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It would be valuable to have a noninvasive method of measuring impaired pulmonary gas exchange in patients with lung disease and thus reduce the need for repeated arterial punctures. This study reports the results of using a new test in a group of outpatients attending a pulmonary clinic.

Georges Dreyer was the first Professor of Pathology at Oxford University and he held this post from 1907 to 1934. Although his main research interests were in bacteriology and immunity, he made important contributions to respiratory physiology, but these have been almost completely forgotten. He developed a new apparatus for administering low oxygen mixtures to test the effects of hypoxia in airmen during World War I, developed a high successful oxygen delivery system, was responsible for the first low-pressure chamber in a UK academic institution, and carried out some physiological measurements in the chamber that were years ahead of their time. His chamber was also used by a group from Cambridge and Turin, Italy for a series of important physiological studies. In spite of these contributions, almost nobody who works in respiratory physiology today, even in Oxford, recognizes the name of Dreyer.

West, John B. Paralysis and blindness during a balloon ascent to high altitude. High Alt. Med. Biol. 5:453–456, 2004.—An account of the classic balloon ascent to over 29,000 ft (8840 m) by J. Glaisher and H. T. Coxwell on September 5, 1862, appeared in The Lancet and is reproduced here. Glaisher reported paralysis of his arms and legs and sudden loss of sight. Coxwell also lost the use of his hands and could only open the valve of the balloon to initiate its descent by seizing the cord with his teeth. These symptoms are unusual for acute hypoxia, and in a recent article Michael J. Doherty suggested that they may have been caused by decompression sickness. However, this seems unlikely based on many reported cases of subatmospheric decompression sickness.

WEST, J. B. Vulnerability of pulmonary capillaries during exercise. Exerc. Sport Sci. Rev., Vol. 32, No. 1, pp. 24–30, 2004. Pulmonary capillaries have a dilemma. Their walls must be extremely thin for efficient gas exchange, but be immensely strong to resist the mechanical stresses that develop during heavy exercise. Elite human athletes at maximal exercise develop changes in the structure of the capillary wall as evidenced by red blood cells in their alveoli. Racehorses routinely break their pulmonary capillaries while galloping.

When lowlanders go to high altitude, the resulting oxygen deprivation impairs mental and physical performance, quality of sleep, and general well-being. This paper compares the effects of ventilatory acclimatization and oxygen enrichment of room air on the improvement of oxygenation as judged by the increase in the alveolar PO2 and the reduction in equivalent altitude. The results show that, on the average, complete ventilatory acclimatization at an altitude of 5000 m increases the alveolar PO2 by nearly 8 torr, which corresponds to a reduction in equivalent altitude of about 1000 m, although there is considerable individual variability. By comparison, oxygen enrichment to 27% at 5000 m can easily reduce the equivalent altitude to 3200 m, which is generally well tolerated. Because full ventilatory acclimatization at altitudes up to about 3600 m reduces the equivalent altitude to about 3000 m, oxygen enrichment is not justified for well-acclimatized persons. At an altitude of 4200 m, where several telescopes are located on the summit of Mauna Kea, full acclimatization reduces the equivalent altitude to about 3400 m, but the pattern of commuting probably would not allow this. Therefore, at this altitude, oxygen enrichment would be beneficial but is not essential. At higher altitudes such as 5050 m, where other telescopes are located or planned, the gain in oxygenation from acclimatization is insufficient to produce an adequate mental or physical performance for most work, and oxygen enrichment is highly desirable. Full ventilatory acclimatization requires at least a week of continuous exposure, although much of the improvement is seen in the first 2 days.

The Swiss expedition to Everest (altitude 8848 m) in the spring of 1952 very nearly attained the summit with two of the climbers reaching 8595 m. This would have been the first ascent of Everest. One main reason for failure was the inadequate oxygen equipment which was modified from sets designed for mine rescue using potassium peroxide generators. Oxygen could not be inhaled while the mountaineers were climbing because of the rigid mouthpiece assembly and the high breathing resistance of the equipment. It was argued that breathing oxygen during rest periods would suffice, but this was a fallacy as had been demonstrated by Kellas 30 years before.

The aim of this analysis was to determine the altitude of the highest permanent human habitation in the hope that this will throw some light on what determines the highest altitude that a community can tolerate indefinitely. A number of places where people have lived at very high altitudes for long periods of time are reviewed. Individuals have lived for as long as 2 yr at an altitude of 5950 m, and there was a miner's camp at 5300 m for several years. The highest permanently inhabited town in the world at the present time appears to be La Rinconada, a mining village of over 7000 people in southern Peru at an altitude of up to 5100 m, which has been in existence for over 40 yr. The altitude of the highest permanent human habitation is determined partly by economic factors, rather than solely by human tolerance to hypoxia.

Increasingly, lowlanders are commuting to high altitude for commercial, scientific, or defense reasons. Oxygen enrichment of room air at high altitude is a simple but highly effective way of improving sleep quality, mental performance, work efficiency, and general well-being. This review summarizes some of the practical aspects of providing oxygen enrichment including room construction, oxygen concentrators, ventilation levels, costs, use of liquid oxygen, fire hazard, and safe upper limits for oxygen enrichment. The physiological and medical effects of oxygen enrichment are discussed under the headings of sleep, neuropsychological function, and general well-being, productivity, and fatigue. Oxygen enrichment of room air can play a major role in improving living and working conditions for commuters to high altitude.

The elephant is the only mammal whose pleural space is obliterated by connective tissue. This has been known for 300 years but never explained. The elephant is also the only animal that can snorkel at depth. The resulting pressure differences require changes in the pleural membranes and pleural space.

Oxygen enrichment of room air has proved to be valuable for people who need to work at altitudes of 4000 m and above. In the present study the feasibility of using the same technique in ski and other mountain resorts at the lower altitudes of 2500 to 4000 m is considered. Although many people find these altitudes invigorating, some are distressed by the hypoxia, especially at night. The analysis shows that all resorts up to an altitude of 3250 m (10,600 ft) can have the equivalent altitude reduced to 1000 m (3280 ft) by oxygen enrichment without incurring a fire hazard. (The equivalent altitude is that which provides the same inspired PO2 during air breathing.) Even resorts or laboratories as high as 4250 m can have the equivalent altitude safely reduced to 1500 m, that is, lower than the altitude of Denver, Colorado. This application of oxygen enrichment is likely to be most valuable for improving sleep and assisting in the initial acclimatization process.

Sleep is known to be impaired at high altitude, and this may be a factor contributing to reduced work efficiency, general malaise, and the development of acute mountain sickness (AMS). Nocturnal room oxygen enrichment at 3800 m has been shown to reduce the time spent in periodic breathing and the number of apneas, to improve subjective quality of sleep, and to reduce the AMS score. The present study was designed to evaluate the effect of oxygen enrichment to 24% at 3800 m (lowering the equivalent altitude to 2800 m) on sleep architecture. Full polysomnography and actigraphy were performed on 12 subjects who ascended in 1 day to 3800 m and slept in a specially constructed room that allowed oxygen enrichment or ambient air conditions in a randomized, crossover, double-blind study. The results showed that subjects spent a significantly greater percentage of time in deep sleep (stages III and IV combined, or slow wave sleep) with oxygen enrichment versus ambient air (17.2 ± 10.0% and 13.9 ± 6.7%, respectively; p < 0.05 in paired analysis). No differences between treatments were seen with subjective assessments of sleep quality or with subject's assessment of the extent to which they suffered from AMS. This study provides further objective evidence of improved sleep as a result of oxygen enrichment at 3800 m and suggests that alleviating hypoxia may improve sleep quality.

Human spaceflight was one of the great physiological and engineering triumphs of the 20th century. Although the history of the United States manned space program is well known, the Soviet program was shrouded in secrecy until recently. Konstantin Edvardovich Tsiolkovsky (1857–1935) was an extraordinary Russian visionary who made remarkable predictions about space travel in the late 19th century. Sergei Pavlovich Korolev (1907–1966) was the brilliant “Chief Designer” who was responsible for many of the Soviet firsts, including the first artificial satellite and the first human being in space. The dramatic flight of Sputnik 1 was followed within a month by the launch of the dog Laika, the first living creature in space. Remarkably, the engineering work for this payload was all done in less than 4 wk. Korolev's greatest triumph was the flight of Yuri Alekseyevich Gagarin (1934–1968) on April 12, 1961. Another extraordinary feat was the first extravehicular activity by Aleksei Arkhipovich Leonov (1934–) using a flexible airlock that emphasized the entrepreneurial attitude of the Soviet engineers. By the mid-1960s, the Soviet program was overtaken by the United States program and attempts to launch a manned mission to the Moon failed. However, the early Soviet manned space program has a preeminent place in the history of space physiology.

Oxygen enrichment of room air at high altitude has been shown to improve mental performance, sleep quality, and work capacity. Until now, the usual strategy has been to use an oxygen concentration that reduces the equivalent altitude to about 3000 m, where the equivalent altitude is that which gives the same inspired PO2 during air breathing. However, standards adopted by the National Fire Protection Association allow considerably higher oxygen concentrations without introducing a fire hazard. For example, by raising the oxygen concentration to 31.5% at an altitude of 5000 m, the equivalent altitude can be safely reduced to less than 2000 m. At the extreme altitude of 8000 m, the equivalent altitude can be reduced to less than 4000 m without increasing the fire hazard. These increased levels of oxygen enrichment are feasible in practice using oxygen concentrators. They may be useful if lowlanders need to ascend rapidly and stay at high altitude, or for treating people with high altitude illnesses.

To determine the correlation between ultrastructural and physiological changes in blood-gas barrier function in lungs transiently exposed to very high vascular pressures, we increased capillary transmural pressure (Ptm) of 6 canine isolated perfused left lower lung lobe preparations (high-pressure group) to 80.3 Torr for 3.8 min and then determined the capillary filtration (Kfc) and osmotic reflection (ςd) coefficients at a Ptm of 19.1 Torr in the ventilated lung lobes. This was followed by perfusion fixation of the lobes at a Ptm of 20.5 Torr for ultrastructural analysis. These data were compared with those obtained in six lobes in which Ptm was not transiently elevated before Kfc, ςd, and ultrastructural evaluation.Kfcwas higher [0.249 ± 0.042 (SE) vs. 0.054 ± 0.009 g · min−1· Torr−1· 100 g−1; P< 0.01] and ςdwas lower (0.52 ± 0.07 vs. 0.85 ± 0.08; P< 0.01) in the high-pressure group. In contrast, although endothelial and epithelial breaks were occasionally observed in some experiments, their incidence was not increased in the high-pressure group. These data suggest that the increased transvascular water and protein flux occurred through pathways of a size not resolvable by electron microscopy after vascular perfusion-fixation at a Ptm of 20.5 Torr.

The pulmonary blood-gas barrier is an extraordinary bioengineering structure because of its vast area but extreme thinness. Despite this, almost no attention has been given to its mechanical properties. The remarkable area and thinness come about because gas exchange occurs by passive diffusion. However, the barrier also needs to be immensely strong to withstand the very high stresses in the capillary wall when capillary pressure rises during exercise. The strength of the thin region of the barrier comes from type IV collagen in the basement membranes. When the stresses in the capillary walls rise to high levels, ultrastructural changes occur in the barrier, a condition known as stress failure. Physiological conditions that alter the properties of the barrier include severe exercise in elite human athletes. Animals that have been selectively bred for high aerobic activity, such as Thoroughbred racehorses, consistently break their pulmonary capillaries during galloping. Pathophysiological conditions causing stress failure include high-altitude pulmonary edema and overinflation of the lung, which frequently occurs with mechanical ventilation. Remodeling of the capillary wall occurs in response to increased wall stress in diseases such as mitral stenosis. The barrier is able to maintain its extreme thickness with sufficient strength as a result of continual regulation of its wall structure. How it does this is a central problem in lung biology.

In a randomized, double-blind study, 24 sea-level residents drove to 3800-m altitude in 1 day, and then slept the first night in either ambient air or 24% oxygen, and the second night in the treatment that they did not receive on the first night. Oxygen enrichment, compared with ambient air, resulted in significantly fewer apneas, and significantly less time spent in periodic breathing during the night. The increase in SaO2 between evening and morning was significantly higher after sleeping in the oxygen-enriched atmosphere, compared with ambient air. However, this significant improvement in SaO2 did not persist into mid-day. The overnight treatment did not alter the ventilatory response to hypoxia or to carbon dioxide as measured the following morning. The results suggest that the elevation in SaO2 following overnight oxygen enrichment is probably not due to a change in the control of ventilation, but possibly to differences in subclinical lung pathology.

Studies of physiology in microgravity are remarkably recent, with almost all the data being obtained in the past 40 years. The first human spaceflight did not take place until 1961. Physiological measurements in connection with the early flights were crude, but, in the past 10 years, an enormous amount of new information has been obtained from experiments on Spacelab. The United States and Soviet/Russian programs have pursued different routes. The US has mainly concentrated on relatively short flights but with highly sophisticated equipment such as is available in Spacelab. In contrast, the Soviet/Russian program concentrated on first the Salyut and then the Mir space stations. These had the advantage of providing information about long-term exposure to microgravity, but the degree of sophistication of the measurements in space was less. It is hoped that the International Space Station will combine the best of both approaches. The most important physiological changes caused by microgravity include bone demineralization, skeletal muscle atrophy, vestibular problems causing space motion sickness, cardiovascular problems resulting in postflight orthostatic intolerance, and reductions in plasma volume and red cell mass. Pulmonary function is greatly altered but apparently not seriously impaired. Space exploration is a new frontier with long-term missions to the moon and Mars not far away. Understanding the physiological changes caused by long-duration microgravity remains a daunting challenge.

We measured the isocapnic hypoxic ventilatory response and the hypercapnic ventilatory response by using rebreathing techniques in five normal subjects (ages 37–47 yr) before, during, and after 16 days of exposure to microgravity (μG). Control measurements were performed with the subjects in the standing and supine postures. In both μG and in the supine position, the hypoxic ventilatory response, as measured from the slope of ventilation against arterial O2saturation, was greatly reduced, being only 46 ± 10% (μG) and 52 ± 11% (supine) of that measured standing (P< 0.01). During the hypercapnic ventilatory response test, the ventilation at aPCO2of 60 Torr was not significantly different in μG (101 ± 5%) and the supine position (89 ± 3%) from that measured standing. Inspiratory occlusion pressures agreed with these results. The findings can be explained by inhibition of the hypoxic but not hypercapnic drive, possibly as a result of an increase in blood pressure in carotid baroreceptors in μG and the supine position.

Cognitive and motor function are known to deteriorate with the hypoxia accompanying high altitude, posing a substantial challenge to the efficient operation of high altitude industrial and scientific projects. To evaluate the effectiveness of enriching room air oxygen by 6% at 5000 m altitude in ameliorating such deficits, 24 unacclimatized subjects (16 males, 8 females; mean age 37.8, range 20 to 47) underwent neuropsychological testing in a specially designed facility at 3800 m that can simulate an ambient 5000 m atmosphere and 6% enrichment at 5000 m. Each subject was tested in both conditions in a randomized, double-blinded fashion. The 2-h test battery of 16 tasks assessed various aspects of motor and cognitive performance. Compared with simulated breathing air at 5000 m, oxygen enrichment resulted in higher arterial oxygen saturations (93.0 vs. 81.6%), quicker reaction times, improved hand-eye coordination, and more positive sense of well-being (on 6 of 16 scales), each significant at the p < 0.05 level. Other aspects of neuropsychological function were not significantly improved by 6% additional oxygen.

Climbing Mt. Everest without supplementary oxygen presents a fascinating physiological challenge because, at the summit, humans are very near the limit of tolerance to hypoxia. It was not until 1978 that the feat was accomplished, and this was after many unsuccessful attempts over a period of more than 50 years, and several physiological studies that suggested that it would be impossible. An analysis shows that the critical factors for reaching the summit are the enormous hyperventilation which is necessary to maintain the alveolar Po2at viable levels, the fact that the barometric pressure is substantially higher than predicted by the Standard Atmosphere, and the severe respiratory alkalosis that assists loading of oxygen by the blood in the lung. Even so the maximal oxygen consumption on the summit is extremely low with the result that climbers are critically vulnerable to unexpected setbacks such as changes in the weather.

We performed bolus inhalations of 1-μm particles in four subjects on the ground (1 G) and during parabolic flights both in microgravity (μG) and in ∼1.6 G. Boluses of ∼70 ml were inhaled at different points in an inspiration from residual volume to 1 liter above functional residual capacity. The volume of air inhaled after the bolus [the penetration volume (Vp)] ranged from 200 to 1,500 ml. Aerosol concentration and flow rate were continuously measured at the mouth. The deposition, dispersion, and position of the bolus in the expired gas were calculated from these data. For Vp≥400 ml, both deposition and dispersion increased with Vpand were strongly gravity dependent, with the greatest deposition and dispersion occurring for the largest G level. At Vp= 800 ml, deposition and dispersion increased from 33.9% and 319 ml in μG to 56.9% and 573 ml at ∼1.6 G, respectively (P< 0.05). At each G level, the bolus was expired at a smaller volume than Vp, and this volume became smaller with increasing Vp. Although dispersion was lower in μG than in 1 G and ∼1.6 G, it still increased steadily with increasing Vp, showing that nongravitational ventilatory inhomogeneity is partly responsible for dispersion in the human lung.

We used aerosol boluses to study convective gas mixing in the lung of four healthy subjects on the ground (1 G) and during short periods of microgravity (μG) and hypergravity (∼1.6 G). Boluses of 0.5-, 1-, and 2-μm-diameter particles were inhaled at different points in an inspiration from residual volume to 1 liter above functional residual capacity. The volume of air inhaled after the bolus [the penetration volume (Vp)] ranged from 150 to 1,500 ml. Aerosol concentration and flow rate were continuously measured at the mouth. The dispersion, deposition, and position of the bolus in the expired gas were calculated from these data. For each particle size, both bolus dispersion and deposition increased with Vpand were gravity dependent, with the largest dispersion and deposition occurring for the largest G level. Whereas intrinsic particle motions (diffusion, sedimentation, inertia) did not influence dispersion at shallow depths, we found that sedimentation significantly affected dispersion in the distal part of the lung (Vp>500 ml). For 0.5-μm-diameter particles for which sedimentation velocity is low, the differences between dispersion in μG and 1 G likely reflect the differences in gravitational convective inhomogeneity of ventilation between μG and 1 G.

We performed single-breath washout (SBW) tests in which He and sulfur hexafluoride (SF6) were inspired throughout the vital capacity inspirations or were inhaled as discrete boluses at different points in the inspiration. Tests were performed in normal gravity (1 G) and in up to 27 s of microgravity (μG) during parabolic flight. The phase III slope of the SBW could be accurately reconstructed from individual bolus tests when allowance for airways closure was made. Bolus tests showed that most of the SBW phase III slope results from events during inspiration at lung volumes below closing capacity and near total lung capacity, as does the SF6-He phase III slope difference. Similarly, the difference between 1 G and μG in phase III slopes for both gases was entirely accounted for by gravity-dependent events at high and low lung volumes. Phase IV height was always larger for SF6than for He, suggesting at least some airway closure in close proximity to airways that remain open at residual volume. These results help explain previous studies in μG, which show large changes in gas mixing in vital capacity maneuvers but only small effects in tidal volume breaths.

Barometric pressures (Pb) near the summit of Mt. Everest (altitude 8,848 m) are of great physiological interest because the partial pressure of oxygen is very near the limit for human survival. Until recently, the only direct measurement on the summit was 253 Torr, which was obtained in October 1981, but, despite being only one data point, this value has been used by several investigators. Recently, two new studies were carried out. In May 1997, another direct measurement on the summit was within ∼1 Torr of 253 Torr, and meteorologic data recorded at the same time from weather balloons also agreed closely. In the summer of 1998, over 2,000 measurements were transmitted from a barometer placed on the South Col (altitude 7,986 m). The mean Pbvalues during May, June, July, and August were 284, 285, 286, and 287 Torr, respectively, and there was close agreement with the Pb-altitude (h) relationship determined from the 1981 data. The Pbvalues are well predicted from the equation Pb= exp (6.63268 − 0.1112 h − 0.00149 h2), where h is in kilometers. The conclusion is that on days when the mountain is usually climbed, during May and October, the summit pressure is 251–253 Torr.

We used aerosol boluses to study convective gas mixing in the lung of four healthy subjects on the ground (1 G) and during short periods of microgravity (μG) and hypergravity (~1.6 G). Boluses of 0.5-, 1-, and 2-μm-diameter particles were inhaled at different points in an inspiration from residual volume to 1 liter above functional residual capacity. The volume of air inhaled after the bolus [the penetration volume (Vp)] ranged from 150 to 1,500 ml. Aerosol concentration and flow rate were continuously measured at the mouth. The dispersion, deposition, and position of the bolus in the expired gas were calculated from these data. For each particle size, both bolus dispersion and deposition increased with Vp and were gravity dependent, with the largest dispersion and deposition occurring for the largest G level. Whereas intrinsic particle motions (diffusion, sedimentation, inertia) did not influence dispersion at shallow depths, we found that sedimentation significantly affected dispersion in the distal part of the lung (Vp >500 ml). For 0.5-μm-diameter particles for which sedimentation velocity is low, the differences between dispersion in μG and 1 G likely reflect the differences in gravitational convective inhomogeneity of ventilation between μG and 1 G.

The pulmonary blood-gas barrier has a basic physiological dilemma. On the one hand it needs to be extremely thin for efficient gas exchange. On the other hand it also needs to be immensely strong because the stresses on the pulmonary capillary wall become extremely high when the capillary pressure rises on exercise. Maximal hydrostatic pressures in human pulmonary capillaries during exercise are not accurately known but must exceed 30 mmHg. In some animals, for example thoroughbred horses, the capillary pressure rises to about 100 mmHg. These pressures cause stresses in the capillary wall of 5–10 × 104 N·M-2 (50–100 kPa) which approach the breaking strength of collagen. The strength of the capillary wall on the thin side of the blood-gas barrier can be attributed to the type IV collagen of the extracellular matrix. Raising the capillary pressure to similar levels in experimental preparations causes ultrastructural changes in the wall including disruption of the capillary endothelium, alveolar epithelium, and basement membrane in the interstitium. Essentially all thoroughbred racehorses bleed into their lungs during exercise because they break their capillaries, and some elite human athletes apparently do the same. Avoiding stress failure of pulmonary capillaries poses a challenging problem for some species. Stress failure is a hitherto overlooked factor limiting maximal exercise.

PETER H. HACKETT, ROBERT B. SCHOENE, ROBERT M. WINSLOW, RICHARD M. PETERS, JR., and JOHN B. WEST. Acetazolamide and exercise in sojourners to 6,300 meters—a preliminary study. Med. Sci. Sports Exerc., Vol. 17, No. 5, pp. 593–597, 1985. To examine the effect of acetazolamide on resting acid-base balance and on exercise performance at extreme altitude, we studied four members of the American Medical Research Expedition to Mount Everest at an altitude of 6,300 meters. After an initial progressive exercise test to exhaustion on a bicycle ergometer, subjects were re-studied after taking acetazolamide 250 mg every 8 h for three doses. We measured venous blood during rest for determination of hemoglobin, hematocrit, 2,3-diphosphoglycerate (DPG), bicarbonate, pH, P50, and arterial oxygen saturation by ear oximeter. The results showed that pH, bicarbonate, and DPG:hemoglobin ratio were lower on acetazolamide, whereas P50 at in vivo conditions was unchanged. Exercise ventilation and oxygen consumption for the same workload were slightly higher after acetazolamide, whereas CO2/O2respiratory exchange ratio (R) was lower, and oxygen saturation was unchanged. Two of four subjects had decreased time at maximum workload on acetazolamide; none had an increased performance. The results of this study show that partial carbonic anhydrase inhibition in individuals sojourning to very high altitude produces a further base deficit and a metabolic acidosis, stimulates ventilation, and may impair maximum exercise performance. Although acetazolamide effectively prevents acute mountain sickness, it does not improve performance, and may even impair exercise performance at extreme altitude.

Parker, James C., Ellen C. Breen, and John B. West.High vascular and airway pressures increase interstitial protein mRNA expression in isolated rat lungs. J. Appl. Physiol.83(5): 1697–1705, 1997.—We hypothesized that wall stresses produced by high peak airway (Paw) and venous (Ppv) pressures would increase mRNA levels for structural proteins of the interstitial matrix in isolated rat lungs. Groups of lungs (n= 6) were perfused for 4 h at a peak Paw of 35 cmH2O (HiPaw), cyclical peak Ppv of 28 cmH2O (HiPv), or baseline vascular and airway pressures (LoPress). In two separate groups, comparable peak pressures increased capillary filtration coefficient fourfold in each group. Northern blots were probed for mRNA of α1(I), α1(III), and α2(IV) procollagen chains, laminin B chain, fibronectin, and transforming growth factor-β1, and densities were normalized to 18S rRNA. mRNA was significantly higher in the HiPv group for type I (4.3-fold) and type III (3.8-fold) procollagen and laminin B chain (4.8-fold) and in the HiPaw group for type I (2.4-fold) and type IV (4.5-fold) procollagen and laminin B chain (2.3-fold) than in the LoPress group. Only fibronectin mRNA was significantly increased (3.9-fold) in the LoPress group relative to unperfused lungs. Estimated wall stresses were highest for alveolar septa in the HiPaw group and for capillaries in the HiPv group. The different patterns of mRNA expression are attributed to different regional stresses or extent of injury.

Darquenne, Chantal, Manuel Paiva, John B. West, and G. Kim Prisk. Effect of microgravity and hypergravity on deposition of 0.5- to 3-μm-diameter aerosol in the human lung. J. Appl. Physiol.83(6): 2029–2036, 1997.—We measured intrapulmonary deposition of 0.5-, 1-, 2-, and 3-μm-diameter particles in four subjects on the ground (1 G) and during parabolic flights both in microgravity (μG) and at ∼1.6 G. Subjects breathed aerosols at a constant flow rate (0.4 l/s) and tidal volume (0.75 liter). At 1 G and ∼1.6 G, deposition increased with increasing particle size. In μG, differences in deposition as a function of particle size were almost abolished. Deposition was a nearly linear function of the G level for 2- and 3-μm-diameter particles, whereas for 0.5- and 1.0-μm-diameter particles, deposition increased less between μG and 1 G than between 1 G and ∼1.6 G. Comparison with numerical predictions showed good agreement for 1-, 2-, and 3-μm-diameter particles at 1 and ∼1.6 G, whereas the model consistently underestimated deposition in μG. The higher deposition observed in μG compared with model predictions might be explained by a larger deposition by diffusion because of a higher alveolar concentration of aerosol in μG and to the nonreversibility of the flow, causing additional mixing of the aerosols.

Berg, John T., Zhenxing Fu, Ellen C. Breen, Hung-Cuong Tran, Odile Mathieu-Costello, and John B. West. High lung inflation increases mRNA levels of ECM components and growth factors in lung parenchyma. J. Appl. Physiol.83(1): 120–128, 1997.—Remodeling of pulmonary capillaries occurs after chronic increases in capillary pressure (e.g., mitral stenosis). Also, remodeling of pulmonary arteries begins within 4 h of increased wall stress and is endothelium dependent. We have previously shown that high lung inflation increases wall stress in pulmonary capillaries. This study was designed to determine whether high lung inflation induces remodeling of the extracellular matrix (ECM) in lung parenchyma. Open-chest rabbits were ventilated for 4 h with 9-cmH2O positive end-expiratory pressure (PEEP) on one lung and 1-cmH2O PEEP on the other (High-PEEP group), or with 2-cmH2O PEEP on both lungs (Low-PEEP group). An additional untreated control group was also included. We found increased levels of mRNA in both lungs of High-PEEP rabbits (compared with both the Low-PEEP and untreated groups) for α1(III) and α2(IV) procollagen, fibronectin, basic fibroblast growth factor, and transforming growth factor-β1. In contrast, α2(I) procollagen and vascular endothelial growth factor mRNA levels were not changed. We conclude that high lung inflation for 4 h increases mRNA levels of ECM components and growth factors in lung parenchyma.

Verbanck, Sylvia, Hans Larsson, Dag Linnarsson, G. Kim Prisk, John B. West, and Manuel Paiva. Pulmonary tissue volume, cardiac output and diffusing capacity in sustained microgravity.J. Appl. Physiol.83(3): 810–816, 1997.—In microgravity (μG) humans have marked changes in body fluids, with a combination of an overall fluid loss and a redistribution of fluids in the cranial direction. We investigated whether interstitial pulmonary edema develops as a result of a headward fluid shift or whether pulmonary tissue fluid volume is reduced as a result of the overall loss of body fluid. We measured pulmonary tissue volume (Vti), capillary blood flow, and diffusing capacity in four subjects before, during, and after 10 days of exposure to μG during spaceflight. Measurements were made by rebreathing a gas mixture containing small amounts of acetylene, carbon monoxide, and argon. Measurements made early in flight in two subjects showed no change in Vti despite large increases in stroke volume (40%) and diffusing capacity (13%) consistent with increased pulmonary capillary blood volume. Late in-flight measurements in four subjects showed a 25% reduction in Vti compared with preflight controls (P< 0.001). There was a concomittant reduction in stroke volume, to the extent that it was no longer significantly different from preflight control. Diffusing capacity remained elevated (11%; P< 0.05) late in flight. These findings suggest that, despite increased pulmonary perfusion and pulmonary capillary blood volume, interstitial pulmonary edema does not result from exposure to μG.

Birks, Eric K., Odile Mathieu-Costello, Zhenxing Fu, Walter S. Tyler, and John B. West. Very high pressures are required to cause stress failure of pulmonary capillaries in Thoroughbred racehorses. J. Appl. Physiol.82(5): 1584–1592, 1997.—Thoroughbred horses develop extremely high pulmonary vascular pressures during galloping, all horses in training develop exercise-induced pulmonary hemorrhage, and we have shown that this is caused by stress failure of pulmonary capillaries. It is known that the capillary transmural pressure (Ptm) necessary for stress failure is higher in dogs than in rabbits. The present study was designed to determine this value in horses. The lungs from 15 Thoroughbred horses were perfused with autologous blood at Ptm values (midlung) of 25, 50, 75, 100 and 150 mmHg, and then perfusion fixed, and samples (dorsal and ventral, from caudal region) were examined by electron microscopy. Few disruptions of capillary endothelium were observed at Ptm ≤ 75 mmHg, and 5.3 ± 2.2 and 4.3 ± 0.7 breaks/mm endothelium were found at 100 and 150 mmHg Ptm, respectively. Blood-gas barrier thickness did not change with Ptm. At low Ptm, interstitial thickness was greater than previously found in rabbits but not in dogs. We conclude that the Ptm required to cause stress failure of pulmonary capillaries is between 75 and 100 mmHg and is greater in Thoroughbred horses than in both rabbits and dogs.

The extreme thinness of the pulmonary blood-gas barrier results in high mechanical stresses in the capillary wall when the capillary pressure rises during exercise. We have previously shown that, in elite cyclists, 6–8 min of maximal exercise increase blood-gas barrier permeability and result in higher concentrations of red blood cells, total protein, and leukotriene B4in bronchoalveolar lavage (BAL) fluid compared with results in sedentary controls. To test the hypothesis that stress failure of the barrier only occurs at the highest level of exercise, we performed BAL in six healthy athletes after 1 h of exercise at 77% of maximal O2consumption. Controls were eight normal nonathletes who did not exercise before BAL. In contrast with our previous study, we did not find higher concentrations of red blood cells, total protein, and leukotriene B4in the exercising athletes compared with control subjects. However, higher concentrations of surfactant apoprotein A and a higher surfactant apoprotein A-to-phospholipid ratio were observed in the athletes performing prolonged exercise, compared with both the controls and the athletes from our previous study. These results suggest that, in elite athletes, the integrity of the blood-gas barrier is altered only at extreme levels of exercise.

Prisk, G. Kim, Ann R. Elliott, Harold J. B. Guy, Sylvia Verbanck, Manuel Paiva, and John B. West. Multiple-breath washin of helium and sulfur hexafluoride in sustained microgravity.J. Appl. Physiol.84(1): 244–252, 1998.—We performed multiple-breath washouts of N2and simultaneous washins of He and SF6with fixed tidal volume (∼1,250 ml) and preinspiratory lung volume (approximately the subject’s functional residual capacity in the standing position) in four normal subjects (mean age 40 yr) standing and supine in normal gravity (1 G) and during exposure to sustained microgravity (μG). The primary objective was to examine the influence of diffusive processes on the residual, nongravitational ventilatory inhomogeneity in the lung in μG. We calculated several indexes of convective ventilatory inhomogeneity from each gas species. A normal degree of ventilatory inhomogeneity was seen in the standing position at 1 G that was largely unaltered in the supine position. When we compared the standing position in 1 G with μG, there were reductions in phase III slope in all gases, consistent with a reduction in convection-dependent inhomogeneity in the lung in μG, although considerable convective inhomogeneity persisted in μG. The reductions in the indexes of convection-dependent inhomogeneity were greater for He than for SF6, suggesting that the distances between remaining nonuniformly ventilated compartments in μG were short enough for diffusion of He to be an effective mechanism to reduce gas concentration differences between them.

Lauzon, Anne-Marie, Ann R. Elliott, Manuel Paiva, John B. West, and G. Kim Prisk. Cardiogenic oscillation phase relationships during single-breath tests performed in microgravity.J. Appl. Physiol.84(2): 661–668, 1998.—We studied the phase relationships of the cardiogenic oscillations in the phase III portion of single-breath washouts (SBW) in normal gravity (1 G) and in sustained microgravity (μG). The SBW consisted of a vital capacity inspiration of 5% He-1.25% sulfurhexafluoride-balance O2, preceded at residual volume by a 150-ml Ar bolus. Pairs of gas signals, all of which still showed cardiogenic oscillations, were cross-correlated, and their phase difference was expressed as an angle. Phase relationships between inspired gases (e.g., He) and resident gas (N2) showed no change from 1 G (211 ± 9°) to μG (163 ± 7°). Ar bolus and He were unaltered between 1 G (173 ± 15°) and μG (211 ± 25°), showing that airway closure in μG remains in regions of high specific ventilation and suggesting that airway closure results from lung regions reaching low regional volume near residual volume. In contrast, CO2reversed phase with He between 1 G (332 ± 6°) and μG (263 ± 27°), strongly suggesting that, in μG, areas of high ventilation are associated with high ventilation-perfusion ratio (V˙a/Q˙). This widening of the range ofV˙a/Q˙in μG may explain previous measurements (G. K. Prisk, A. R. Elliott, H. J. B. Guy, J. M. Kosonen, and J. B. West. J. Appl. Physiol.79: 1290–1298, 1995) of an overall unaltered range ofV˙a/Q˙in μG, despite more homogeneous distributions of both ventilation and perfusion.

Lauzon, Anne-Marie, G. Kim Prisk, Ann R. Elliott, Sylvia Verbanck, Manuel Paiva, and John B. West. Paradoxical helium and sulfur hexafluoride single-breath washouts in short-term vs. sustained microgravity. J. Appl. Physiol.82(3): 859–865, 1997.—During single-breath washouts in normal gravity (1 G), the phase III slope of sulfur hexafluoride (SF6) is steeper than that of helium (He). Two mechanisms can account for this:1) the higher diffusivity of He enhances its homogeneous distribution; and2) the lower diffusivity of SF6results in a more peripheral location of the diffusion front, where airway asymmetry is larger. These mechanisms were thought to be gravity independent. However, we showed during the Spacelab Life Sciences-2 spaceflight that in sustained microgravity (μG) the SF6-to-He slope difference is abolished. We repeated the protocol during short periods (27 s) of μG (parabolic flights). The subjects performed a vital-capacity inspiration and expiration of a gas containing 5% He-1.25% SF6-balance O2. As in sustained μG, the phase III slopes of He and SF6decreased. However, during short-term μG, the SF6-to-He slope difference increased from 0.17 ± 0.03%/l in 1 G to 0.29 ± 0.06%/l in μG, respectively. This is contrary to sustained μG, in which the SF6-to-He slope difference decreased from 0.25 ± 0.03%/l in 1 G to −0.01 ± 0.06%/l in μG. The increase in phase III slope difference in short-term μG was caused by a larger decrease of He phase III slope compared with that in sustained μG. This suggests that changes in peripheral gas mixing seen in sustained μG are mainly due to alterations in the diffusive-convective inhomogeneity of He that require >27 s of μG to occur. Changes in pulmonary blood volume distribution or cardiogenic mixing may explain the differences between the results found in short-term and sustained μG.

We have previously shown that raising the capillary transmural pressure (Ptm) in rabbit lung causes disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers of the wall. In those studies the lungs were perfused with autologous blood (1 min), then saline/dextran (3 min), followed by glutaraldehyde fixative (10 min), all at the same pressure. The present study was designed to determine whether increasing the time of exposure of the capillaries to the increased pressure altered the frequency of stress failure. The procedure was identical to that of the previous study except that the duration of the blood perfusion was extended from 1 to 10 and 100 min. We chose a Ptm of 32.5 cm H₂O because our previous studies showed that this caused only a few disruptions per millimeter endothelial and epithelial boundary length (0.7 ± 0.4 and 0.9 ± 0.6 (SE), respectively). Ten New Zealand white rabbit lungs were perfused with autologous blood plus homologous blood from additional rabbits for 10 and 100 min. After 100 min of blood perfusion the number of disruptions per millimeter endothelial and epithelial boundary length (0.66 ± 0.4 and 0.52 plusmn; 0.33 (SE), respectively) was not significantly different from the earlier study. Thus, increasing the duration of the increased Ptm during blood perfusion by 100-fold did not alter the incidence of stress failure. These results indicated that any viscoelastic behavior resulting in further strain and ultimately failure of the capillary walls is insignificant over a wide range of exposure times to increased pressure under the conditions of this study. Copyright 1995, 1999 Academic Press

During the last ten years, two major experiments have elucidated the factors determining acclimatization and tolerance to extreme altitude (over 7000 m). These were the American Medical Research Expedition to Everest, and the low pressure chamber simulation, Operation Everest II. Extreme hyperventilation is one of the most important responses to extreme altitude. Its chief value is that it allows the climber to maintain an alveolar PO2which keeps the arterial PO2above dangerously low levels. Even so, there is evidence of residual impairment of central nervous system function after ascents to extreme altitude, and maximal oxygen consumption falls precipitously above 7000 m. The term ‘acclimatization’ is probably not appropriate for altitudes above 8000 m, because the body steadily deteriorates at these altitudes. Tolerance to extreme altitude is critically dependent on barometric pressure, and even seasonal changes in pressure probably affect climbing performance near the summit of Mt Everest. Supplementary oxygen always improves exercise tolerance at extreme altitudes, and rescue oxygen should be available on climbing expeditions to 8000 m peaks.

Hyperventilation is one of the most important features of acclimatization to high altitude. Resting ventilation at extreme altitudes increases up to fourfold and exercise ventilation for a given work level increases to the same extent. Hypoxic stimulation of the peripheral chemoreceptors is the chief mechanism for the hyperventilation but there is also evidence that central sensitization of the respiratory centres occurs. Permanent residents of high altitude have a blunted hypoxic ventilatory response compared to acclimatized lowlanders. Cardiac output increases in response to acute hypoxia but returns to normal in acclimatized lowlanders. Oxygen uptake at extreme altitudes is markedly limited by the diffusion properties of the blood gas barrier. As a consequence the maximal oxygen consumption of a climber near the summit of Mount Everest is near his basal oxygen requirements. Maximal oxygen consumption is so sensitive to barometric pressure that it may be that day-to-day variations will affect the chances of a climber reaching the summit without supplementary oxygen.