microgravity. We carried out an extensive series of measurements on astronauts in the orbiting laboratory known as SpaceLab in the 1990s. Many aspects of pulmonary function are affected by gravity, so it was not surprising that many changes were found. However, overall gas exchange remained efficient. Some of the findings such as an anomalous behavior of inhaled helium and sulfur hexafluoride have still not been explained. Measurements made after astronauts were exposed to 6 months of microgravity in the International Space Station indicate that the function of the lung returns to its preexposure state within a few days.

Venous gas bubbles occur in recreational SCUBA divers in the absence of decompression sickness, forming venous gas emboli (VGE) which are trapped within pulmonary circulation and cleared by the lung without overt pathology. We hypothesized that asymptomatic VGE would transiently increase ventilation-perfusion mismatch due to their occlusive effects within the pulmonary circulation. Two sets of healthy volunteers (n = 11, n = 12) were recruited to test this hypothesis with a single recreational ocean dive or a baro-equivalent dry hyperbaric dive. Pulmonary studies (intrabreath V A/Q (iV/Q), alveolar dead space, and FVC) were conducted at baseline and repeat 1- and 24-h after the exposure. Contrary to our hypothesis V A/Q mismatch was decreased 1-h post-SCUBA dive (iV/Q slope 0.023 ± 0.008 ml−1 at baseline vs. 0.010 ± 0.005 NS), and was significantly reduced 24-h post-SCUBA dive (0.000 ± 0.005, p

BackgroundClimbers on the summit of Mt. Everest are exposed to extreme hypoxia, and the physiological implications are of great interest. Inferences have been made from alveolar gas samples collected on the summit, but arterial blood samples would give critical information. We propose a plan to insert an arterial catheter at an altitude of 8000 m, take blood samples above this using an automatic sampler, store the samples in glass syringes in an ice-water slurry, and analyze them lower on the mountain 4 to 6 hours later.ResultsA preliminary design of the automatic sampler was successfully tested at the White Mountain Research Station (altitude 3800 m-4300 m). To determine how much the blood gases changed over a long period, rabbit blood was tonometered to give a gas composition close to that expected on the summit (PO2 4.0 kPa (30 mmHg), PCO2 1.3 kPa (10 mmHg), pH 7.7) and the blood gases were measured every 2 hours for 8 hours both at sea level and 3800 m. The mean changes were PO2 +0.3 to +0.4 kPa (+2 to +3 mmHg), PCO2 0 to +0.13 kPa (+1 mmHg), pH -0.02 to +0.04, base excess -0.7 to +1.2 mM. In practice the delay before analysis should not exceed 4 to 6 hours. The small paradoxical rise in PO2 is presumably caused mainly by contamination of the blood with air.ConclusionWe conclude that automatic arterial blood sampling at high altitude is technically feasible and that the changes in the blood gases over a period of several hours are acceptably small.

Background and Objective: The COVID-19 pandemic magnified the importance of gas exchange abnormalities in early respiratory failure. Pulse oximetry (SpO2) has not been universally effective for clinical decision-making, possibly because of limitations. The alveolar gas monitor (AGM100) adds exhaled gas tensions to SpO2 to calculate the oxygen deficit (OD). The OD parallels the alveolar-to-arterial oxygen difference (AaDO2) in outpatients with cardiopulmonary disease. We hypothesized that the OD would discriminate between COVID-19 patients who require hospital admission and those who are discharged home, as well as predict need for supplemental oxygen during the index hospitalization. Methods: Patients presenting with dyspnea and COVID-19 were enrolled with informed consent and had OD measured using the AGM100. The OD was then compared between admitted and discharged patients and between patients who required supplemental oxygen and those who did not. The OD was also compared to SpO2 for each of these outcomes using receiver operating characteristic (ROC) curves. Results: Thirty patients were COVID-19 positive and had complete AGM100 data. The mean OD was significantly (p = 0.025) higher among those admitted 50.0 ± 20.6 (mean ± SD) vs. discharged 27.0 ± 14.3 (mean ± SD). The OD was also significantly (p < 0.0001) higher among those requiring supplemental oxygen 60.1 ± 12.9 (mean ± SD) vs. those remaining on room air 25.2 ± 11.9 (mean ± SD). ROC curves for the OD demonstrated very good and excellent sensitivity for predicting hospital admission and supplemental oxygen administration, respectively. The OD performed better than an SpO2 threshold of <94%. Conclusions: The AGM100 is a novel, noninvasive way of measuring impaired gas exchange for clinically important endpoints in COVID-19. [ABSTRACT FROM AUTHOR]

Compare and contrast strategies remain common pedagogical practices within physiological education. With the support of an American Physiological Society Teaching Career Enhancement Award, we have developed a junior- or senior-level undergraduate curriculum for exercise physiology that compares and contrasts the physiological adaptations of chronic terrestrial exercise (TEx) and microgravity ([mu]G). We used a series of peer-reviewed publications to demonstrate that many of the physiological adaptations to TEx and [mu]G are opposite. For example, TEx typically improves cardiovascular function and orthostatic tolerance, whereas [mu]G can lead to declines in both. TEx leads to muscle hypertrophy, and [mu]G elicits muscle atrophy. TEx increases bone mineral density and red blood cell mass, whereas [mu]G decreases bone mineral density and red blood cell mass. Importantly, exercise during spaceflight remains a crucial countermeasure to limit some of these adverse physiological adaptations to [mu]G. This curriculum develops critical thinking skills by dissecting peer-reviewed articles and discussing the strengths and weaknesses associated with simulated and actual [mu]G studies. Moreover, the curriculum includes studies on both animals and humans, providing a strong translational component to the curriculum. In summary, we have developed a novel space physiology curriculum delivered during the final weeks of an exercise physiology course in which students gain critical new knowledge that reinforces key concepts presented throughout the semester.

The mechanics of breathing has always been a difficult topic for some medical and graduate students. The subject is very quantitative and contains a number of concepts that some students have trouble with, including physical principles such as pressure, flow, volume, resistance, elasticity, and compliance. Apparently, present-day students find the subject more difficult than students of 20 years ago. A possible reason for this is that the teaching of elementary physics in high school and college is now given less emphasis, whereas other topics, such as molecular biology, receive a great deal of attention. Another factor may be that many of us grew up building radios and other such devices, whereas modern students tend to plug in an electronic unit with little idea of its function. Some examples of misconceptions of present-day students who have taken our course are given. To help the weaker students, we now include a primer at the beginning of our handout for the course that covers simple physical principles. Examples of some of the most difficult concepts for students are given. (Contains 17 figures.)

A complete course of respiratory physiology suitable for first-year medical and graduate students has been placed on the Web for our own students and for other educational institutions. There are several reasons for doing this. The first is that the modern-day student uses a variety of options for acquiring knowledge. These include attending lectures, reading texts, iPod downloads, and surfing the internet. This Web-based course is another option that may be preferable for some students. A second reason is that it is becoming increasingly difficult for some medical schools to find faculty members who are willing and able to teach the principles of respiratory physiology. This is a potentially serious problem because a sound knowledge of respiratory physiology will always be necessary for the intelligent practice of medicine. Schools with limited faculty may find it useful to use these Web-based lectures followed by a discussion session with students. Another reason is that some schools have moved away from systematic lectures to case-based discussions, with the possibility that students will not be exposed to some of the principles of respiratory physiology. The hope is that this comprehensive course of lectures will help students to assimilate this important material as the medical school curriculum continues to expand at a rapid rate. (Contains 1 table.)

West JB. Comparative physiology of the pulmonary blood-gas barrier: the unique avian solution. Am J Physiol Regul Integr Comp Physiol 297: R1625-R1634, 2009. First published September 30, 2009; doi: 10.1152/ajpregu.00459.2009.--Two opposing selective pressures have shaped the evolution of the structure of the blood-gas barrier in air breathing vertebrates. The first pressure, which has been recognized for 100 years, is to facilitate diffusive gas exchange. This requires the barrier to be extremely thin and have a large area. The second pressure, which has only recently been appreciated, is to maintain the mechanical integrity of the barrier in the face of its extreme thinness. The most important tensile stress comes from the pressure within the pulmonary capillaries, which results in a hoop stress. The strength of the barrier can be attributed to the type IV collagen in the extracellular matrix. In addition, the stress is minimized in mammals and birds by complete separation of the pulmonary and systemic circulations. Remarkably, the avian barrier is about 2.5 times thinner than that in mammals and also is much more uniform in thickness. These advantages for gas exchange come about because the avian pulmonary capillaries are unique among air breathers in being mechanically supported externally in addition to the strength that comes from the structure of their walls. This external support comes from epithelial plates that are part of the air capillaries, and the support is available because the terminal air spaces in the avian lung are extremely small due to the flow-through nature of ventilation in contrast to the reciprocating pattern in mammals. evolution; pulmonary circulation; gas exchange; type IV collagen; wall stress; stress failure; respiratory physiology doi: 10.1152/ajpregu.00459.2009.

The gas exchanging region in the avian lung, although proportionally smaller than that of the mammalian lung, efficiently manages respiration to meet the high energetic requirements of flapping flight. Gas exchange in the bird lung is enhanced, in part, by an extremely thin blood-gas barrier (BGB). We measured the arithmetic mean thickness of the different components (endothelium, interstitium, and epithelium) of the BGB in the domestic chicken lung and compared the results with three mammals. Morphometric analysis showed that the total BGB of the chicken lung was significantly thinner than that of the rabbit, dog, and horse (54, 66, and 70% thinner, respectively) and that all layers of the BGB were significantly thinner in the chicken compared with the mammals. The interstitial layer was strikingly thin in the chicken lung (~86% thinner than the dog and horse, and 75% thinner than rabbit) which is a paradox because the strength of the BGB is believed to come from the interstitium. In addition, the thickness of the interstitium was remarkably uniform, unlike the mammalian interstitium. The uniformity of the interstitial layer in the chicken is attributable to a lack of the supportive type I collagen cable that is found in mammalian alveolar lungs. We propose that the surrounding air capillaries provide additional structural support for the pulmonary capillaries in the bird lung, thus allowing the barrier to be both very thin and extremely uniform. The net result is to improve gas exchanging efficiency. capillary stress failure; lung morphology; bird respiratory physiology; air capillary; extracellular matrix; interstitium

I. Introduction II. Design of the Blood-Gas Barrier for Gas Exchange A. Flux of oxygen across the blood-gas barrier, biophysical factors and quantitative considerations B. Comparative observations on the structure [...]

The pulmonary blood-gas barrier is an extraordinary structure because of its extreme thinness, immense strength, and enormous area. The essential components of the barrier were determined early in evolution and have been highly conserved. For example, the barriers of the African, Australian, and South American lungfish that date from as much as 400 million years ago have essentially the same structure as in the modern mammal or bird. In the evolution of vertebrates from bony fishes through amphibia, reptiles, and ultimately mammals and birds, changes in the pulmonary circulation occurred to limit the stresses in the blood-gas barrier. Only in mammals and birds is there a complete separation of the pulmonary and systemic circulations, which is essential to protect the extremely thin barrier from the necessary high-vascular pressures. To provide the blood-gas barrier with its required strength, evolution has exploited the high ultimate tensile strength of type IV collagen in basement membrane. Nevertheless, stress failure of the barrier occurs under physiological conditions in galloping Thoroughbred racehorses and also apparently in elite human athletes at maximal exercise. The human blood-gas barrier maintains its integrity during all but the most extreme physiological conditions. However, many pathological conditions cause stress failure. The structure of the blood-gas barrier is apparently continually regulated in response to wall stress, and this regulation is essential to maintain the extreme thinness but adequate strength. The mechanisms of this regulation remain to be elucidated and constitute one of the fundamental problems in lung biology. vertebrate evolution; stress failure; type IV collagen; exercise-induced pulmonary hemorrhage; lung overinflation; pulmonary circulation

The pulmonary capillaries of neonatal lungs are potentially vulnerable to stress failure because of the complex changes in the pulmonary circulation that occur at birth. We studied the ultrastructure of the blood-gas barrier (BGB) in premature and 1-day-old rabbit lungs and compared it with the ultrastructure of adult lungs. Normal gestation of rabbits is 30 days. After extensive pilot measurements, three premature (27 days gestation) and three newborn (1 day old) rabbit lungs were perfusion-fixed at arterial, venous, and airway pressures of 25, 0, and 10 cm[H.sub.2]O, respectively, and the measurements were compared with those of three adult lungs. The thickness of the capillary endothelium, alveolar epithelium, and interstitium of the BGB was measured at right angles to the barrier at random points. A striking finding was the large number of measurements of the interstitial thickness in 1-day-old lungs that were very thin (0-0.1 [micro]m). The percentages of occurrence of very thin interstitium in premature, 1-day-old, and adult lungs were 35.3 [+ or -] 9.4, 71.7 [+ or -] 5.2, and 43.0 [+ or -] 2.6, respectively (P < 0.02 for 1 day old vs. premature and adult). Given the previously found relationship between stress failure and interstitial thickness, this large proportion of very thin interstitial layers in the capillaries of 1-day-old lungs is a reasonable explanation for their previously demonstrated vulnerability to stress failure. lung morphology; capillary stress; stress failure; pulmonary edema; pulmonary hemorrhage

The pulmonary capillaries of neonatal lungs are potentially vulnerable to stress failure because of the complex changes in the pulmonary circulation that occur at birth. We perfusion fixed the lungs from nine anesthetized newborn rabbits at capillary transmural pressures ([P.sub.tm]) of 5 [+ or -] 5, 10 [+ or -] 5, and 15 [+ or -] 5 cm[H.sub.2]O. Normal microscopic appearances were seen at [P.sub.tm] values of 5 [+ or -] 5 and 10 [+ or -] 5 cm[H.sub.2]O, but massive airway edema was observed in lungs perfused at a [P.sub.tm] of 15 [+ or -] 5 cm[H.sub.2]O. Consistent with this, no disruptions of the alveolar epithelium were observed at [P.sub.tm] values of 5 [+ or -] 5 cm[H.sub.2]O, but mean values of 0.11 and 1.22 breaks/mm epithelium were found at [P.sub.tm] of 10 [+ or -] 5 and 15 [+ or -] 5 cm[H.sub.2]O, respectively (P < 0.05 for 5 [+ or -] 5 vs. 15 [+ or -] 5 cm[H.sub.2]O). These pressures are in striking contrast to those in the adult rabbit in which, by a similar procedure, a [P.sub.tm] of 52.5 cm[H.sub.2]O, is required before stress failure is consistently seen. We conclude that stress failure of pulmonary capillaries in newborn rabbit lungs can occur at [P.sub.tm] values of less than one-third of those that are required in adult lungs. neonatal lung; lung morphometry; capillary wall stress; stress failure

The efficiency of pulmonary gas exchange has long been assessed using the alveolar-arterial difference in PO2, the A-aDO2, a construct developed by Richard Riley ~70years ago. However, this measurement is invasive (requiring an arterial blood sample), time consuming, expensive, uncomfortable for the patients, and as such not ideal for serial measurements. Recent advances in the technology now provide for portable and rapidly responding measurement of the PO2 and PCO2 in expired gas, which combined with the well-established measurement of arterial oxygen saturation via pulse oximetry (SpO2) make practical a non-invasive surrogate measurement of the A-aDO2, the oxygen deficit. The oxygen deficit is the difference between the end-tidal PO2 and the calculated arterial PO2 derived from the SpO2 and taking into account the PCO2, also measured from end-tidal gas. The oxygen deficit shares the underlying basis of the measurement of gas exchange efficiency that the A-aDO2 uses, and thus the two measurements are well-correlated (r 2~0.72). Studies have shown that the new approach is sensitive and can detect the age-related decline in gas exchange efficiency associated with healthy aging. In patients with lung disease the oxygen deficit is greatly elevated compared to normal subjects. The portable and non-invasive nature of the approach suggests potential uses in first responders, in military applications, and in underserved areas. Further, the completely non-invasive and rapid nature of the measurement makes it ideally suited to serial measurements of acutely ill patients including those with COVID-19, allowing patients to be closely monitored if required. [ABSTRACT FROM AUTHOR]

Weightlessness appears to alter some aspects of lung function but not enough to cause serious effects. This was the conclusion of a study of 8 members of the Spacelab, which is carried in the payload bay of the space shuttle. While they were in the Spacelab, the astronauts used machines to measure various aspects of lung function. The lung surface area where gas exchange takes place increased as did the output of the heart. The lung was more uniformly ventilated than it is under gravity. Many of the changes confirmed that the lungs are sensitive to gravity., The lung is exquisitely sensitive to gravity, and so d is of interest to know how its function is altered in the weightlessness of space. Studies on National Aeronautics nautics and Space Administration (NASA) Spacelabs during the last 4 years have provided the first comprehensive data on the extensive changes in pulmonary function that occur in sustained microgravity. Measurements of pulmonary function were made on astronauts during space shuttle flights lasting 9 and 14 days and were compared with extensive ground-based measurements before and after the flights. Compared with preflight measurements, cardiac output increased by 18% during space flight, and stroke volume increased by 46%. Paradoxically, the increase in stroke volume occurred in the face of reductions in central venous pressure and circulating blood volume. Diffusing capacity increased by 28% and the increase in the diffusing capacity of the alveolar membrane was unexpectedly large based on findings in normal gravity. The change in the alveolar membrane may reflect the effects of uniform filling of the pulmonary capillary bed. Distributions of blood flow and ventilation throughout the lung were more uniform in space, but some unevenness remained, indicating the importance of nongravitational factors. A surprising finding was that airway closing volume was approximately the same in microgravity and in normal gravity, emphasizing the importance of mechanical properties of the airways in determining whether they close. Residual volume was unexpectedly reduced by 18%, in microgravity, possibly because of uniform alveolar expansion. The findings indicate that pulmonary function is greatly altered in microgravity, but none of the changes observed so far will apparently limit long-term space flight. in addition, the data help to clarify how gravity affects pulmonary function in the normal gravity environment on Earth. JAMA 1997;277:1957-1961

West, John B. High altitude limits of living things. High Alt Med Biol. 22:342–345, 2021.—The tolerance of animals to high altitude is generally limited by the low partial pressure of oxygen (PO2) in the air. Plant growth at high altitude is also limited but by different mechanisms. This article is a brief survey of the limiting factors of all living things. By a curious coincidence, the highest point on earth, that is Mt. Everest at 8,848 m, appears to be right at the limit of human tolerance to hypoxia. The altitude of the highest permanent human habitation, that is a town, is 5,100 m. This altitude is partly determined by the hypoxia, but also by economic factors. For other terrestrial mammals, birds, and insects, the highest altitudes for permanent habitation apparently belong to field mice (Phyllotis xanthopygus rupestris) and jumping spiders (Euophrys omnisuperstes) at about 6,700 m. Birds have been known to fly as high as 11,000 m although how much they are elevated by atmospheric updrafts is not clear. The record for animals for survival in extreme hypoxia is arguably held by the primitive invertebrate, the tardigrade (Hypsibius dujardini). This has been shown to tolerate the hard vacuum of space where the PO2 is essentially zero for many days. Less is known about the tolerance of plants to extreme altitude. However, vascular plants have been collected at >6,000 m in the Himalayas, and moss grows even higher. Lichens are very tolerant of severe hypoxia. There is evidence that global warming is increasing the highest altitudes at which plants can survive. [ABSTRACT FROM AUTHOR]

Alexander von Humboldt (1769–1859) was one of the most distinguished German scientists of the late 18th and early 19th centuries. His fame came chiefly from his extensive explorations in South America and his eminence as a plant naturalist. He attempted to climb the inactive volcano Chimborazo in Ecuador, which was thought to be the highest mountain in the world at the time, and he reached an altitude of about 5,543 m, which was a record height for humans. During the climb, he had typical symptoms of acute mountain sickness, which he correctly attributed to the low level of oxygen, and he was apparently the first person to make this connection. His ability as a naturalist enabled him to recognize the effect of high altitude on the distribution of plants, and by comparing his observations on Chimborazo with those in the European Alps and elsewhere, he inferred that the deleterious effects of high altitude were universal. During his return trip to Europe, he called on President Thomas Jefferson in Washington, where he was given a warm reception, and discussed conservation issues. He then returned to Paris, where he produced 29 volumes over a period of 31 years describing his travels. Here the effects of high altitude on the distribution of plants compared with animals are briefly reviewed. Following Humboldt’s death in 1859, there was extensive coverage of his contributions, but curiously, his fame has diminished over the years, and inexplicably, he now has a lower profile in North America. [ABSTRACT FROM AUTHOR]