Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD.

Surfactant protein (SP)-D is a lung-derived protein that has been proposed as a biomarker for inflammatory lung disease. Serum SP-D was evaluated as a biomarker for components of chronic obstructive pulmonary disease (COPD) in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort and its response assessed to the administration of the anti-inflammatory agent prednisolone. The median level of serum SP-D was significantly elevated in 1,888 individuals with COPD compared to 296 current and former smokers without airflow obstruction (121.1 and 114.3 ng x mL(-1), respectively; p = 0.021) and 201 nonsmokers (82.2 ng x ml(-1); p<0.001). There was no correlation with the severity of COPD. Individuals with COPD who had a serum SP-D concentration that was greater than the 95th percentile of nonsmokers (175.4 ng x mL(-1)) showed an increased risk of exacerbations over the following 12 months (adjusted OR 1.30; 95% CI 1.03-1.63). Treatment with 20 mg x day(-1) prednisolone for 4 weeks resulted in a fall in serum SP-D levels (126.0 to 82.1 ng x mL(-1); p<0.001) but no significant change in post-bronchodilator forced expiratory volume in 1 s. Serum SP-D concentration is raised in smokers and may be useful in identifying individuals who are at increased risk of exacerbations of COPD. It may represent an intermediate measure for the development of novel anti-inflammatory agents.

Bronchoconstriction in asthmatics exposed to sulfur dioxide during repeated exercise.

Young male volunteers with mild asthma and hypersensitivity to methacholine were exposed for 75 min with natural breathing to 0.0, 0.25, 0.5, and 1.0 ppm SO2. Each exposure included three 10-min periods of moderate treadmill exercise (minute ventilation 21 l . m-2 . min-1, O2 consumption 25 ml . kg-1, and heart rate 120/min). Specific airway resistance (sRaw) was not significantly increased after exercise in 0.25 ppm SO2, relative to the control exposure (clean air). In 0.5 and 1.0 ppm SO2, sRaw was increased twofold and threefold above preexposure levels, respectively, corresponding to increases of 3.2 and 9.2 cmH2O . s in excess over the increases seen in clean air (P less than 0.001). There was a broad range of responses to exercise and SO2. The increases in sRaw after the second and third exercises were significantly less than after the first exercise. Respiratory impedance measured by forced random noise suggests that the induced bronchoconstriction was primarily associated with peripheral airways. These results confirm that mild asthmatics selected for methacholine sensitivity have as a group significant bronchoconstriction in response to short-term moderate exercise with natural breathing in 1.0 and 0.5 ppm SO2. In addition, the induced bronchoconstriction is decreased after short-term repeated exercise in SO2.

Role of the parasympathetic nervous system in acute lung response to ozone.

We conducted an ozone (O3) exposure study using atropine, a muscarinic receptor blocker, to determine the role of the parasympathetic nervous system in the acute response to O3. Eight normal subjects with predetermined O3 responsiveness were randomly assigned an order for four experimental exposures. For each exposure a subject inhaled either buffered saline or atropine aerosol followed by exposure either to clean air or 0.4 ppm O3. Measurements of lung mechanics, ventilatory response to exercise, and symptoms were obtained before and after exposure. O3 exposure alone resulted in significant changes in specific airway resistance, forced vital capacity (FVC), forced expiratory flow rates, tidal volume (VT), and respiratory rate (f). Atropine pretreatment prevented the significant increase in airway resistance with O3 exposure and partially blocked the decrease in forced expiratory flow rates but did not prevent a significant fall in FVC, changes in f and VT, or the frequency of reported respiratory symptoms after O3. These results suggest that the increase in pulmonary resistance during O3 exposure is mediated by a parasympathetic mechanism and that changes in other measured variables are mediated, at least partially, by mechanisms not dependent on muscarinic cholinergic receptors of the parasympathetic nervous system.

Amelioration of the symptoms of acute mountain sickness by staging and acetazolamide.

Treatment by 4 d of residence at 1600 m plus the administration of 500 mg acetazolamide b.i.d. for the last 2 d at 1600 m and the first 2 d at 4300 m was compared with no treatment prior to ascent to 4300 m for prophylaxis of acute mountain sickness. The treatment successfully prevented almost all symptoms of acute mountain sickness. It had no effect on the diminished capacity for maximal or prolonged heavy physical work. The treatment produced a relative acidosis and a comparatively greater arterial oxygen tension at 4300 m.

Respiratory response of humans exposed to low levels of ozone for 6.6 hours.

Recent evidence suggests that prolonged exposures of exercising men to 0.08 ppm ozone (O3) result in significant decrements in lung function, induction of respiratory symptoms, and increases in nonspecific airway reactivity. The purpose of this study was to confirm or refute these findings by exposing 38 healthy young men to 0.08 ppm O3 for 6.6 h. During exposure, subjects performed exercise for a total of 5 h, which required a minute ventilation of 40 l/min. Significant O3-induced decrements were observed for forced vital capacity (FVC, -0.25 l), forced expiratory volume in 1 s (FEV1.0, -0.35 l), and mean expiratory flow rate between 25% and 75% of FVC (FEF25-75, -0.57 l/s), and significant increases were observed in airway reactivity (35%), specific airway resistance (0.77 cm H2O/s), and respiratory symptoms. These results essentially confirm previous findings. A large range in individual responses was noted (e.g., percentage change in FEV1.0; 4% increase to 38% decrease). Responses also appeared to be nonlinear in time under these experimental conditions.

Psychometric correlates of pain perception.

There is disagreement in the literature as to whether responsivity to painful stimuli possesses psychometric correlates. A series of methodological and statistical factors are specified in this paper which could account for the equivocality of the literature. A series of experiments were performed in which (a) various methodological and statistical issues were first resolved and (b) psychometric correlates of pain perception were then identified by means of a stepwise multiple regression procedure. The criterion variable consisted of the psychophysical judgment of pain during a 2-min. exposure to a 3,000 gm. force on the periosteum of the left fore-finger's second digit. The predictor variables consisted of selected psychological states and traits measured by the State-Trait Anxiety Inventory, Somatic Perception Questionnaire, Depression Adjective Checklist, Profile of Mood States, Eysenck Personality Inventory, and the Embedded Figures Test. The test-retest reliability of the pain test ranged from .64 to .84 across trials separated by a 3-wk. period. In the first experiment significant multiple regressions ranging between .57 and .72 were observed and psychological traits (field dependence, extraversion and trait anxiety) accounted for the variance in these analyses. In the next experiment significant multiple Rs ranging from .62 to .68 were observed. This served as cross-validation for the first experiment. The major difference was that psychological states (depression and vigor) as well as traits entered the multiple regression equations for certain of the analyses. It was concluded that selected psychological states and traits are significantly correlated with the perception of pain.

Perception of effort during constant work to self-imposed exhaustion.

The purpose of this study was to describe the pattern of change in effort sense and the value of this pattern in predicting work end-point at relatively high work intensity (80% VO2 max). The patterns of change of various physiological functions were also observed. Two modes of work (walking and running) were compared to ascertain generalizability of results. 26 healthy male volunteers served as subjects. Time to exhaustion (ET) did not differ between walking and running. As work continued during both tasks, significant increases of VE, VE/VO2, VE/VCO2 and HR and a significant decrease of ETCO2 were observed; while VO2 and R remained fairly constant. VO2 and VE during the run were about 5% greater than during the walk; there were no differences in other measures. Ratings of perceived exertion (RPE) from the Borg Scale were identical for both conditions, increasing in a near linear fashion from a value of 12.9 at 25% of total work time to 18.9 at exhaustion. Ratings obtained at 25 and 50% ET were extrapolated to time of exhaustion; the point of intercept corresponded to ratings of perceived exertion for maximal work. At exhaustion, subjects rated perception of respiratory exertion for the walk as less than that for the run; perception of leg exertion was not different for the two conditions. Plasma lactate, epinephrine and norepinephrine concentrations following exercise did not differ between the two conditions. The findings for the walking experiment were essentially replicated in a second investigation involving another 28 subjects. It is concluded that, with the exception of VO2 and some ventilatory parameters, walking and running at the same relative work intensity resulted in comparable perceptual and physiological responses. Psychophysical judgments made early during work were reasonably accurate predictors of exhaustion time.

Normal acid-base status of arterial blood from the conscious, chair-restrained squirrel monkey.

Normal acid-base status of arterial blood (pHa =7.40, PaCO2=38.1 Torr) was demonstrated for conscious, restrained squirrel monkeys when environmental stimuli were minimized and monkeys are habituated to experimental procedures. These results indicate the potential for using squirrel monkeys in experiments in which normal acid-base status is a significant factor.

Hypoxia-induced metabolic and core temperature changes in the squirrel monkey.

To identify components of reduced core temperature (Tre) with exposure to hypoxia, oxygen uptake (VO2) and skin temperatures were measured in chair-restrained squirrel monkeys during conditions of 21% O2, 11% O2, and 11% O2 + 5% CO2. Exposure to 11% O2 resulted in a 20% decrease in VO2 and a 1.8 degrees C reduction of Tre with skin temperatures closely paralleling Tre. The addition of 5% CO2 to 11% O2 effectively blocked the decrease of both VO2 and Tre. The responses of one monkey (LD) exhibiting decreased Tre (greater than 2.0 degrees C) and 20% decrease in VO2 were compared to those of another (SD) exhibiting decreased Tre (less than 0.5 degrees C) and little change of VO2 under the same experimental conditions. Increased mean arterial blood pressure (BPa) and heart rate (HR) occurred for monkey SD, while for monkey LD BPa decreased and HR increased slightly. Arterial pressure of oxygen (PaO2) and calculated arterial saturation of oxygen (SaO2) were higher, while PaCO2 was lower for monkey SD than for monkey LD. When 5% CO2 was added to 11% O2 both animals exhibited decreased PaO2, little change of Tre, VO2, PaCO2, arterial pH, and calculated SaO2, and increased BPa and HR. These data suggest that decreased Tre resulted from reduced heat production and reduced oxygen transport was primarily responsible for reduction of heat production.

Acclimatization to dry heat: active men vs. active women.

Physiological responses to exercise in dry heat were compared between six active men [maximum O2 consumption (VO2max), 51.4 +/- 1.2 ml . kg-1 . min-1] and four active women (VO2max, 47.2 +/- 1.3 ml . kg-1 . min-1) before, during, and after heat acclimatization. Subjects cycled a maximum of 2 h at 40% VO2max at 45 degrees C dry-bulb temperature, 23 degrees C wet-bulb temperature for 11 days. Prior to acclimatization there were no sexual differences for performance time, rate of increase of rectal temperature (delta Tre), or sweat rate per degree C increase of rectal temperature (msw/delta Tre). Sweat rate (msw) was greater for the men than for the women. Although there was no difference in the rate of increase of heart rate (delta HR), HR for the women was maintained 15-20 beats . min-1 higher than for the men. Acclimatization occurred for both sexes as indicated by reduced Tre and HR and increased msw and performance time. With acclimatization the women had longer performance times than the men. Even though the men still had greater msw, delta Tre was also greater; therefore msw/delta Tre for the men was less than for the women. Neither HR nor delta HR was different between the sexes. Throughout, resting hematocrit for the women was less than for the men; no changes in hematocrit were observed during exercise or with acclimatization. Plasma protein concentration increased during exercise on all days; no changes in plasma osmolality were observed. It is concluded that active women perform exercise of equal relative intensity in dry heat as well as active men. Moreover active women acclimatized to heat at a faster rate or to a greater extent than did active men.

Effects of altering O2 delivery on VO2 of isolated, working muscle.

Maximal oxygen consumption (VO2 max) and muscle blood flow (Q max) were measured in an isolated gracilis muscle preparation before and after alteration in perfusion pressure (BP), arterial oxygen saturation (SaO2), and hemoglobin concentration (Hb). Q varied directly with BP and inversely with Hb (viscosity) but was unaffected by changes in arterial SaO2. VO2 max varied directly with oxygen delivery under all conditions. These results indicate that VO2 max is normally limited by oxygen delivery rather than any intrinsic limiting of oxygen consumption of the muscle.

The nature of the perception of effort at sea level and high altitude.

The purpose of this study was to compare perceptual responses (RPE) and selected physiological measures during both short term and prolonged exercise of equal relative intensities at 4300 m to those at sea level. Specifically, we compared results obtained (n=20) for 6 min of exercise at 60, 80 and 95% VO2max and at 5 min intervals during exercise to exhaustion at 85% VO2max. At 4300 m, VO2max was reduced 19%, while VEmax and Rmax increased 17 and 8%, respectively. HRmax and RPEmax was unchanged. For any given relative exercise intensity, VO2 and absolute exercise intensity (kpm-min-1) were reduced, while VE was about 12% and R about 7% greater at 4300 m; HR was unchanged. At 4300 m, RPE at the lower intensities of submaximal exercise and early during prolonged exercise were significantly less than at sea level. These differences were reduced and finally eliminated as exercise intensity increased toward maximal or as prolonged exercise continued to exhaustion. Endurance time to exhaustion at 4300 m was not different from that at sea level. To account for the perceptual differences between exercise at 4300 m an sea level, we proposed that local factors (muscular strain) exert greater influence on the perception of effort at exercise intensities which do not greatly stress ventilation and circulation, while central factors exert greater influence on the perception of effort at exercise intensities at which tachypnea and tachycardia are of sufficient magnitude to be perceived as extremely stressful.

Red blood cell antioxidants in human volunteers exposed to ozone.

Indices of red blood cell (RBC) antioxidant capacity can undergo changes upon exposure to oxidants, either acutely or chronically. To investigate whether these changes might provide a biochemical marker for acute environmental ozone exposure, we assessed RBC glutathione (GSH) and catalase (CAT) responses in seven normal volunteers exposed to 0.16 ppm ozone for 7.5 hours compared to the same measurements following sham exposure to clean air. For each subject, an interim period of two weeks separated the two exposure studies. Investigators performing the RBC assays were unaware of the environmental conditions. No changes in either GSH or CAT were observed for any study condition when compared to pre-study values. Our conclusion is that RBC antioxidants do not accurately reflect in vivo exposure to ozone at concentrations readily attainable during periods of heavy urban pollution. Our data dispute the value of these indices as markers of acute environmental photochemical oxidant exposure.

An air quality data analysis system for interrelating effects, standards, and needed source reductions: Part 11. A lognormal model relating human lung function decrease to O3 exposure.

Forced expiratory volume in 1 second (FEV1) was measured in 21 men exercising while exposed to four O3 concentrations (0.0, 0.08, 0.10, and 0.12 ppm). A lognormal multiple linear regression model was fitted to their mean FEV1 measurements to predict FEV1 percent decrease as a function of O3 concentration and exposure duration. The exercise level used was probably comparable to heavy manual labor. The longest O3 exposure studied was 6 h. Extrapolating cautiously to an 8-h workday of heavy manual labor, the model predicts that O3 concentrations of 0.08, 0.10, and 0.12 ppm would decrease FEV1 by 9, 15, and 20 percent, respectively.

Differing response of asthmatics to sulfur dioxide exposure with continuous and intermittent exercise.

Ten subjects with mild asthma were initially exposed in an environmental chamber (26 degrees C 70% relative humidity) to clean air and 1.0 ppm SO2 while performing 3 sets of 10-min treadmill exercises (ventilation, 41 L/min) broken by 15-min rest periods. To evaluate the effects of the pattern and duration of exercise on the response to SO2 exposure, the subjects were then exposed to the same environmental conditions while exercising continuously for 30 min. Specific airway resistance (SRaw) was measured by body plethysmography before each exposure and after each exercise. All SO2 responses were significantly greater than the clean air responses. With intermittent exercise and SO2 exposure, mean SRaw measurements (preexposure and after 10, 20, and 30 min of exercise) were 5.4, 14.7, 12.8, and 11.1 cm H2O/s. After SO2 exposure with continuous exercise, the mean SRaw showed an increase from 5.2 to 17.3 cm H2O/s. This increase was significantly (p = 0.018) greater than the response after the third exercise in the intermittent protocol. It appears that asthmatics show an attenuated response to repetitive exercise in an atmosphere of 1.00 ppm SO2 and that the response to SO2 exposure develops rapidly and is maintained during 30 min of continuous exercise.

The relationship between exposure duration and sulfur dioxide-induced bronchoconstriction in asthmatic subjects.

The purpose of this study was to determine the shortest duration of exposure to 1.0 ppm sulfur dioxide (SO2) sufficient to induce bronchoconstriction significantly greater than that observed with exposure to clean air (CA) in exercising SO2-sensitive asthmatics. Asymptomatic, nonmedicated, male asthmatics (n = 12) with airway hyperresponsiveness to both methacholine and SO2 were exposed in a chamber (20 degrees C, 40% relative humidity) for 0.0, 0.5, 1.0, 2.0 and 5.0 min to both CA and 1.0 ppm SO2 on separate days (10 exposures). Just prior to each exposure, subjects walked on a treadmill in CA for 5 min at a predetermined speed/elevation to elicit a target ventilation of about 40 L/min, i.e., a brisk pace up a slight incline. After this walk, subjects rapidly entered an adjoining exposure chamber containing either CA or SO2 and immediately walked at the same speed/elevation for the specified exposure duration. Subjects then rapidly exited the chamber. Specific airway resistance (SRaw) and ratings of respiratory symptoms associated with asthma [shortness of breath/chest discomfort (SB/CD) and wheezing (WHZ)] were measured prior to any exercise and following each exposure. Postexposure SRaw and symptom ratings increased with increased exposure duration in SO2; postexposure SRaw also was increased with increased exposure duration in CA but to a lesser extent. After adjusting for the CA response, significantly greater SO2-induced bronchoconstriction was observed for the 2.0 and 5.0 min exposures as indicated by substantially greater increases in SRaw and substantially higher ratings of respiratory symptoms. The authors conclude that with the above exposure conditions, on average, SO2-sensitive asthmatics exhibit significant bronchoconstriction at exposure durations of 2.0 min or more.

Reproducibility of individual responses to ozone exposure.

Because large intersubject differences in the magnitudes of response to a single ozone (O3) exposure have been observed, we undertook to determine if this variability were due to differences in intrinsic responsiveness to O3 or to other factors. Thirty-two subjects were exposed to 1 of 5 O3 concentrations (0.12, 0.18, 0.24, 0.30, or 0.40 ppm), and each underwent one or more repeat exposures separated by from 3 wk to 14 months. Magnitudes of change for pulmonary function variables, respiratory rate and tidal volume, and for reported symptoms were compared for the repeated exposures. Changes induced in forced expiratory spirometric measurements were highly reproducible for as long as 10 months and for all tested O3 concentrations of 0.18 ppm or greater. This high degree of reproducibility indicates that the magnitude of response to a single exposure is a precise estimate of that subject's intrinsic O3 responsiveness. We conclude that the previously observed intersubject variability in magnitude of O3-induced effects is the result of large differences in intrinsic responsiveness to O3.

Comparison of pulmonary responses of asthmatic and nonasthmatic subjects performing light exercise while exposed to a low level of ozone.

To determine if asthmatic subjects (ASTH, n = 17) experience greater O3-induced pulmonary decrements than nonasthmatic subjects (NONA, n = 13), both groups were exposed for 7.6 h to both clean air and 0.16 ppm O3. Exposures consisted of seven 50-min periods of light exercise (VE = 14.2 and 15.3 l/min/m2 for ASTH and NONA, respectively), each followed by 10 min rest. A 35-min lunch period followed the third exercise. Following O3 exposure, decrements in forced expiratory volume in one second (FEV1) and FEV1 divided by forced vital capacity (FVC), corrected for air exposure, for ASTH (-19.4 +/- 3.1% and -6.2 +/- 2%, respectively) were significantly greater (p = 0.04 and 0.02) than for NONA (-9.8 +/- 1.9% and -1 +/- 1%, respectively). There was no difference (p = 0.33) for decrements in FVC between ASTH (-11.8 +/- 1.9%) and NONA (-8.8 +/- 2.1%). Nine of 17 ASTH experienced wheezing with O3, while only one experienced wheezing with air (p = 0.004); no NONA experienced wheezing. Six of 17 ASTH requested inhaled beta-agonist bronchodilator prior to and/or during O3 exposure and experienced some temporary alleviation of decrements. At end exposure, however, ASTH who were medicated had greater O3-induced decrements than those who were not medicated. ASTH who had the larger O3-induced decrements had lower baseline FEV1/FVC and lower baseline %predicted FEV1. These data indicate that in ASTH, unlike NONA, some portion of O3-induced pulmonary decrements experienced was related to bronchoconstriction, and that O3-responsiveness for ASTH depended upon baseline airway status.

Effects of acute plasma volume expansion on altering exercise-heat performance.

To determine the effect an acute plasma volume expansion has on body temperature responses and exercise performance in the heat, seven unacclimatized male volunteers attempted to complete two 90-min walks (45% of VO2 max) in a hot/dry (45 degrees C/20% rh) environment. The experimental walk was preceded by an infusion of human albumin (50 g in a 200-ml solution) and the control walk was preceded by an infusion of isotonic saline (200 ml). Saline infusion did not alter the plasma volume. The albumin infusion was found to significantly (p less than 0.01) increase plasma volume approximately 13% over control levels. No significant differences were found for performance time, final heart rate or final rectal temperature values between the two walks. In general, significant differences were not found for systolic blood pressure, rectal temperature, mean skin temperature, heat storage, sweat rate, plasma lactate, plasma osmolality, or plasma protein content values between the two walks. However, heart rate responses were found to be significantly lower (p less 0.05; approximately 13 bt x min-1) during the 25-min and 40-min measurements of the experimental walk. These data suggest that plasma volume expansion may be a supportive adaptation to enable lowered heart rate responses but does not improve thermoregulatory function or performance time in the heat.

Ozone concentration and pulmonary response relationships for 6.6-hour exposures with five hours of moderate exercise to 0.08, 0.10, and 0.12 ppm.

The magnitudes of pulmonary responses we previously observed (1) following 6.6-h exposures to 0.12 ppm ozone (O3) suggested that responses would also occur with similar exposures at lower O3 concentrations. The objective of this study was to determine the extent of pulmonary function decrements, respiratory discomfort, and increased airway reactivity to methacholine induced by exposure to O3 below 0.12 ppm. Separate 6.6-h chamber exposures to 0.00, 0.08, 0.10, and 0.12 ppm O3 included six 50-min periods of moderate exercise (VE approximately equal to 39 L/min, HR approximately equal to 115 bpm, and VO2 approximately equal to 1.5 L/min). Each exercise period was followed by 10 min of rest. A 35-min lunch break was included midway through the exposure. Although not intended as an exact simulation, the overall duration, intensity, and metabolic requirements of the exercise performed were representative of a day of moderate to heavy work or play. Preexposure FEV1 averaged 4.39 L, and essentially no change (+0.03 L) occurred with exposure to 0.00 ppm O3. Significant decreases (p less than 0.01) of -0.31, -0.30, and -0.54 L were observed with exposures to 0.08, 0.10, and 0.12 ppm, respectively. The provocative dose of methacholine required to increase airway resistance by 100% (PD100) was 58 cumulative inhalation units (CIU) following exposure to 0.00 ppm and was significantly reduced (p less than 0.01) to 37 CIU at 0.08, 31 CIU at 0.10, and 26 CIU at 0.12 ppm O3; reductions in PD100 are considered indicative of increases in nonspecific airway responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)