bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions of lung stretch, hyperoxia, and MIP-2 production in ventilator-induced lung injury
Authors: Quinn Deborah A. , Moufarrej Ramzi K. , Volokhov Alexey , Hales Charles A.
Published: March 2015

The use of positive pressure mechanical ventilation can cause ventilator-induced lung injury (VILI). We hypothesized that hyperoxia in combination with large tidal volumes (Vt) would accentuate noncardiogenic edema and neutrophil infiltration in VILI and be dependent on stretch-induced macrophage inflammatory protein-2 (MIP-2) production. In rats ventilated with Vt 20 ml/kg, there was pulmonary edema formation that was significantly increased by hyperoxia. Total lung neutrophil infiltration and MIP-2 in bronchoalveolar lavage (BAL) fluid were significantly elevated, in animals exposed to high Vt both on room air (RA) and with hyperoxia. Hyperoxia markedly augmented the migration of neutrophils into the alveoli. Anti-MIP-2 antibody blocked migration of neutrophils into the alveoli in RA by 51% and with hyperoxia by 65%. We concluded that neutrophil migration into the alveoli was dependent on stretch-induced MIP-2 production. Hyperoxia significantly increased edema formation and neutrophil migration into the alveoli with Vt 20 ml/kg, although BAL MIP-2 levels were nearly identical to Vt 20 ml/kg with RA, suggesting that other mechanisms may be involved in hyperoxia-augmented neutrophil alveolar content in VILI.
Immediate sensory nerve-mediated respiratory responses to irritants in healthy and allergic airway-diseased mice
Authors: Morris John B. , Symanowicz Peter T. , Olsen Joshua E. , Thrall Roger S. , Cloutier Michelle M. , Hubbard Andrea K.
Published: March 2015

The immediate responses of the upper respiratory tract (URT) to the irritants acrolein and acetic acid were examined in healthy and allergic airway-diseased C57Bl/6J mice. Acrolein (1.1 ppm) and acetic acid (330 ppm) vapors induced an immediate increase in flow resistance, as measured in the surgically isolated URT of urethane-anesthetized healthy animals. Acrolein, but not acetic acid, induced a small URT vasodilatory response. In awake spontaneously breathing mice, both vapors induced a prolonged pause at the start of expiration (a response mediated via stimulation of nasal trigeminal nerves) and an increase in total respiratory specific airway flow resistance, the magnitude of which was similar to that observed in the isolated URT. Both responses were significantly reduced in animals pretreated with large doses of capsaicin to defunctionalize sensory nerves, strongly suggesting a role for sensory nerves in development of these responses. The breathing pattern and/or obstructive responses were enhanced in mice with ovalbumin-induced allergic airway disease. These results suggest that the primary responses to acrolein and acetic acid vapors are altered breathing patterns and airway obstruction, that sensory nerves play an important role in these responses, and that these responses are enhanced in animals with allergic airway disease.
Vascular endothelial growth factor in patients with high-altitude pulmonary edema
Authors: Hanaoka Masayuki , Droma Yunden , Naramoto Atsuhiko , Honda Takayuki , Kobayashi Toshio , Kubo Keishi
Published: March 2015

To examine the role of VEGF in the pathogenesis of high-altitude pulmonary edema (HAPE), we measured the concentrations of VEGF in venous serum and bronchoalveolar lavage fluid in patients with HAPE and in healthy volunteers. The VEGF in venous serum of the patients was normal at admission and significantly increased at recovery. Similarly, the VEGF in bronchoalveolar lavage fluid of the patients was increased at recovery compared with admission, but values at both admission and recovery were significantly lower than those of the controls. The present finding suggests that VEGF probably is destroyed in the lung of HAPE, and it appears less likely to have a critical part in the pathogenesis of HAPE but has rather an important role in the repair process for the impaired cell layer.
Respiratory system loop gain in normal men and women measured with proportional-assist ventilation
Authors: Wellman Andrew , Malhotra Atul , Fogel Robert B. , Edwards Jill K. , Schory Karen , White David P.
Published: March 2015

We hypothesized that increased chemical control instability (CCI) in men could partially explain the male predominance in obstructive sleep apnea (OSA). CCI was assessed by sequentially increasing respiratory control system loop gain (LG) with proportional-assist ventilation (PAV) in 10 men (age 24–48 yr) and 9 women (age 22–36 yr) until periodic breathing or awakening occurred. Women were studied in both the follicular and luteal phases of the menstrual cycle. The amount by which PAV amplified LG was quantified from the tidal volume amplification factor [(VtAF) assisted tidal volume/unassisted tidal volume]. LG was calculated as the inverse of the VtAF occurring at the assist level immediately preceding the emergence of periodic breathing (when LG × VtAF = 1). Only 1 of 10 men and 2 of 9 women developed periodic breathing with PAV. The rest were resistant to periodic breathing despite moderately high levels of PAV amplification. We conclude that LG is low in the majority of normal men and women and that higher volume amplification factors are needed to determine whether gender differences exist in this low range.
Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans
Authors: Moosavi S. H. , Golestanian E. , Binks A. P. , Lansing R. W. , Brown R. , Banzett R. B.
Published: March 2015

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via “corollary discharge” to higher centers; absence of dyspnea during low inspired Po 2 may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po 2 = 60–40 Torr) and hypercapnic hyperoxia (end-tidal Pco 2= 40–50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, “matched” by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. “Air hunger” was rated every 30 s on a visual analog scale. Air hunger-Pet O2 curves rose sharply at Pet O2 <50 Torr. Air hunger was not different between matched stimuli ( P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.
Volume dependence of airway and tissue impedances in mice
Authors: Sly Peter D. , Collins Rachel A. , Thamrin Cindy , Turner Debra J. , Hantos Zoltan
Published: March 2015

We measured respiratory input impedance (1–25 Hz) in mice and obtained parameters for airway and tissue mechanics by model fitting. Lung volume was varied by inflating to airway opening pressure (Pao) between 0 and 20 cmH2O. The expected pattern of changes in respiratory mechanics with increasing lung volume was seen: a progressive fall in airway resistance and increases in the coefficients of tissue damping and elastance. A surprising pattern was seen in hysteresivity (η), with a plateau at low lung volumes (Pao < 10 cmH2O), a sharp fall occurring between 10 and 15 cmH2O, and η approaching a second (lower) plateau at higher lung volumes. Studies designed to elucidate the mechanism(s) behind this behavior revealed that this was not due to chest wall properties, differences in volume history at low lung volume, time dependence of volume recruitment, or surface-acting forces. Our data are consistent with the notion that at low lung volumes the mechanics of the tissue matrix determine η, whereas at high lung volumes the properties of individual fibers (collagen) become more important.
Increased insulin receptor signaling and glycogen synthase activity contribute to the synergistic effect of exercise on insulin action
Authors: Christ-Roberts Christine Y. , Pratipanawatr Thongchai , Pratipanawatr Wilailak , Berria Rachele , Belfort Renata , Mandarino Lawrence J.
Published: March 2015

The purpose of this study was to determine the factors contributing to the ability of exercise to enhance insulin-stimulated glucose disposal. Sixteen insulin-resistant nondiabetic and seven Type 2 diabetic subjects underwent two hyperinsulinemic (40 mU · m-2· min-1) clamps, once without and once with concomitant exercise at 70% peak O2consumption. Exercise was begun at the start of insulin infusion and was performed for 30 min. Biopsies of the vastus lateralis were performed before and after 30 min of insulin infusion (immediately after cessation of exercise). Exercise synergistically increased insulin-stimulated glucose disposal in nondiabetic [from 4.6 ± 0.4 to 9.5 ± 0.8 mg · kg fat-free mass (FFM)-1· min-1] and diabetic subjects (from 4.3 ± 1.0 to 7.9 ± 0.7 mg · kg FFM-1· min-1) subjects. The rate of glucose disposal also was significantly greater in each group after cessation of exercise. Exercise enhanced insulin-stimulated increases in glycogen synthase fractional velocity in control (from 0.07 ± 0.02 to 0.22 ± 0.05, P < 0.05) and diabetic (from 0.08 ± 0.03 to 0.15 ± 0.03, P < 0.01) subjects. Exercise also enhanced insulin-stimulated glucose storage (glycogen synthesis) in nondiabetic (2.9 ± 0.9 vs. 4.9 ± 1.1 mg · kg FFM-1· min-1) and diabetic (1.7 ± 0.5 vs. 4.2 ± 0.8 mg · kg FFM-1· min-1) subjects. Increased glucose storage accounted for the increase in whole body glucose disposal when exercise was performed during insulin stimulation in both groups; effects of exercise were correlated with enhancement of glucose disposal and glucose storage ( r = 0.93, P < 0.001). Exercise synergistically enhanced insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity ( P < 0.05) and Akt Ser473phosphorylation ( P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects. The data indicate that exercise, performed in conjunction with insulin infusion, synergistically increases insulin-stimulated glucose disposal compared with insulin alone. In nondiabetic and diabetic subjects, increased glycogen synthase activation is likely to be involved, in part, in this effect. In nondiabetic, but not diabetic, subjects, exercise-induced enhancement of insulin stimulation of the phosphatidylinositol 3-kinase pathway is also likely to be involved in the exercise-induced synergistic enhancement of glucose disposal.
Effects of respiratory muscle unloading on exercise-induced diaphragm fatigue
Authors: Babcock Mark A. , Pegelow David F. , Harms Craig A. , Dempsey Jerome A.
Published: March 2015

We previously compared the effects of increased respiratory muscle work during whole body exercise and at rest on diaphragmatic fatigue and showed that the amount of diaphragmatic force output required to cause fatigue was reduced significantly during exercise (Babcock et al., J Appl Physiol 78: 1710, 1995). In this study, we use positive-pressure proportional assist ventilation (PAV) to unload the respiratory muscles during exercise to determine the effects of respiratory muscle work, per se, on exercise-induced diaphragmatic fatigue. After 8–13 min of exercise to exhaustion under control conditions at 80–85% maximal oxygen consumption, bilateral phrenic nerve stimulation using single-twitch stimuli (1 Hz) and paired stimuli (10–100 Hz) showed that diaphragmatic pressure was reduced by 20–30% for up to 60 min after exercise. Usage of PAV during heavy exercise reduced the work of breathing by 40–50% and oxygen consumption by 10–15% below control. PAV prevented exercise-induced diaphragmatic fatigue as determined by bilateral phrenic nerve stimulation at all frequencies and times postexercise. Our study has confirmed that high- and low-frequency diaphragmatic fatigue result from heavy-intensity whole body exercise to exhaustion; furthermore, the data show that the workload endured by the respiratory muscles is a critical determinant of this exercise-induced diaphragmatic fatigue.
Effects of postnatal maturation on energetics and cross-bridge properties in rat diaphragm
Authors: Orliaguet Gilles , Langeron Olivier , Bouhemad Belaid , Coriat Pierre , LeCarpentier Yves , Riou Bruno
Published: March 2015

The effects of maturation on cross-bridge (CB) properties were studied in rat diaphragm strips obtained at postnatal days 3, 10, and 17 and in adults (10–12 wk old). Calculations of muscle energetics and characteristics of CBs were determined from standard Huxley equations. Maturation did not change the curvature of the force-velocity relationship or the peak of mechanical efficiency. There was a significant increase in the total number of CBs per cross-sectional area (m) with aging but not in single CB force. The turnover rate of myosin ATPase increased, the duration of the CB cycle decreased, and the velocity of CBs decreased significantly only after the first week postpartum. There was a linear relationship between maximum total force and m ( r = 0.969, P < 0.001), and between maximum unloaded shortening velocity and m ( r = 0.728, P < 0.001). When this study in the rat and previous study in the hamster are compared, it appears that there are few species differences in the postnatal maturation process of the diaphragm.
Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia
Authors: Peng Ying-Jie , Prabhakar Nanduri R.
Published: March 2015

Long-term facilitation (LTF) of breathing elicited by episodic hypoxia (EH) is an extensively studied example of plasticity of respiratory motor behavior. Previous studies employed the paradigm of EH wherein each episode of hypoxia was 5 min. This paradigm is rarely encountered in nature. Brief episodes of hypoxia are encountered frequently with recurrent apneas, wherein hypoxic episodes last a few seconds only. Recent studies suggest that chronic intermittent hypoxia (CIH) represents a form of oxidative stress involving reactive O2species. The objectives of the present study were to determine 1) whether acute, repeated, brief EH (15 s) elicit LTF in breathing and 2) whether prior conditioning with CIH modulates acute EH-induced LTF of breathing, and if so whether reactive O2 species are involved. Experiments were performed on anesthetized, vagotomized, paralyzed, and mechanically ventilated rats, and efferent phrenic nerve activity was monitored as an index of respiratory motor output. In control animals, acute EH (15-s hypoxia; 10 episodes; n = 9) increased minute neural respiration, which persisted during 60 min of the posthypoxic period, suggesting LTF of breathing. EH-induced LTF of respiration was markedly augmented in CIH-conditioned animals (15-s hypoxia, 9 episodes/h, 8 h/day for 10 days; n = 9). By contrast, conditioning with a comparable, cumulative duration of sustained hypoxia (4-h hypoxia; n = 8) did not augment LTF elicited by acute EH. Systemic administration of manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (5 mg · kg−1 · day−1for 10 days), a potent scavenger of O[Formula: see text]·, prevented CIH-induced potentiation of LTF ( n = 9). These results demonstrate that 1) acute, brief EH elicits LTF in respiratory motor output; 2) prior conditioning with CIH, but not with comparable, cumulative duration of sustained hypoxia, augments LTF elicited by acute EH; and 3) O[Formula: see text]· radical scavenger prevents CIH-induced potentiation of LTF of respiration.
Anatomical arrangement of hypercapnia-activated cells in the superficial ventral medulla of rats
Authors: Okada Yasumasa , Chen Zibin , Jiang Wuhan , Kuwana Shun-Ichi , Eldridge Frederic L.
Published: March 2015

The anatomical structure of central respiratory chemoreceptors in the superficial ventral medulla of rats was studied by using hypercapnia-induced c- foslabeling to identify cells directly stimulated by extracellular pH or Pco 2. The distribution of c- fos-positive cells was found to be predominantly perivascular to surface vessels. In the superficial ventral medullary midline, parapyramidal, and ventrolateral regions where c- fos-positive cells were concentrated, we found a common, characteristic, anatomical architecture. The medullary surface showed an indentation covered by a surface vessel, and the marginal glial layer was thickened. We classified c- fos-positive cells into two types. One (type I cell) was small, was located inside the marginal glial layer and close to the medullary surface, and surrounded fine vessels. The other (type II cell) was large and located dorsal to the marginal glial layer. c- fos Expression under synaptic blockade suggested that type I cells are intrinsically chemosensitive. The chemosensitivity of surface cells (possible type I cells) surrounding vessels was confirmed electrophysiologically in slice preparations. We suggest that this characteristic anatomical structure may be the central chemoreceptor.
Passive tension of rat skeletal soleus muscle fibers: effects of unloading conditions
Authors: Toursel Thierry , Stevens Laurence , Granzier Henk , Mounier Yvonne
Published: March 2015

In this work we studied changes in passive elastic properties of rat soleus muscle fibers subjected to 14 days of hindlimb unloading (HU). For this purpose, we investigated the titin isoform expression in soleus muscles, passive tension-fiber strain relationships of single fibers, and the effects of the thick filament depolymerization on passive tension development. The myosin heavy chain composition was also measured for all fibers studied. Despite a slow-to-fast transformation of the soleus muscles on the basis of their myosin heavy chain content, no modification in the titin isoform expression was detected after 14 days of HU. However, the passive tension-fiber strain relationships revealed that passive tension of both slow and fast HU soleus fibers increased less steeply with sarcomere length than that of control fibers. Gel analysis suggested that this result could be explained by a decrease in the amount of titin in soleus muscle after HU. Furthermore, the thick filament depolymerization was found to similarly decrease passive tension in control and HU soleus fibers. Taken together, these results suggested that HU did not change titin isoform expression in the soleus muscle, but rather modified muscle stiffness by decreasing the amount of titin.
Pulmonary surfactant and inflammation in septic adult mice: role of surfactant protein A
Authors: Malloy Jaret L. , Veldhuizen Ruud A. W. , McCormack Francis X. , Korfhagen Thomas R. , Whitsett Jeffery A. , Lewis James F.
Published: March 2015

Surfactant alterations, alveolar cytokine changes, and the role of surfactant protein (SP)-A in septic mice were investigated. Sepsis was induced via cecal ligation and perforation (CLP). Septic and sham mice were euthanized at 0, 3, 6, 9, 12, 15, and 18 h after surgery. Mice deficient in SP-A and mice that overexpressed SP-A were euthanized 18 h after surgery. In wild-type, sham-operated mice, surfactant pool sizes were similar at all time points, whereas in the CLP groups there was a significant decrease in small-aggregate surfactant pool sizes beginning 6 h after CLP. Interleukin-6 concentrations in bronchoalveolar lavage fluid from septic animals increased from 6 to 18 h after surgery. Identical surfactant alterations and concentrations of cytokines were observed in septic mice that were SP-A deficient or that overexpressed SP-A. In conclusion, alterations of pulmonary surfactant and alveolar cytokines occur simultaneously, 6 h after a systemic insult. In addition, we did not detect a role for SP-A in regulating surfactant phospholipid pool sizes or pulmonary inflammation in septic mice.
Early onset of pulmonary gas exchange disturbance during progressive exercise in healthy active men
Authors: Aguilaniu B. , Flore P. , Maitre J. , Ochier J. , Lacour J. R. , Perrault H.
Published: March 2015

10.1152/japplphysiol.00630.1999.—Some recent studies of competitive athletes have shown exercise-induced hypoxemia to begin in submaximal exercise. We examined the role of ventilatory factors in the submaximal exercise gas exchange disturbance (GED) of healthy men involved in regular work-related exercise but not in competitive activities. From the 38 national mountain rescue workers evaluated (36 ± 1 yr), 14 were classified as GED and were compared with 14 subjects matched for age, height, weight, and maximal oxygen uptake (V˙o 2 max; 3.61 ± 0.12 l/min) and showing a normal response (N). Mean arterial Po 2 was already lower than N ( P= 0.05) at 40% V˙o 2 max and continued to fall until V˙o 2 max (GED: 80.2 ± 1.6 vs. N: 91.7 ± 1.3 Torr). A parallel upward shift in the alveolar-arterial oxygen difference vs. %V˙o 2 max relationship was observed in GED compared with N from the onset throughout the incremental protocol. At submaximal intensities, ideal alveolar Po 2, tidal volume, respiratory frequency, and dead space-to-tidal volume ratio were identical between groups. As per the higher arterial Pco 2 of GED at V˙o 2 max, subjects with an exaggerated submaximal alveolar-arterial oxygen difference also showed a relative maximal hypoventilation. Results thus suggest the existence of a common denominator that contributes to the GED of submaximal exercise and affects the maximal ventilatory response.
Footstrike is the major cause of hemolysis during running
Authors: Telford R. D. , Sly G. J. , Hahn A. G. , Cunningham R. B. , Bryant C. , Smith J. A.
Published: March 2015

There is a wide body of literature reporting red cell hemolysis as occurring after various forms of exercise. Whereas the trauma associated with footstrike is thought to be the major cause of hemolysis after running, its significance compared with hemolysis that results from other circulatory stresses on the red blood cell has not been thoroughly addressed. To investigate the significance of footstrike, we measured the degree of hemolysis after 1 h of running. To control for the potential effects of oxidative and circulatory stresses on the red blood cell, the same subjects cycled for 1 h at equivalent oxygen uptake. Our subjects were 10 male triathletes, who each completed two separate 1-h sessions of running and cycling at 75% peak oxygen uptake, which were performed in random order 1 wk apart. Plasma free hemoglobin and serum haptoglobin concentrations were measured as indicators of hemolysis. We also measured methemoglobin as a percentage of total hemoglobin immediately postexercise as an indicator of red cell oxidative stress. Plasma free hemoglobin increased after both running ( P < 0.01) and cycling ( P < 0.01), but the increase was fourfold greater after running ( P < 0.01). This was reflected by a significant fall in haptoglobin 1 h after the running trials, whereas no significant changes occurred after cycling at any sample point. Methemoglobin increased twofold after both running and cycling ( P < 0.01), with no significant differences between modes of exercise. The present data indicate that, whereas general circulatory trauma to the red blood cells associated with 1 h of exercise at 75% maximal oxygen uptake may result in some exercise-induced hemolysis, footstrike is the major contributor to hemolysis during running.
Middle ear pressure change during controlled breathing with gas mixtures containing nitrous oxide
Authors: Doyle William J. , Banks Juliane M.
Published: March 2015

The change in middle ear pressure while breathing gas mixtures containing N2O was studied in four monkeys. At each of three experimental sessions, monkeys were anesthetized, acclimated for 60 min, breathed with room air for 60 min, and then breathed with 5, 10, or 20% N2O for 60 min. Middle ear pressure, rectal temperature, and vital signs were recorded throughout. The time constant for blood-middle ear N2O exchange was calculated from these data. Middle ear pressure decreased during acclimation, was stable during air breathing, and increased during N2O breathing. The rate of pressure change was similar for both ears of each animal and was directly related to N2O percent. The calculated time constant ranged from 0.003 to 0.008 min−1 across animals but was not different for a given ear across sessions. These results show that breathing gas mixtures containing N2O causes predictable and quantifiable increases in middle ear pressure.
Neutral and DEAE dextrans as tracers for assessing lung microvascular barrier permeability and integrity
Authors: Sanders Jonathan R. , Pou N. Adrienne , Roselli Robert J.
Published: March 2015

Steady-state lymph-to-plasma concentration ratios (L/Ps) of neutral dextrans, cationic DEAE dextrans, and endogenous proteins were determined under normal and increased permeability conditions in six unanesthetized yearling sheep prepared with chronic lung lymph fistulas. Fluorescent dextrans with radii ranging from 1 to 30 nm were intravenously infused, and after 24 h, perilla ketone (PK) was given to alter permeability while the dextran infusion was maintained. Plasma and lymph samples were collected before and after PK administration and analyzed for dextran and protein concentrations after high-performance liquid chromatography size separation. Under both baseline and increased permeability conditions, DEAE dextrans had higher L/Ps than neutral dextrans of similar size but lower L/Ps than proteins of similar size. Comparison of L/Ps before and after PK revealed that the percentage change in permeability for neutral and DEAE dextrans was significantly larger than that for proteins. These results suggest that 1) the pulmonary microvascular barrier behaves as a net negative barrier, 2) some transport mechanisms for proteins and dextrans are different, and 3) neutral and cationic dextrans are more sensitive markers than proteins of the same size for assessing changes in pulmonary capillary permeability.
Changes in muscle activation can prolong the endurance time of a submaximal isometric contraction in humans
Authors: Hunter Sandra K. , Enoka Roger M.
Published: March 2015

Fourteen young subjects (7 men and 7 women) performed a fatiguing isometric contraction with the elbow flexor muscles at 20% of maximal voluntary contraction (MVC) force on three occasions. Endurance time for session 3 [1,718 ± 1,189 (SD) s] was longer than for session 1 (1,225 ± 683 s) and session 2 (1,410 ± 977 s). Five men and four women increased endurance time between session 1 and 3 by 60 ± 28% (responders), whereas two men and three women did not (−3 ± 11%; nonresponders). The MVC force was similar for the responders and nonresponders, both before and after the fatiguing contraction. Fatiguing contractions were characterized by an increase in the electromyogram (EMG) amplitude and number of bursts during the fatiguing contractions. The responders achieved a similar level of EMG at exhaustion but a reduced rate of increase in the EMG across sessions. The rate of increase in EMG across sessions declined for the nonresponders, but it remained greater than that of the responders. The increase in burst rate during the contractions declined across sessions with a negative relation between burst rate and endurance time ( r = −0.42). Normalized force fluctuations increased during the fatiguing contractions, and there was a positive relation ( r = 0.60) between the force fluctuations and burst rate. Changes in mean arterial pressure and heart rate during the fatiguing contraction were similar for the responders and nonresponders across the three sessions. The results indicate that those subjects who increased the endurance time of a submaximal contraction across three sessions did so by altering the level and pattern of muscle activation.
Effects of fatigue and training on sarcoplasmic reticulum Ca2+regulation in human skeletal muscle
Authors: Li Jia L. , Wang Xiao N. , Fraser Steve F. , Carey Michael F. , Wrigley Tim V. , McKenna Michael J.
Published: March 2015

Little is known about fatigue and training effects on sarcoplasmic reticulum (SR) function in human muscle, and we therefore investigated this in eight untrained controls (UT), eight endurance-trained (ET), and eight resistance-trained athletes (RT). Muscle biopsies (vastus lateralis) taken at rest and after 50 maximal quadriceps contractions (180°/s, 0.5 Hz) were analyzed for fiber composition, metabolites and maximal SR Ca2+release, Ca2+uptake, and Ca2+-ATPase activity. Fatigue reduced ( P < 0.05) Ca2+release (42.1 ± 3.8%, 43.4 ± 3.9%, 31.3 ± 6.1%), Ca2+uptake (43.0 ± 5.2%, 34.1 ± 4.6%, 28.4 ± 2.8%), and Ca2+-ATPase activity (38.6 ± 4.2%, 48.5 ± 5.7%, 29.6 ± 5.0%), in UT, RT, and ET, respectively. These decreases were correlated with fatigability and with type II fiber proportion ( P < 0.05). Resting SR measures were correlated with type II proportion ( r ≥ 0.51, P < 0.05). ET had lower resting Ca2+release, Ca2+uptake, and Ca2+-ATPase ( P < 0.05) than UT and RT ( P < 0.05), probably because of their lower type II proportion; only minor effects were found in RT. Thus SR function is markedly depressed with fatigue in controls and in athletes, is dependent on fiber type, and appears to be minimally affected by chronic training status.
Effect of gravity on chest wall mechanics
Authors: Bettinelli D. , Kays C. , Bailliart O. , Capderou A. , Techoueyres P. , Lachaud J. L. , Vaïda P. , Miserocchi G.
Published: March 2015

Chest wall mechanics was studied in four subjects on changing gravity in the craniocaudal direction (Gz) during parabolic flights. The thorax appears very compliant at 0 Gz: its recoil changes only from −2 to 2 cmH2O in the volume range of 30–70% vital capacity (VC). Increasing Gz from 0 to 1 and 1.8 Gzprogressively shifted the volume-pressure curve of the chest wall to the left and also caused a fivefold exponential decrease in compliance. For lung volume <30% VC, gravity has an inspiratory effect, but this effect is much larger going from 0 to 1 Gz than from 1 to 1.8 Gz. For a volume from 30 to 70% VC, the effect is inspiratory going from 0 to 1 Gz but expiratory from 1 to 1.8 Gz. For a volume greater than ∼70% VC, gravity always has an expiratory effect. The data suggest that the chest wall does not behave as a linear system when exposed to changing gravity, as the effect depends on both chest wall volume and magnitude of Gz.
Estimate of the subepithelial hydrostatic pressure that drives inflammatory transudate into the airway lumen
Authors: Serikov V. B. , Jang Y. J. , Widdicombe J. H.
Published: March 2015

Inflammatory diseases of the upper respiratory tract are characterized by flow of plasma filtrate across the epithelium into the airway lumen (“transudation”). Elsewhere, we have proposed that extravasation from microvessels causes edema, and this is associated with elevated subepithelial hydrostatic pressure that drives transudation. To test this hypothesis, we have attempted to block transudation by elevating luminal hydrostatic pressure. We measured the appearance of plasma markers into the lumen of an isolated perfused segment of rat trachea in vivo and found that stimulation of one vagal nerve caused a rapid (half-time ∼5 min) and nonselective increase in the flow of markers from blood to airway lumen. Leukocyte migration also caused transudation that developed much more slowly (half-time = 2–3 h). In both cases, transudation was blocked by application of luminal hydrostatic pressures. The critical luminal pressure needed to block vagally induced transudation was ∼4.5 cmH2O, and, to block epithelial transudation induced by leukocyte traffic, it was 3 cmH2O, and we conclude that these are the subepithelial pressures that drive inflammatory transudation into the airway lumen.
Low levels of nitric oxide and carbon monoxide in α1-antitrypsin deficiency
Authors: Machado Roberto F. , Stoller James K. , Laskowski Daniel , Zheng Shuo , Lupica Joseph A. , Dweik Raed A. , Erzurum Serpil C.
Published: March 2015

Quantitations of exhaled nitric oxide (NO) and carbon monoxide (CO) have been proposed as noninvasive markers of airway inflammation. We hypothesized that exhaled CO is increased in individuals with α1-antitrypsin (AT) deficiency, who have lung inflammation and injury related to oxidative and proteolytic processes. Nineteen individuals with α1-AT deficiency, 22 healthy controls, and 12 patients with non-α1-AT-deficient chronic obstructive pulmonary disease (COPD) had NO, CO, CO2, and O2 measured in exhaled breath. Individuals with α1-AT deficiency had lower levels of NO and CO than control or COPD individuals. α1-AT-deficient and COPD patients had lower exhaled CO2 than controls, although only α1-AT-deficient patients had higher exhaled O2 than healthy controls. NO was correlated inversely with exhaled O2 and directly with exhaled CO2, supporting a role for NO in regulation of gas exchange. Exhaled gases were not significantly related to corticosteroid use or lung function. Demonstration of lower than normal CO and NO levels may be useful as an additional noninvasive method to evaluate α1-AT deficiency in individuals with a severe, early onset of obstructive lung disease.
Changes in muscle fiber conduction velocity indicate recruitment of distinct motor unit populations
Authors: Houtman C. J. , Stegeman D. F. , Van Dijk J. P. , Zwarts M. J.
Published: March 2015

To obtain more insight into the changes in mean muscle fiber conduction velocity (MFCV) during sustained isometric exercise at relatively low contraction levels, we performed an in-depth study of the human tibialis anterior muscle by using multichannel surface electromyogram. The results show an increase in MFCV after an initial decrease of MFCV at 30 or 40% maximum voluntary contraction in all of the five subjects studied. With a peak velocity analysis, we calculated the distribution of conduction velocities of action potentials in the bipolar electromyogram signal. It shows two populations of peak velocities occurring simultaneously halfway through the exercise. The MFCV pattern implies the recruitment of two different populations of motor units. Because of the lowering of MFCV of the first activated population of motor units, the newly recruited second population of motor units becomes visible. It is most likely that the MFCV pattern can be ascribed to the fatiguing of already recruited predominantly type I motor units, followed by the recruitment of fresh, predominantly type II, motor units.
Membrane leakage and increased content of Na+-K+ pumps and Ca2+ in human muscle after a 100-km run
Authors: Overgaard Kristian , Lindstrøm Tue , Ingemann-Hansen Thorsten , Clausen Torben
Published: March 2015

During prolonged exercise, changes in the ionic milieu in and surrounding the muscle fibers may lead to fatigue or damage of the muscle and thereby impair performance. In 10 male subjects, we investigated the effects of 100 km running on muscle and plasma electrolyte contents, muscle Na+-K+ pump content, and plasma concentrations of creatine kinase (CK) and lactate dehydrogenase (LDH). After completion of a 100-km run, significant increases were found in plasma K+ (from 4.0 ± 0.1 to 5.5 ± 0.2 mM, P < 0.001), muscle Na+-K+ pump content (from 334 ± 11 to 378 ± 17 pmol/g, P < 0.05), and total muscle Ca2+ content (from 0.84 ± 0.03 to 1.02 ± 0.04 μmol/g, P < 0.001). There was also a large increase in the plasma levels of the muscle-specific enzymes CK and LDH, which reached peak values at the end of the run and lasted several days after the run, indicating that a significant degree of muscle membrane leakage was present. The simultaneous occurrence of raised cellular Ca2+ content and muscle membrane leakage supports the theory that Ca2+ plays a role in the initiation of degenerative processes in muscles after severe exercise.
No effect of menstrual cycle phase on lactate threshold
Authors: Dean Teresa M. , Perreault Leigh , Mazzeo Robert S. , Horton Tracy J.
Published: March 2015

No previous exercise studies in women have assessed the effects of the normal menstrual cycle on the lactate threshold (LT) measured during a graded, maximal exercise test. This is relevant to our understanding of exercise training and metabolism in eumenorrheic women. The present study, therefore, examined the effect of menstrual cycle phase on the LT. Eight moderately active, eumenorrheic women performed three maximal exercise tests with simultaneous determination of LT. Tests were performed in the early follicular (low estrogen and progesterone), midfollicular (elevated estrogen and low progesterone), and midluteal (elevated estrogen and progesterone) phases of the menstrual cycle. No significant differences were observed in LT measured across phases of the menstrual cycle whether data were expressed in absolute terms (1,299 ± 70, 1,364 ± 80, and 1,382 ± 71 ml O2/min, respectively) or relative to maximal oxygen uptake (V̇o2 max; 52.1 ± 1.7, 54.7 ± 1.7, and 55.7 ± 1.6%, respectively). In addition, there were no significant cycle phase differences in V̇o2 max, maximal heart rate, heart rate at LT, or final lactate concentration. With data combined across all phases of the menstrual cycle, there was a significant correlation between the LT and the epinephrine breakpoint ( r = 0.91, P < 0.0002) and norepinephrine breakpoint ( r = 0.94, P < 0.0001). For epinephrine only, there was close correspondence between the epinephrine breakpoint (ml O2/min) and the LT. In conclusion, LT as well as V̇o2 max and other measures of cardiorespiratory fitness are not significantly affected by the changing sex steroid levels observed across the normal menstrual cycle. Data suggest that the onset of the steep increase in epinephrine determines the LT during graded exercise.
Correlation properties of tidal volume and end-tidal O2 and CO2 concentrations in healthy infants
Authors: Cernelc Mateja , Suki Béla , Reinmann Benjamin , Hall Graham L. , Frey Urs
Published: March 2015

We investigated whether breath-to-breath fluctuations in tidal volume (Vt) and end-tidal O2 and CO2exhibit long-range correlations and whether parameters describing the correlations can be used as noninvasive descriptors of control of breathing. We measured Vt and end-tidal O2 and CO2 over n = 352 ± 104 breaths in 26 term, healthy, unsedated infants (mean age ± SD: 36 ± 6 days) and calculated the detrended fluctuation function [F( n)]. The F( n) of the breath-to-breath time series of Vt, O2, and CO2 revealed a linear increase with a breath number on log-log plots with a slope that was significantly different from 0.5 (random) and thus consistent with scale-invariant behavior. Long-range correlations were stronger for O2 than for Vt and CO2. The F( n) of many individual signals exhibited a crossover behavior indicating that control mechanisms regulating fluctuations of Vt, O2, and CO2 may be different on different time scales. Thus breathing has a memory up to at least 400 breaths that can be characterized by the simple indicator α.
Determinants of erythropoietin release in response to short-term hypobaric hypoxia
Authors: Ge Ri-Li , Witkowski S. , Zhang Y. , Alfrey C. , Sivieri M. , Karlsen T. , Resaland G. K. , Harber M. , Stray-Gundersen J. , Levine B. D.
Published: March 2015

We measured blood erythropoietin (EPO) concentration, arterial O2saturation (SaO2), and urine Po2in 48 subjects (32 men and 16 women) at sea level and after 6 and 24 h at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m. Renal blood flow (Doppler) and Hb were determined at sea level and after 6 h at each altitude ( n = 24) to calculate renal O2delivery. EPO increased significantly after 6 h at all altitudes and continued to increase after 24 h at 2,454 and 2,800 m, although not at 1,780 or 2,085 m. The increase in EPO varied markedly among individuals, ranging from −41 to 400% after 24 h at 2,800 m. Similar to EPO, urine Po2decreased after 6 h at all altitudes and returned to baseline by 24 h at the two lowest altitudes but remained decreased at the two highest altitudes. Urine Po2was closely related to EPO via a curvilinear relationship ( r2= 0.99), although also with prominent individual variability. Renal blood flow remained unchanged at all altitudes. SaO2decreased slightly after 6 h at the lowest altitudes but decreased more prominently at the highest altitudes. There were only modest, albeit statistically significant, relationships between EPO and SaO2( r = 0.41, P < 0.05) and no significant relationship with renal O2delivery. These data suggest that 1) the altitude-induced increase in EPO is “dose” dependent: altitudes ≥2,100–2,500 m appear to be a threshold for stimulating sustained EPO release in most subjects; 2) short-term acclimatization may restore renal tissue oxygenation and restrain the rise in EPO at the lowest altitudes; and 3) there is marked individual variability in the erythropoietic response to altitude that is only partially explained by “upstream” physiological factors such as those reflecting O2delivery to EPO-producing tissues.
Nongenomic vasodilator action of progesterone on primate coronary arteries
Authors: Minshall Richard D. , Pavcnik Dusan , Browne David L. , Hermsmeyer Kent
Published: March 2015

In the present investigation, we test the hypothesis that progesterone can rapidly relax, via a nongenomic mechanism, persistent flow occluding, agonist-activated coronary artery (CA) vasospasm, and hyperreactive vascular muscle cell (VMC) Ca2+responses in ovariectomized rhesus monkeys. CA vasospasm, induced by injection of 100 μM serotonin and 1 μM U-46619 (5-HT+U; 1 ml/30 s), resulted in a decrease in CA diameter (φ) from 1.8 ± 0.2 to 0.3 ± 0.1 mm at the site of focal constriction. Injection of 100 ng progesterone into the CA significantly relieved the severe vasoconstriction (1.3 ± 0.2 mm) and reestablished distal flow in 3 min; the preconstriction φ was completely restored in 8.2 ± 2.6 min ( n = 6). Similarly, cell impermeant albumin-conjugated progesterone, but not albumin-conjugated 17β-estradiol, decreased 5-HT+U stimulated VMC Ca2+responses (250 ± 34% of basal 30 min after stimulation) back to the prestimulation level (113 ± 17% of basal) in 25 min (half time = 7 min). The presence of a rapid vasodilator action of progesterone in the primate CA and isolated VMC suggests its benefits in hormone replacement therapy may also include nongenomic vascular relaxant actions.
Lipolysis in human adipose tissue during exercise: comparison of microdialysis and a-v measurements
Authors: Lange Kai Henrik Wiborg , Lorentsen Jeanne , Isaksson Fredrik , Simonsen Lene , Bülow Jens , Kjær Michael
Published: March 2015

Subcutaneous adipose tissue lipolysis was studied in vivo by Fick's arteriovenous (a-v) principle using either calculated (microdialysis) or directly measured (catheterization) adipose tissue venous glycerol concentration. We compared results during steady-state (rest and prolonged continuous exercise), as well as during non-steady-state (onset of exercise and early exercise) experimental settings. Fourteen healthy women [age: 74 ± 1 (SE) yr] were studied at rest and during 60-min continuous bicycling at 60% of peak O2 uptake. Calculated and measured subcutaneous abdominal adipose tissue venous glycerol concentrations increased substantially from rest to exercise but were similar both at rest and during later stages of exercise. In contrast, during the initial ∼40 min of exercise, calculated glycerol concentration was significantly lower (∼40%) than measured adipose tissue venous glycerol concentration. Despite several methodological limitations inherent to both techniques, the results strongly suggest that microdialysis and catheterization provide similar estimates of subcutaneous adipose tissue lipolysis in steady-state experimental settings like rest and continuous prolonged exercise. However, during shorter periods of exercise (<40 min), the results from the two techniques may differ quantitatively in the studied subjects. Caution should, therefore, be taken when lipolysis is evaluated, based on results obtained by the two techniques under non-steady-state conditions.
Role of capacitative Ca2+entry in bronchial contraction and remodeling
Authors: Sweeney Michele , McDaniel Sharon S. , Platoshyn Oleksandr , Zhang Shen , Yu Ying , Lapp Bethany R. , Zhao Ying , Thistlethwaite Patricia A. , Yuan Jason X.-J.
Published: March 2015

Asthma is characterized by airway inflammation, bronchial hyperresponsiveness, and airway obstruction by bronchospasm and bronchial wall thickening due to smooth muscle hypertrophy. A rise in cytosolic free Ca2+concentration ([Ca2+]cyt) may serve as a shared signal transduction element that causes bronchial constriction and bronchial wall thickening in asthma. In this study, we examined whether capacitative Ca2+entry (CCE) induced by depletion of intracellular Ca2+stores was involved in agonist-mediated bronchial constriction and bronchial smooth muscle cell (BSMC) proliferation. In isolated bronchial rings, acetylcholine (ACh) induced a transient contraction in the absence of extracellular Ca2+because of Ca2+release from intracellular Ca2+stores. Restoration of extracellular Ca2+in the presence of atropine, an M-receptor blocker, induced a further contraction that was apparently caused by a rise in [Ca2+]cytdue to CCE. In single BSMC, amplitudes of the store depletion-activated currents ( ISOC) and CCE were both enhanced when the cells proliferate, whereas chelation of extracellular Ca2+with EGTA significantly inhibited the cell growth in the presence of serum. Furthermore, the mRNA expression of TRPC1, a transient receptor potential channel gene, was much greater in proliferating BSMC than in growth-arrested cells. Blockade of the store-operated Ca2+channels by Ni2+decreased ISOCand CCE and markedly attenuated BSMC proliferation. These results suggest that upregulated TRPC1 expression, increased ISOC, enhanced CCE, and elevated [Ca2+]cytmay play important roles in mediating bronchial constriction and BSMC proliferation.
Selected Contribution: Differential expression of stress-related genes with aging and hyperthermia
Authors: Zhang Hannah J. , Drake Victoria J. , Morrison Joanna P. , Oberley Larry W. , Kregel Kevin C.
Published: March 2015

Aging is associated with a reduced capacity to cope with physiological stress. To study the molecular mechanisms associated with the decline in stress tolerance that accompanies aging, differences in gene expression between young and old Fischer 344 rats under euthermic control conditions or in response to hyperthermic challenge were evaluated using a cDNA array containing 207 stress-related genes. In the nonstressed control condition, aging resulted in selective upregulation of stress protein genes and transcripts involved in cell growth, death, and signaling, along with a downregulation of genes involved in antioxidant defenses and drug metabolism. Heat stress resulted in a broad induction of genes in the antioxidant and drug metabolism categories and transcripts involved in DNA, RNA, and protein synthesis for both age groups. Old animals had a robust upregulation of genes involved in cell growth, death, and signaling after heat challenge, along with a blunted expression of stress-response genes. In contrast, young animals had a strong induction of stress-response genes after hyperthermic challenge. Changes in expression of selected genes were confirmed by RT-PCR analysis. These findings suggest that aging results in altered gene expression in response to heat stress that is indicative of decreased stress protein transcription and increased expression of oxidative stress-related genes. Thus our findings support the postulate that transcriptional changes in response to a physiological challenge such as hyperthermia contribute to the loss of stress tolerance in older organisms.