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Chronic hypoxia (CH) during postnatal development attenuates the hypoxic ventilatory response (HVR) in mammals, but there are conflicting reports on whether this plasticity is permanent or reversible. This study tested the hypothesis that CH-induced respiratory plasticity is reversible in neonatal rats and investigated whether the initial plasticity or recovery differs between sexes. Rat pups were exposed to 3 d of normobaric CH (12 % O 2) beginning shortly after birth. Ventilation and metabolic CO 2 production were then measured in normoxia and during an acute hypoxic challenge (12 % O 2) immediately following CH and after 1, 4–5, and 7 d in room air. CH pups hyperventilated when returned to normoxia immediately following CH, but normoxic ventilation was similar to age-matched control rats within 7 d after return to room air. The early phase of the HVR (minute 1) was only blunted immediately following the CH exposure, while the late phase of the HVR (minute 15) remained blunted after 1 and 4–5 d in room air; recovery appeared complete by 7 d. However, when normalized to CO 2 production, the late phase of the hypoxic response recovered within only 1 d. The initial blunting of the HVR and subsequent recovery were similar in female and male rats. Carotid body responses to hypoxia (in vitro) were also normal in CH pups after approximately one week in room air. Collectively, these data indicate that ventilatory and metabolic responses to hypoxia recover rapidly in both female and male neonatal rats once normoxia is restored following CH. • 3 days of chronic hypoxia (CH) elicited respiratory plasticity in neonatal rats. • Normoxic ventilation remained elevated for several days after return to room air. • Hypoxic ventilatory response (HVR) was blunted by CH but recovered within one week. • Recovery of HVR in male rat pups contrasts with studies showing lifelong blunting. • Plasticity after postnatal CH resembled ventilatory acclimatization in adult rats. [ABSTRACT FROM AUTHOR]

The present study investigated the maintenance/repeatability of expiratory flow limitation (EFL) between normoxia and hypoxia. Fifty-one healthy active individuals (27 men and 24 women) performed a lung function test and a maximal incremental cycling test in both normoxia and hypoxia (inspired oxygen fraction = 0.14) on two separate visits. During exercise in normoxia, 28 participants exhibited EFL (55 %). In hypoxia, another cohort of 28 participants exhibited EFL. The two groups only partly overlapped. Individuals with EFL only in normoxia reported lower maximal ventilation values in hypoxia than in normoxia (n=5; −13.5 ± 7.8 %) compared to their counterparts with EFL only in hypoxia (n=5; +6.7 ± 6.3 %) or without EFL (n=18; +5.1 ± 10.3 %) (p=0.004 and p<0.001, respectively). EFL development may be induced by different mechanisms in hypoxia vs. normoxia since the individuals who exhibited flow limitation were not the same between the two environmental conditions. This change seems influenced by the magnitude of the maximal ventilation change. • Most of the individuals flow limited in normoxia are flow limited in hypoxia. • About 20 % are flow limited only in one condition, either in normoxia or in hypoxia. • The change between flow limited and non-limited seems rely on ventilatory demands. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) and intermittent transcutaneous electrical stimulation (ITES) might benefit patients with obstructive sleep apnea (OSA). However, the therapeutic value of combined IH and ITES in OSA is unknown. In this prospective, randomized, controlled crossover study, normoxia (air exposure for 50 min before sleep and sham stimulation for 6 h during sleep), IH (5 repeats of 5 min 10–12 % O 2 alternating with 5 min air for 50 min, and sham stimulation for 6 h), ITES (air exposure for 50 min and 6 repeats of 30 min transcutaneous electrical stimulation alternating with 30 min of sham stimulation for 6 h), and IH&ITES (10–12 % O 2 alternating with air for 50 min and transcutaneous electrical stimulation alternating with sham stimulation for 6 h) were administered to patients with OSA over four single-night sessions. The primary endpoint was difference in OSA severity between the interventions according to apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). The efficacy was response to IH, ITES, IH&ITES defined as a ≥50 % reduction in AHI compared with normoxia. Twenty participants (17 male, 3 female) completed the trial. The median (IQR) AHI decreased from 14.5 (10.8, 17.5) events/h with normoxia to 6.9 (3.9, 14.8) events/h with IH (p=0.020), 5.7 (3.4, 9.1) events/h with ITES (p=0.001), and 3.5 (1.8, 6.4) events/h with IH&ITES (p=0.001). AHI was significantly different between IH and IH&ITES (p=0.042) but not between ITES and IH&ITES (p=0.850). For mild-moderate OSA (n=17), IH, ITES, and IH&ITES had a significant effect on AHI (p=0.013, p=0.001, p=0.001, respectively) compared with normoxia, but there were no differences in post hoc pairwise comparisons between intervention groups. No serious adverse events were observed. In conclusion, IH, ITES, and IH&ITES significantly reduced OSA severity. IH&ITES showed better efficacy in mild-moderate OSA than IH and was comparable to ITES. Our data do not support recommending IH&ITES over ITES for OSA. • This is the first study to evaluate the efficacy of intermittent hypoxia (IH) combined with intermittent transcutaneous electrical stimulation (ITES) on OSA. • IH, ITES and IH&ITES showed significant improvements on patients with mild-moderate OSA. The efficacy of IH & ITES was better than IH and was comparable to ITES. • The data validate the efficacy of IH or ITES on OSA, and the current evidence does not support the superior efficacy of IH & ITES over ITES. [ABSTRACT FROM AUTHOR]

The state-dependent noradrenergic activation of hypoglossal motoneurons plays an important role in the maintenance of upper airway patency and pathophysiology of obstructive sleep apnea (OSA). Chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, contributes to the risk for developing neurodegenerative disorders in OSA patients. Using anterograde tracer, channelrhodopsin-2, we mapped axonal projections from noradrenergic A7 and SubCoeruleus neurons to hypoglossal nucleus in DBH-cre mice and assessed the effect of CIH on these projections. We found that CIH significantly reduced the number of axonal projections from SubCoeruleus neurons to both dorsal (by 68%) and to ventral (by73%) subregions of the hypoglossal motor nucleus compared to sham-treated animals. The animals' body weight was also negatively affected by CIH. Both effects, the decrease in axonal projections and body weight, were more pronounced in male than female mice, which was likely caused by less sensitivity of female mice to CIH as compared to males. The A7 neurons appeared to have limited projections to the hypoglossal nucleus. Our findings suggest that CIH-induced reduction of noradrenergic innervation of hypoglossal motoneurons may exacerbate progression of OSA, especially in men. • SubCoeruleus (SubC) noradrenergic neurons project evenly to hypoglossal nucleus. • Chronic intermittent hypoxia (CIH) decreases body weight in male, not female, mice. • CIH decreases SubC projections to subregions of the hypoglossal nucleus. • CIH effect on SubC innervation is more prominent in male than female mice. [ABSTRACT FROM AUTHOR]

The pathogenesis of hypoxemia during acute respiratory distress syndrome caused by SARS-CoV-2 infection (C-ARDS) is debated. Some observations led to hypothesize ventilation to perfusion mismatch, rather than anatomical shunt, as the main determinant of hypoxemia. In this observational study 24 C-ARDS patients were studied 1 (0–1) days after intubation. Patients underwent a CT scan analysis to estimate anatomical shunt and a clinical test to measure venous admixture at two fractions of inspired oxygen (FiO 2), to eliminate oxygen-responsive mechanisms of hypoxemia (ventilation to perfusion mismatch and diffusion limitation). In 10 out of 24 patients venous admixture was higher than anatomical shunt both at clinical (≈50 %) and 100 % FiO 2. These patients were ventilated with a higher PEEP and had lower amount of anatomical shunt compared with patients with venous admixture equal/lower than anatomical shunt. In a subset of C-ARDS patients early after endotracheal intubation, hypoxemia might be explained by an abnormally high perfusion of a relatively low anatomical shunt. • The cause of hypoxemia in COVID-19 acute respiratory failure (C-ARDS) is unclear. • Anatomical shunt and venous admixture were measured in intubated C-ARDS patients. • In 42 % patients venous admixture exceeded shunt even with pure oxygen ventilation. • Shunt hyper-perfusion might explain hypoxemia in a subset of C-ARDS patients. [ABSTRACT FROM AUTHOR]

To clarify the contribution of KCNK3/TASK-1 channel chemoreflex in response to hypoxia and hypercapnia, we used a unique Kcnk3 - deficient rat. We assessed ventilatory variables using plethysmography in Kcnk3 - deficient and wild-type rats at rest in response to hypoxia (10% O 2) and hypercapnia (4% CO 2). Immunostaining for C-Fos , a marker of neuronal activity, was performed to identify the regions of the respiratory neuronal network involved in the observed response.Under basal conditions, we observed increased minute ventilation in Kcnk3 - deficient rats, which was associated with increased c-Fos positive cells in the ventrolateral region of the medulla oblongata. Kcnk3 - deficient rats show an increase in ventilatory response to hypoxia without changes in response to hypercapnia. In Kcnk3 - deficient rats, linked to an increased hypoxia response, we observed a greater increase in c-Fos-positive cells in the first central relay of peripheral chemoreceptors and Raphe Obscurus. This study reports that KCNK3/TASK-1 deficiency in rats induces an inadequate peripheral chemoreflex, alternating respiratory rhythmogenesis, and hypoxic chemoreflex. • Controversial results exist regarding KCNK3/TASK-1 in controlling breathing in mice. • Minute ventilation in Kcnk3 -deficient rats was increased in basal conditions. • Increased c-Fos positive cells in the ventrolateral region of the medulla oblongata were found in Kcnk3 -deficient rats. • Kcnk3 -deficiency is associated with an increase of c-fos in the first peripheral chemoreceptors and Raphe Obscurus. [ABSTRACT FROM AUTHOR]

• Intermittent hypoxemia events (IH) progressively increase during the first weeks of life in extremely preterm infants. • IH are associated with retinopathy of prematurity, neurodevelopmental impairment, bronchopulmonary dysplasia, and mortality. • Multiple IH induced pathways can cause sequelae including initiation of a pathological oxidative stress induced cascade. Intermittent hypoxemia events (IH) are common in extremely preterm infants and are associated with many poor outcomes including retinopathy or prematurity, wheezing, bronchopulmonary dysplasia, cognitive or language delays and motor impairment. More recent data in animal and rodent models have suggested that specific patterns of IH may increase the risk for morbidity. The pathway by which these high risk patterns of IH initiate a pathological cascade is unknown but animal models suggest that oxidative stress may play a role. This review describes early postnatal patterns of IH in preterm infants, their relationship with morbidity, oxidative stress biomarkers relevant to the newborn infant and the relationship between IH and reactive oxygen species. [ABSTRACT FROM AUTHOR]

• In native highlanders, S P O 2 was greater in the upright-seated than in the flat posture. • Changes in oxyhemoglobin saturation were greatest in older subjects. • Flat posture may be a significant contributor to hypoxemia during sleep. • Postural maneuvers may mitigate nocturnal hypoxemia and its sequelae in highlanders. At high altitude, hypoxia amplifies oxyhemoglobin saturation (S P O 2) swings with changes in respiratory mechanics. Our objective was to examine the effects of posture on S P O 2 and determine predictors of postural S P O 2 changes in highlanders. 50 native highlanders from Puno, Peru (3825 m) assumed supine and upright-seated postures, in rotating sequence, while undergoing continuous pulse-oximetry. We compared mean S p O 2 in each posture with a paired t -test. We examined associations of BMI, age, sex and spirometry with postural S p O 2 changes with mixed-effects linear regression. In highlanders, S p O 2 was 84% in the supine posture and was 1.0% ± 1.1 (p < 0.0001) greater in the upright-seated posture. Greater postural changes in S p O 2 were associated with older age (p = 0.01 for interaction) but not with sex, BMI, FVC or FEV 1. In highlanders, S p O 2 is higher in the upright-seated compared to supine posture, especially with older age. Because we generally sleep flat, posture may contribute significantly to highlanders' hypoxemic burden during sleep. Postural intervention during sleep may mitigate nocturnal hypoxemia. [ABSTRACT FROM AUTHOR]

• Phrenic long-term facilitation (pLTF) induced by intermittent hypoxia (IH) is inhibited by the systemic injection of lipopolysaccharide (LPS). • Microglia can be recruited by systemic LPS, so we tested whether microglial modulators affect LTF of the preBötzinger complex in brainstem slices. • We found that microglial "activators", "inhibitors" and a microgliotoxin, partially reduce IH-induced LTF of the preBötzinger complex in vitro. Inflammation inhibits the expression of some, but not all forms of respiratory motor plasticity. For example, systemic application of lipopolysaccharide (LPS) inhibits the phrenic long-term facilitation induced by moderate-intermittent hypoxia in vivo. There are multiple pro-inflammatory processes triggered by the systemic application of LPS, including neuroinflammation in the CNS. Considering that microglia can be activated by the systemic application of LPS, it is likely that this cell type influences the response of the respiratory circuits to intermittent hypoxia (IH). Thus, we aimed to test whether modulators of microglial function would affect the response to IH of the preBötzinger complex (preBötC) isolated in a brainstem slice preparation. This experimental approach avoids the systemic influences of these microglial modulators and limits their effects on cells, mostly microglia, included in the slice. First, we found that IH (3 × 5-min episodes of bubbling with 95% N 2 and 5% CO 2 , mixed with 5-min normoxic intervals by bubbling with 95% O 2 and 5% CO 2) induces a long-lasting increase in the respiratory rhythm frequency recorded directly from the preBötC, called in vitro long-term facilitation (LTF), which occurs simultaneously with a long-lasting decrease in burst amplitude. Moreover, we found that bath applications of "microglial activators" (LPS and fractalkine), "microglial inhibitors" (minocycline and fucoidan) and a microgliotoxin (liposomal clodronate) partially reduce in vitro LTF. These findings reveal a complex scenario in which both the activation and the inhibition of microglia halts IH-induced preBötC plasticity and suggest that experimental or pathological conditions that affect this cell type, almost in any way, could affect breathing and its plastic responses. [ABSTRACT FROM AUTHOR]

Highlights • In a previous report capsaicin increased ventilation in young rats via injection. • Respiratory function changes with age and may be altered via capsaicin in the diet. • Breathing was quantified in aged mice before/after 1 mo of capsaicin/control diet. • Supplementation resulted in similar baseline breathing in aged mice fed both diets. • Capsaicin led to increased minute ventilation during short term hypoxic exposure. Abstract Capsaicin is an agonist for transient receptor potential vanilloid 1 (TRPV1), and acute injection results in an increased frequency and tidal volume in young rats. It is unknown how capsaicin influences breathing in aged mice. We tested the hypothesis that capsaicin supplementation would elicit an augmented pattern of breathing in old mice compared to controls. Male 22-month old C57BL/6 J mice consumed a diet containing capsaicin (50 ppm) or lecithin control for one month. Breathing patterns were obtained prior to/following the dietary supplementation period using unrestrained barometric plethysmography. Frequency, tidal volume (VT), minute ventilation (VE), VE to expelled carbon dioxide ratio (VE/VCO 2) and VT divided by inspiratory time (VT/T i) were analyzed at baseline and during a 15-minute hypoxic exposure (10% O 2). Capsaicin supplemented mice showed greater VE, VE/VCO 2 and TV/T i during hypoxic exposure compared to controls, with no change at baseline. Overall, these findings suggest an acute augmented response to hypoxia following capsaicin administration in older mice. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Mid distance hypobaric flight simulation decreases six minute walking distance by 10%. • In flight hypoxia was determined to be 72% at average, was well tolerated and unrelated to dyspnea symptoms. • Lung diffusion capacity was the only significant predictor for in-flight hypoxemia. Abstract Background Chronic obstructive pulmonary disease (COPD) is a disease that compromises fitness to fly. Objective To investigate, whether hypobaric mid-distance flight simulation limits exercise endurance in COPD patients. Methods Patients with COPD GOLD stages 2–4 were challenged by hypobaric flight simulation. Patients completed 6-minute walking distances before and after the simulation test. Pulse oximetry and Borg dyspnea scale were measured every 30 min during the test. Results Thirty-five patients were included in the study. The distance of the 6-min walking exercise decreased from 343 ± 93 m to 308 ± 101 m (p < 0.0001). The oxygen saturation nadir for the whole group was 72.2% ± 9.1%. The Borg-dypnea-score did not correlate with oxygen desaturation (R-square 0.009, p > 0.05). Conclusions A 3-h hypobaric flight simulation compromises exercise endurance by 35 m or 10%. Hypoxia was well tolerated and more liberal recommendations might by justifiable since hypoxemia appears to be unrelated to dyspnea perception. [ABSTRACT FROM AUTHOR]

Highlights • Locomotor and respiratory muscles compete for oxygen in high-intensity exercise. • When intermittent sprint cycling was performed in normoxia and hypoxia, locomotor muscle oxygenation was reduced in hypoxia • Oxygenation of the respiratory muscles was maintained in hypoxia. • The evidence supports preferential oxygen distributed to the respiratory muscle. Abstract This study aimed to investigate whether exercise hyperpnoea contributes to an impairment of locomotor muscle oxygenation and performance during repeated-sprint exercise in normoxia and hypoxia. Subjects performed ten 10-s sprints, separated by 30 s of passive rest while breathing either a normoxic (21% O 2) or hypoxic (15% O 2) gas mixture. Muscle oxygenation of the vastus lateralis and intercostal muscles was examined with near-infrared spectroscopy. Sprint and recovery vastus lateralis deoxyhaemoglobin was elevated in hypoxia by 9.2% (90% confidence interval 0.2 to 18.0) and 14.1% (90% CL 4.9 to 23.3%) compared to normoxia, respectively. There were no clear differences in respiratory muscle deoxyhaemoglobin (−0.1%, 90% CL −2.9 to 0.9%) or oxyhaemoglobin (0.9%, 90% CL −0.8 to 2.6%) between conditions. Maintenance of respiratory muscle oxygenation may contribute to the rise of vastus lateralis deoxyhaemoglobin in hypoxia during intermittent sprint cycling. This manuscript presents data which extends the fact that oxygen competition could be a limiting factor of exercise capacity. [ABSTRACT FROM AUTHOR]

Highlights • Rats were exposed to alternating bouts of hypercapnic hypoxia and hyperoxia P0-P14. • Carotid body (CB) hypoxic responses were reduced but CB volumes were normal at P14. • Hypoxic ventilatory responses were normal despite weaker carotid body responses. • In contrast, sustained exposure to 30% O 2 blunted the HVR in neonatal rats. • Intermittent hypercapnic hypoxia reduced hyperoxia-induced plasticity in the HVR. Abstract Chronic exposure to intermittent hyperoxia causes abnormal carotid body development and attenuates the hypoxic ventilatory response (HVR) in neonatal rats. We hypothesized that concurrent exposure to intermittent hypercapnic hypoxia would influence this plasticity. Newborn rats were exposed to alternating bouts of hypercapnic hypoxia (10% O 2 /6% CO 2) and hyperoxia (30–40% O 2) (5 cycles h−1, 24 h d−1) through 13–14 days of age; the experiment was run twice, once in a background of 21% O 2 and once in a background of 30% O 2 (i.e., "relative hyperoxia"). Hyperoxia had only small effects on carotid body development when combined with intermittent hypercapnic hypoxia: the carotid chemoafferent response to hypoxia was reduced, but this did not affect the HVR. In contrast, sustained exposure to 30% O 2 reduced carotid chemoafferent activity and carotid body size which resulted in a blunted HVR. When given alone, chronic intermittent hypercapnic hypoxia increased carotid body size and reduced the hypercapnic ventilatory response but did not affect the HVR. Overall, it appears that intermittent hypercapnic hypoxia counteracted the effects of hyperoxia on the carotid body and prevented developmental plasticity of the HVR. [ABSTRACT FROM AUTHOR]

Highlights • Hypoxia increased carotid body (CB) H 2 S levels, sensory nerve activity, and elevated [Ca2+] i in glomus cells. • Anoxia had no effect on CB H 2 S levels but produced only weak sensory excitation and robust elevation of [Ca2+] i in glomus cells. • Inhibition of H 2 S synthesis or genetic deletion of cystathionine-γ-lyase (CSE) prevented the effects of hypoxia but not anoxia on the CB. • Hypoxia stimulated breathing in wild-type but not in CSE knockout mice, whereas anoxia inhibited breathing in both strains of mice. • Hypoxia and anoxia are not similar stimuli for studying CB physiology, and H 2 S contributes to CB response to hypoxia but not to anoxia. Abstract The role of cystathionine-γ-lyase (CSE) derived H 2 S in the hypoxic and anoxic responses of the carotid body (CB) were examined. Experiments were performed on Sprague-Dawley rats, wild type and CSE knockout mice on C57BL/6 J background. Hypoxia (pO 2 = 37 ± 3 mmHg) increased the CB sensory nerve activity and elevated H 2 S levels in rats. In contrast, anoxia (pO 2 = 5 ± 4 mmHg) produced only a modest CB sensory excitation with no change in H 2 S levels. DL-propargylglycine (DL-PAG), a blocker of CSE, inhibited hypoxia but not anoxia-evoked CB sensory excitation and [Ca2+] i elevation of glomus cells. The inhibitory effects of DL-PAG on hypoxia were seen: a) when it is dissolved in saline but not in dimethyl sulfoxide (DMSO), and b) in glomus cells cultured for18 h but not in cells either soon after isolation or after prolonged culturing (72 h) requiring 1–3 h of incubation. On the other hand, anoxia-induced [Ca2+] i responses of glomus cell were blocked by high concentration of DL-PAG (300μM) either alone or in combination with aminooxyacetic acid (AOAA; 300μM) with a decreased cell viability. Anoxia produced a weak CB sensory excitation and robust [Ca2+] i elevation in glomus cells of both wild-type and CSE null mice. As compared to wild-type, CSE null mice exhibited impaired CB chemo reflex as evidenced by attenuated efferent phrenic nerve responses to brief hyperoxia (Dejours test), and hypoxia. Inhalation of 100% N 2 (anoxia) depressed breathing in both CSE null and wild-type mice. These observations demonstrate that a) hypoxia and anoxia are not analogous stimuli for studying CB physiology and b) CSE-derived H 2 S contributes to CB response to hypoxia but not to that of anoxia. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • High altitude induced oxidative stress may contribute to alveolar collapse. • Surfactants production is altered under reduced oxygen supply. • Nrf2 and HIF 1- α are the major players in surfactant homeostasis. • Curcumin enhances Nrf2 and HO-1 thereby augments survival signalling at HA. Abstract Background Pulmonary surfactant oxidation leads to alveolar collapse- a condition often noticed in high altitude pulmonary edema (HAPE). The present study was aimed to determine the effect of curcumin prophylaxis in augmenting the phase II antioxidant enzymes and surfactant proteins expression in enabling the pulmonary surfactant homeostasis under hypoxia. Methods A549 cells were exposed to 3% hypoxia for different time durations (1 h, 3 h, 6 h, 12 h and 24 h). The Cells were pretreated (1 h) with 10 μM curcumin and exposed to hypoxia. The in-vivo results were extrapolated into in–vivo system using male Sprague Dawley rats, exposed to a stimulated altitude of 7620 m for 6 h. The rats were supplemented with curcumin (50 mg/kgBW) 1 h prior to hypoxia exposure. Results Results showed that, the expression of surfactant proteins (SPs) A and B decreased from 3 h of hypoxic exposure, whereas expression of SP-C and SP-D proteins were increased within 1 h of hypoxic exposure over control cells. Hypoxic exposure resulted into significant increase in protein and lipid peroxidation (p < 0.001), reduced levels of antioxidants (GSH, GPx and SOD) (p < 0.001) along with significant down regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Heme oxygenase-1 (HO-1) in A549 cells over control. However, the curcumin supplementation both in-vitro and in-vivo resulted into increased expressions of HO-1 and Nrf2 significantly (p < 0.001), which enabled the cells in balanced expression of SPs with reduced levels of oxidants. Further curcumin significantly enhanced the levels of antioxidant enzymes in BALF along with stabilized expression of hypoxia inducible factor 1(HIF-1α) followed by reduced expression of vascular endothelial growth factor (VEGF) in lungs of rats. The immunohistochemistry observations provided substantial evidence of enhanced surfactant protein expressions in lungs of curcumin administered hypoxia exposed rats. Conclusion These results indicate that curcumin augment survival signaling by reinforcing the induction of phase II antioxidant enzymes thereby enabling the pulmonary surfactant homeostasis under hypoxia. [ABSTRACT FROM AUTHOR]

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition – from blunting to augmenting the HVR – occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O 2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 – 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one "typical" pattern for VAH in adult rats. • Chronic hypoxia causes respiratory plasticity, but it reportedly varies with age. • The plasticity might transition from blunting to enhancing the HVR in older rats. • In contrast, we found that chronic hypoxia blunted the HVR across all ages studied. • A review of published studies showed blunting to be a common result for adult rats. • There is no "typical" pattern of ventilatory acclimatization to hypoxia in rats. [ABSTRACT FROM AUTHOR]

The purpose of the study was to characterize exercise induced arterial hypoxemia (EIAH) in female masters athletes (FMA). We hypothesized that FMA would experience EIAH during treadmill running. Eight FMA (48–57 years) completed pulmonary function testing and an incremental exercise test until exhaustion ( V ̇ O 2 max ⁡ = 45.7 ± 6.5, range:35–54 ml/kg/min). On a separate day, the participants were instrumented with a radial arterial catheter and an esophageal temperature probe. Participants performed three to four constant load exercise tests at 60–70 %, 75 %, 90 %, 95 %, and 100 % of maximal oxygen uptake while sampling arterial blood and recording esophageal temperature. We found that FMA decrease their partial pressure of oxygen (86.0 ± 7.6, range:73–108 mmHg), arterial saturation (96.2 ± 1.2, range:93–98 %), and widen their alveolar to arterial oxygen difference (23.2 ± 8.8, range:5–42 mmHg) during all exercise intensities however, with variability in terms of severity and pattern. Our findings suggest that FMA experience EIAH however aerobic fitness appears unrelated to occurrence or severity (r = 0.13, p = 0.756). • Older females experience exercise-induced arterial hypoxemia during exercise. • Experiencing exercise-induced arterial hypoxemia was variable in terms of severity and pattern. • Aerobic fitness may be unrelated to determining exercise induced arterial hypoxemia. [ABSTRACT FROM AUTHOR]

Daily acute intermittent hypoxia (dAIH) elicits respiratory plasticity, enhancing respiratory motor output and restoring breathing capacity after incomplete cervical spinal injuries (cSCI). We hypothesized that dAIH-induced functional recovery of breathing capacity would occur after both acute (2 weeks) and chronic (8 weeks) cSCI, but through distinct cellular mechanisms. Specifically, we hypothesized that dAIH-induced breathing recovery would occur through serotonin- independent mechanisms 2wks post C2 cervical hemisection (C2Hs), versus serotonin- dependent mechanisms 8wks post C2Hs. In two independent studies, dAIH or sham (normoxia) was initiated 1 week (Study 1) or 7 weeks (Study 2) post-C2Hs to test our hypothesis. Rats were pre-treated with intra-peritoneal vehicle or methysergide, a broad-spectrum serotonin receptor antagonist, to determine the role of serotonin signaling in dAIH-induced functional recovery. Our data support the hypothesis that dAIH-induced recovery of breathing capacity transitions from a serotonin- independent mechanism with acute C2Hs to a serotonin- dependent mechanism with chronic C2Hs. An understanding of shifting mechanisms giving rise to dAIH-induced respiratory motor plasticity is vital for clinical translation of dAIH as a therapeutic modality. [ABSTRACT FROM AUTHOR]

Ventilatory acclimatization to hypoxia involves an increase in the acute hypoxic ventilatory response that is blocked by non-steroidal anti-inflammatory drugs administered during sustained hypoxia. We tested the hypothesis that inflammatory signals are necessary to sustain ventilatory acclimatization to hypoxia once it is established. Adult, rats were acclimatized to normoxia or chronic hypoxia (CH, P i O 2 = 70 Torr) for 11–12 days and treated with ibuprofen or saline for the last 2 days of hypoxia. Ventilation, metabolic rate, and arterial blood gas responses to O 2 and CO 2 were not affected by ibuprofen after acclimatization had been established. Immunohistochemistry and image analysis showed acute (1 h) hypoxia activated microglia in a medullary respiratory center (nucleus tractus solitarius, NTS) and this was blocked by ibuprofen administered from the beginning of hypoxic exposure. Microglia returned to the control state after 7 days of CH and were not affected by ibuprofen administered for 2 more days of CH. In contrast, NTS astrocytes were activated by CH but not acute hypoxia and activation was not reversed by administering ibuprofen for the last 2 days of CH. Hence, ibuprofen cannot reverse ventilatory acclimatization or astrocyte activation after they have been established by sustained hypoxia. The results are consistent with a model for microglia activation or other ibuprofen-sensitive processes being necessary for the induction but not maintenance of ventilatory acclimatization to hypoxia. [ABSTRACT FROM AUTHOR]

Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory motor plasticity induced by moderate acute intermittent hypoxia (AIH), but not by moderate acute sustained hypoxia (ASH) of similar cumulative duration. Thus, moderate AIH-induced pLTF is sensitive to the pattern of hypoxia. On the other hand, pLTF induced by severe AIH protocols is neither pattern sensitive nor serotonin dependent (it converts to an adenosine-dependent mechanism). Although moderate AIH also induces hypoglossal LTF (hLTF), no data are available concerning its sensitivity/insensitivity to the pattern of hypoxia. Since hLTF following moderate hypoxia is serotonin-dependent, we hypothesized that hLTF is pattern-sensitive, similar to serotonin-dependent pLTF. Integrated hypoglossal nerve activity was recorded in urethane-anesthetized, vagotomized, paralyzed, and ventilated rats exposed to isocapnic AIH (3, 5 min episodes of 11% O 2 ) or ASH (a single 25 min episode of 11% O 2 ). Similar to previous studies of pLTF, hypoglossal motor output was elevated for more than 1 h following AIH (50 ± 20%, p < 0.01), but not ASH (–6 ± 9%, p > 0.05). Frequency LTF was not observed following either hypoxic exposure. Thus, in agreement with our hypothesis, hypoglossal LTF following moderate AIH is pattern-sensitive, similar to phrenic LTF. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) has been linked to increased mortality in pulmonary fibrosis. Its key feature, chronic intermittent hypoxia (CIH), can lead to oxidative stress and inflammation, known to lead to fibrotic pathology in other organs. We tested the effects of CIH in an animal model of bleomycin-induced lung fibrosis. Sprague Dawley rats were instilled intratracheally with bleomycin (Blm) or saline (Sal), and exposed to CIH or normal air (Norm) for 9 or 30 days. Pulmonary function was tested and lungs were harvested for histological and molecular analyses. In Blm-treated animals, 30 days of CIH compared to Norm increased total lung collagen content (p = 0.008) and reduced Quasi-static lung compliance (p = 0.04). CIH upregulated lipid peroxidation and increased NF-κB activation, IL-17 mRNA and Col1α1 mRNA expression. Our results indicate that following Blm-induced lung injury, CIH amplifies collagen deposition via oxidative and inflammatory pathways, culminating in stiffer lungs. Thus, OSA may augment fibrosis in patients with interstitial lung disease. [ABSTRACT FROM AUTHOR]

Sleep disordered breathing (SDB) and obstructive sleep apnea (OSA) during pregnancy are growing health concerns because these conditions are associated with adverse outcomes for newborn infants. SDB/OSA during pregnancy exposes the mother and the fetus to intermittent hypoxia. Direct exposure of adults and neonates to IH causes neuroinflammation and neuronal apoptosis, and exposure to IH during gestation (GIH) causes long-term deficits in offspring respiratory function. However, the role of neuroinflammation in CNS respiratory control centers of GIH offspring has not been investigated. Thus, the goal of this hybrid review/research article is to comprehensively review the available literature both in humans and experimental rodent models of SDB in order to highlight key gaps in knowledge. To begin to address some of these gaps, we also include data demonstrating the consequences of GIH on respiratory rhythm generation and neuroinflammation in CNS respiratory control regions. Pregnant rats were exposed to daily intermittent hypoxia during gestation (G10-G21). Neuroinflammation in brainstem and cervical spinal cord was evaluated in P0-P3 pups that were injected with saline or lipopolysaccharide (LPS; 0.1 mg/kg, 3 h). In CNS respiratory control centers, we found that GIH attenuated the normal CNS immune response to LPS challenge in a gene-, sex-, and CNS region-specific manner. GIH also altered normal respiratory motor responses to LPS in newborn offspring brainstem-spinal cord preparations. These data underscore the need for further study of the long-term consequences of maternal SDB on the relationship between inflammation and the respiratory control system, in both neonatal and adult offspring. [ABSTRACT FROM AUTHOR]

Hypoxia elicits complex cell signaling mechanisms in the respiratory control system that can produce long-lasting changes in respiratory motor output. In this article, we review experimental approaches used to elucidate signaling pathways associated with hypoxia, and summarize current hypotheses regarding the intracellular signaling pathways evoked by intermittent exposure to hypoxia. We review data showing that pharmacological treatments can enhance neuroplastic responses to hypoxia. Original data are included to show that pharmacological modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function can reveal a respiratory neuroplastic response to a single, brief hypoxic exposure in anesthetized mice. Coupling pharmacologic treatments with therapeutic hypoxia paradigms may have rehabilitative value following neurologic injury or during neuromuscular disease. Depending on prevailing conditions, pharmacologic treatments can enable hypoxia-induced expression of neuroplasticity and increased respiratory motor output, or potentially could synergistically interact with hypoxia to more robustly increase motor output. [ABSTRACT FROM AUTHOR]

The deleterious effects of intermittent hypoxia (IH) on cancer biology have been primarily evaluated in the context of the aberrant circulation observed in solid tumors which results in recurrent intra-tumoral episodic hypoxia. From those studies, IH has been linked to an accelerated tumor progression, metastasis and resistance to therapies. More recently, the role of IH in cancer has also been studied in the context of obstructive sleep apnea (OSA), since IH is a hallmark characteristic of this condition. Such recent studies are undoubtedly adding more information regarding the role of IH on tumor malignancy. In terms of the IH patterns associated with OSA, this altered oxygenation paradigm has been recently proposed as a determinant factor in fostering cancer incidence and progression from both in vitro and in vivo experimental models. Here, we summarize all the available evidence to date linking IH effects on several types of cancer. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (ChIH) is a dominant feature of obstructive sleep apnoea (OSA) and is associated to metabolic alterations and oxidative stress (OS). Although management of OSA is well established, the research of new biomarkers that are independent of confounding factors remains necessary to improve the early detection of comorbidity and therapeutic follow-up. In this study, the urinary metabonomic profile associated to intermittent hypoxia was evaluated in a mouse model. When exposed to intermittent hypoxia, animals showed a significant alteration in energy metabolism towards anaerobic pathways and signs of OS imbalance. A compensatory response was observed over time. Our data also indicates an excess production of vitamin B3, liver function modulations and a stimulation of creatine synthesis which could be used to evaluate the ChIH repercussions. As well, TMAO and allantoin could constitute interesting biomarker candidates, respectively in the context of cardiovascular risk and OS associated to OSA. [ABSTRACT FROM AUTHOR]

We studied the differential responses of autonomic function in sea level residents (SLR), acclimatized lowlanders (ALH) in high altitude (HA) and HA natives (HAN) at >3500 m. Out of 771 male volunteers included in this cross-sectional study, SLR, ALH and HAN groups were comprised of 351, 307 and 113 volunteers, respectively. Our results showed persistent sympathetic dominance with significantly reduced ( p <  0.05) parasympathetic response in ALH as compared to SLR and HAN populations. This may be attributed to significantly increased ( p <  0.05) concentration of coronary risk factors and plasma catecholamines in ALH as compared to SLR and HAN. The ALH also showed significantly increased ( p <  0.05) level of serum homocysteine as compared to SLR. The HAN exhibited no changes in autonomic function despite significantly elevated ( p <  0.05) homocysteine level as compared to SLR. Our findings may have clinical relevance for assessment of susceptibility to cardiovascular risks in HA dwellers, native highlanders and patients with hypoxemia. [ABSTRACT FROM AUTHOR]

We examined whether slower pulmonary O 2 uptake ( V ˙ O 2 p ) kinetics in hypoxia is a consequence of: a) hypoxia alone (lowered arterial O 2 pressure), b) hyperventilation-induced hypocapnia (lowered arterial CO 2 pressure), or c) a combination of both. Eleven participants performed 3–5 repetitions of step-changes in cycle ergometer power output from 20W to 80% lactate threshold in the following conditions: i) normoxia (CON; room air); ii) hypoxia (HX, inspired O 2  = 12%; lowered end-tidal O 2 pressure [P ET O 2 ] and end-tidal CO 2 pressure [P ET CO 2 ]); iii) hyperventilation (HV; increased P ET O 2 and lowered P ET CO 2 ); and iv) normocapnic hypoxia (NC-HX; lowered P ET O 2 and P ET CO 2 matched to CON). Ventilation was increased (relative to CON) and matched between HX, HV, and NC-HX conditions. During each condition V O 2 p ˙ was measured and phase II V ˙ O 2 p kinetics were modeled with a mono-exponential function. The V ˙ O 2 p time constant was different (p < 0.05) amongst all conditions: CON, 26 ± 11s; HV, 36 ± 14s; HX, 46 ± 14s; and NC-HX, 52 ± 13s. Hypocapnia may prevent further slowing of V ˙ O 2 p kinetics in hypoxic exercise. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the effects of moderate normobaric hypoxia on the parameters of the work-time relationship in the upper body. Methods Twenty-one recreationally active men completed a graded exercise test in both normobaric hypoxia (H) and normoxia (N) to exhaustion on an arm ergometer to determine V̇O 2 peak and peak power output (PPO). Each participant completed four constant work-rate (CWR) arm-cranking tests at 90–120% PPO in both environmental conditions. Linear regression was used to estimate critical power (CP) and anaerobic working capacity (AWC) via work-time relationship during the CWR tests. Results H significantly reduced V̇O 2 peak (N: 2.34 ± 0.34 L vs. H: 2.27 ± 0.34 L, p  = 0.041), PPO (N: 125.29 ± 17.98 W vs. H: 121.11 ± 17.98 W, p  = 0.001), and CP (N: 90.22 ± 12.88 W vs. H: 85.26 ± 9.64 W, p  = 0.042), but had no effect on AWC (N: 9.16 ± 2.81 kJ vs. H: 8.75 ± 3.23 kJ, p  = 0.600). Discussion Moderate normobaric hypoxia appears to reduce CP in the upper body but has a variable effect on AWC. [ABSTRACT FROM AUTHOR]

Endothelial injury is considered as a trigger of pulmonary vascular lesions in the pathogenesis of hypoxic pulmonary hypertension (HPH). Although endothelial colony-forming cells (ECFCs) have vascular regeneration potential to maintain endothelial integrity, hypoxia-induced precise alteration in ECFCs function remains controversial. This study investigated the impact of hypoxia on human ECFCs function in vitro and the underlying mechanism. We found that hypoxia inhibited ECFCs proliferation, migration and angiogenesis. Compared with no treatment, the expression of hypoxia inducible factor-1α (HIF-1α) in hypoxia-treated ECFCs was increased, with an up-regulation of p27 and a down-regulation of cyclin D1. The over-secreted vascular endothelial growth factor (VEGF) was detected, with the imbalanced expression of fetal liver kinase 1 (flk-1) and fms related tyrosine kinase 1 (flt-1). Hypoxia-induced changes in ECFCs could be reversed by HIF-1α inhibitor KC7F2. These data suggest that HIF-1α holds the key in regulating ECFCs function which may open a new perspective of ECFCs in HPH management. [ABSTRACT FROM AUTHOR]

The O 2 diffusion limitation across the air blood barrier (DO 2 and subcomponents Dm and Vc ) was evaluated in 17 healthy participants exposed to hypobaric hypoxia (HA, 3840m, P I O 2 ∼90 mmHg). A 10% decrease in alveolar volume ( VA ) in all participants suggested the development of sub-clinical interstitial lung edema. In >80% of participants DO 2 /VA increased, reflecting an individual strategy to cope with the hypoxia stimulus by remodulating Vc or Dm . Opposite changes in Dm / Vc ratio were observed and participants decreasing Vc showed reduced alveolar blood capillary transit time. The interplay between diffusion and perfusion (cardiac output) was estimated in order to investigate the individual adaptive response to hypoxia. It appears remarkable that despite individual differences in the adaptive response to HA, diffusion limitation did not exceed ∼11% of the alveolar-venous PO 2 gradient, revealing an admirable functional design of the air-blood barrier to defend the O 2 diffusion/perfusion function when facing hypobaric hypoxia corresponding to 50 mmHg decreased P A O 2 . [ABSTRACT FROM AUTHOR]

Recent studies have shown that normal subjects exhibit periodic breathing when submitted to concomitant environmental (hypoxia) and physiological (exercise) stresses. A mathematical model including mass balance equations confirmed the short period of ventilatory oscillations and pointed out an important role of dead space in the genesis of these phenomena. Ten healthy subjects performed mild exercise on a cycloergometer in different conditions: rest/exercise, normoxia/hypoxia and no added dead space/added dead space (aDS). Ventilatory oscillations ( V ˙ E peak power) were augmented by exercise, hypoxia and aDS (P < 0.001, P < 0.001 and P < 0.01, respectively) whereas V ˙ E period was only shortened by exercise (P < 0.001), with an 11-s period. aDS also increased V ˙ E (P < 0.001), tidal volume (VT, P < 0.001), and slightly augmented PETCO 2 (P < 0.05) and the respiratory frequency (P < 0.05). These results confirmed our previous model, showing an exacerbation of breathing instability by increasing dead space. This underlines opposite effects observed in heart failure patients and normal subjects, in which added dead space drastically reduced periodic breathing and sleep apneas. It also points out that alveolar ventilation remains very close to metabolic needs and is not affected by an added dead space. Clinical Trial reg. n °: NCT02201875 [ABSTRACT FROM AUTHOR]

We tested if the addition of CO to inspired gases with different inspired O 2 and CO 2 fractions ( F I O 2 and F I CO 2 ) stimulates ventilation at rest or during submaximal exercise. We measured minute ventilation ( V E ) in goats breathing combinations of F I O 2 ranging from 0.21 to 0.06 and F I CO 2 from 0 to 0.05, both with and without inspired CO resulting in carboxyhemoglobin fractions ( F HbCO ) of 0.02 (no CO added), 0.15, or 0.45. We did this while they stood on a treadmill, walked at 1.4, or trotted at 2.5 m s −1 . Hypoxia, hypercapnia, and exercise, alone and in combination, increased ventilation compared to breathing air at rest. Both elevated F HbCO increased V E compared with ambient F HbCO during exercise (increases of 1.50 and 5.53 ml s −1 kg −1 for F HbCO 0.15 and 0.45, respectively; P = 0.035), but not at rest ( P = 0.958), when the ventilatory effects of F I O 2 and F I CO 2 are factored out. Additionally, F HbCO 0.45 (but not 0.15) increased V E compared to F HbCO 0.02 for all F I O 2 and F I CO 2 when the ventilatory effects of exercise are factored out. Taken together, these data suggest that exercise intensity and F HbCO dose interact to stimulate ventilation during exercise. [ABSTRACT FROM AUTHOR]

Cystathionine-γ-lyase (CSE) is a multifunctional enzyme, and hydrogen sulfide (H 2 S) is one of its products. CSE and H 2 S have recently been proposed to be critical signaling molecules in hypoxia-induced excitation of carotid body (CB) glomus cells and the chemosensory response. Because the role of H 2 S in arterial chemoreception is still debated, we further examined the role of CSE by studying the effects of hypoxia on TASK K + channel activity, cell depolarization, [Ca 2+ ] i and ventilation using CSE +/+ and CSE −/− mice. As predicted, hypoxia reduced TASK activity and depolarized glomus cells isolated from CSE +/+ mice. These effects of hypoxia were not significantly altered in glomus cells from CSE −/− mice. Basal [Ca 2+ ] i and hypoxia-induced elevation of [Ca 2+ ] were also not significantly different in glomus cells from CSE +/+ and CSE −/− mice. In whole-body plethysmography, hypoxia (10%O 2 ) increased minute ventilation in both CSE +/+ and CSE −/− mice equally well, and no significant differences were found in either males or females when adjusted by body weight. Together, these results show that deletion of the CSE gene has no effects on hypoxia-induced changes in TASK, cell depolarization, [Ca 2+ ] i and ventilation, and therefore do not support the idea that CSE/H 2 S signaling is important for CB chemoreceptor activity in mice. [ABSTRACT FROM AUTHOR]

Carotid chemoreceptors detect changes in PO 2 and elicit a peripheral respiratory chemoreflex (PCR). The PCR can be tested through a transient hypoxic ventilatory response test (TT-HVR), which may not be safe nor feasible at altitude. We characterized a transient hyperoxic ventilatory withdrawal test in the setting of steady-state normobaric hypoxia (13.5–14% F I O 2 ) and compared it to a TT-HVR and a steady-state poikilocapnic hypoxia test, within-individuals. No PCR test magnitude was correlated with any other test, nor was any test magnitude correlated with oxygenation while in steady-state hypoxia. Due to the heterogeneity between the different PCR test procedures and magnitudes, and the confounding effects of alterations in CO 2 acting on both central and peripheral chemoreceptors, we developed a novel method to assess prevailing steady-state chemoreflex drive in the context of hypoxia. Quantifying peak hypoxic/hyperoxic responses at low altitude may have minimal utility in predicting oxygenation during ascent to altitude, and here we advance a novel index of chemoreflex drive. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that low testosterone levels alter the regulation of breathing in mice exposed to intermittent hypoxia (IH). We used orchiectomized (ORX) or control (Sham-operated) mice exposed to normoxia or IH (12 h/day, 10 cycles/h, 6% O 2) for 14 days. Breathing was measured by whole-body plethysmography to asses the stability of the breathing pattern (frequency distribution of total cycle time - Ttot) and the frequency and duration of spontaneous and post-sigh apneas (PSA). We characterized sighs as inducing one (S1) or more (S2) apnea and determined the sigh parameters (volume, peak inspiratory and expiratory flows, cycle times) associated with PSA. IH increased the frequency and duration of PSA and the proportion of S1 and S2 sighs. The PSA frequency was mostly related to the sigh expiratory time. The effects of IH on PSA frequency were amplified in ORX-IH mice. Our experiments using ORX support the hypothesis that testosterone is involved in the regulation of breathing in mice following IH. • The interaction between testosterone and intermittent hypoxia in models of sleep apnea are unknown. • We used sham operated and orchidectomized (ORX) mice exposed to room air or intermittent hypoxia (IH). • We evaluated respiratory stability and apnea frequency during sleep. • ORX mice exposed to IH had lower respiratory stability and elevated frequency of apneas during sleep. • Low testosterone and IH might interact to alter the respiratory control system. [ABSTRACT FROM AUTHOR]

Circadian patterns are at the core of many physiological processes, and their disruption can have short- and long-term consequences. This essay focuses on one of the best known patterns, the daily oscillation of body temperature (Tb), and the possibility of its difference between genders. From human and animal studies globally considered, the tentative conclusion is reached that differences in Tb circadian pattern between genders are very small and probably limited to the timing of the rhythm, not to its amplitude. Such similarity between genders, despite the differences in hormonal systems, presumably testifies to the importance that the Tb circadian pattern plays in the economy of the organism and its survival against environmental challenges. The second part of the article presents some previously unpublished experimental data from behaving male and female rats during hypoxia in synchronized conditions. In adult rats hypoxia (10.5% O 2 for three days) caused a profound drop of the Tb daily oscillations; by day 3 they were 55% (♀) and 22% (♂) of the normoxic amplitudes, with a statistically significant gender difference. In pre-puberty rats (26-day old) hypoxia caused a major disruption of the circadian pattern qualitatively similar to the adults but not different between genders. Hence, on the basis of this preliminary set of data, it seems that sex-hormones may be a factor in how the Tb daily pattern responds to hypoxia. The implications of the effects of hypoxia on the circadian patterns, and the possibility that such effects may differ between genders, are matters that could have biological and clinical implications and deserve further investigations. [ABSTRACT FROM AUTHOR]

The human ventilatory response during acute hypoxia appears to be biphasic (growth and decay), but the effect of sex on the size and timing of this response is not known. We studied the effects of 15 min of poikilocapnic and isocapnic hypoxia (F i O 2 ≈ 0.10) on ventilation ( V ˙ i ) in 14 healthy female and 13 healthy male subjects. Parameters (amplitudes, time delays, time constants) describing individual V ˙ i responses were estimated using a biexponential function. There were no significant effects of sex on any of these parameters. CO 2 regulation significantly altered the amplitudes of growth and decay phases and the onset of the latter phase in females and males. These human data suggest that sex does not affect the biphasic response of ventilation during hypoxia. However, additional evidence in this study suggests that sex influences the breathing frequency response during hypoxia and that this effect depends on the control of CO 2 . [ABSTRACT FROM AUTHOR]

During postnatal life, the respiratory control system undergoes intense development and is highly responsive to stimuli emerging from the environment. In fact, interruption of breathing prevents gas exchange and results in systemic hypoxia that, if prolonged, can lead to cardio-respiratory failure or sudden infant death. Moreover, in newborns and infants, respiratory disorders related to neural control dysfunction show significant sexual dimorphism with a higher prevalence in males. To this day, the therapeutic tools available to alleviate these respiratory disorders remain limited. Furthermore, the factors explaining the sexual dimorphism in newborns and during infancy remain unknown. Erythropoietin (Epo) was originally discovered as a cytokine able to increase the production of red blood cells upon conditions of reduced oxygen availability. We now know that Epo is a cytokine also secreted by neurons and astrocytes that protects the brain during trauma or hypoxic stress in a sex dependent manner. In this novel line of research, our previous studies demonstrated at adult ages that cerebral Epo acts as a respiratory stimulant in rodents and humans. These results provided a strong rationale for exploring the role of cerebral Epo in neuronal respiratory control during postnatal development. The objective of this review is to summarize our recent findings showing that cerebral Epo is a potent sex-specific respiratory stimulant at neonatal ages. Keeping in mind that Epo is routinely and safely administrated in newborn humans for anemia and neonatal asphyxia, we predict that our research provides the basis necessary to promote the clinical use of Epo against neonatal respiratory disorders related to neural control dysfunction. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen–oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women. [ABSTRACT FROM AUTHOR]

Introduction Fatiguing of respiratory muscles reduces peripheral muscle perfusion. Further, acute hypoxia enhances respiratory muscle fatigue. This study investigated the effects of inspiratory muscle loading (IML) on resting locomotor muscle perfusion in hypoxia compared to normoxia. Methods Ten subjects completed two study days of fatiguing IML (blinded, randomized) in normobaric hypoxia (targeted oxygen saturation 80%) and normoxia, respectively. Contrast-enhanced ultrasound (CEUS) of the gastrocnemius muscle and popliteal doppler ultrasonography were used to monitor muscle perfusion. Based on CEUS and monitored cardiac output, perfusion surrogate parameters (CLP aer and CLP ap ) were established. Results Muscle perfusion declines early during IML in normoxia (CLP aer : −54 ± 25%, p < 0.01; CLP ap : −58 ± 32%, p < 0.01) and hypoxia (CLP aer : −43 ± 23%, p < 0.01; CLP ap : −41 ± 20%, p < 0.01). Hypoxia compared to normoxia increased cardiac output before (+23 ± 19%, p < 0.01 ANOVA) and during (+22 ± 20%, p < 0.01 ANOVA) IML, while local muscle perfusion during IML remained unchanged (CLP aer : p = 0.41 ANOVA; CLP ap : p = 0.29 ANOVA). Conclusion Acute hypoxia compared to normoxia does not affect locomotor muscle perfusion during fatiguing IML. [ABSTRACT FROM AUTHOR]

Purpose Central sleep apnea (CSA) and Cheyne-Stokes respiration (CSR) are highly prevalent in heart failure (HF) and are linked to increased mortality. Impaired pulmonary diffusion capacity [DLCO] and [KCO]) have been suggested to play a key role in CSA-CSR pathophysiology. This study investigated the relationship between HF, CSR, DLCO and KCO in well-characterized HF patients. Methods This prospective study included HF patients with CSR, all patients underwent full overnight polysomnography (PSG) and lung function testing. Results A total of 100 patients were included (age 70.7 ± 9.7 years, 95% male, body mass index 28.9 ± 5.3kg/m 2 , left ventricular ejection fraction 33.5 ± 7.7%, New York Heart Association class III 65%. DLCO and oxygenation were significantly correlated with hypoxemic burden (p < 0.05). Mean oxygen saturation, oxygen desaturation, C-reactive protein level and pH were significantly associated with CSA-CSR severity (p < 0.05). Conclusion The finding that lung diffusion capacity is significantly associated with hypoxemic burden in HF patients with CSA-CSR highlights the important of lung function in HF patients. [ABSTRACT FROM AUTHOR]

We aimed to assess lung fluid balance before and after gradual ascent to 5150 m. Lung diffusion capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm CO ) and ultrasound lung comets (ULCs) were assessed in 12 healthy lowlanders at sea-level, and on Day 1, Day 5 and Day 9 after arrival at Mount Everest Base Camp (EBC). EBC was reached following an 8-day hike at progressively increasing altitudes starting at 2860 m. DLCO was unchanged from sea-level to Day 1 at EBC, but increased on Day 5 (11 ± 10%) and Day 9 (10 ± 9%) vs. sea-level ( P ≤ 0.047). Dm CO increased from sea-level to Day 1 (9 ± 6%), Day 5 (12 ± 8%), and Day 9 (17 ± 11%) (all P ≤ 0.001) at EBC. There was no change in ULCs from sea-level to Day 1, Day 5 and Day 9 at EBC. These data provide evidence that interstitial lung fluid remains stable or may even decrease relative to at sea-level following 8 days of gradual exposure to high-altitude in healthy humans. [ABSTRACT FROM AUTHOR]

Among 740 children born extremely preterm, we evaluated the relationship between the highest and lowest quartiles of the distributions of PaO 2 and PaCO 2 , as well as the lowest quartile of pH on one day, and separately on two days, and the risk of neurocognitive, language, and behavioral dysfunctions at age 10 years. Children who had hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidemia, sometimes on only one day, and sometimes on two or more days, were more likely than others to have a high illness severity score (within the first 12 postnatal hours), and 10 years later to have multiple dysfunctions. The tendency of blood gas derangements to be associated with high illness severity scores and with multiple dysfunctions 10 years later is compatible with the possibility that blood gas derangements are indicators of physiologic instability/vulnerability/immaturity rather than contributors to brain damage. [ABSTRACT FROM AUTHOR]

Most experiments examining acid-base regulation of chicken embryos have employed static, single time point measurements rather than dynamic, multiple time point measurements that might reveal additional components of developing acid-base regulation. Thus, we studied blood acid-base balance and hematology of day 15 chicken embryos under 24 h exposure to graded hypercapnia (1%–7% CO 2 ) accompanied by graded hypoxia (20% O 2 down to 13% O 2 ). Across all hypercapnic/hypoxic environments, respiratory acidosis occurred 2 h after exposure in proportion to the magnitude of hypercapnia. An additional metabolic alkalosis occurred in ≥16% O 2 , and metabolic acidosis in ≤14% O 2 . As exposure progressed, compensatory metabolic alkalosis occurred in all groups at 6 h, but partial metabolic compensation could not be preserved as hypoxia increased (≤18% O 2 ). Across all hypercapnic/hypoxic groups, hematocrit, mean corpuscular volume and red blood cell concentration significantly increased by 24 h, most likely due to hypoxia rather than hypercapnia. Overall, day 15 chicken embryos cannot maintain even partial compensation in their acid-base physiology after 24 h exposure to hypercapnic/hypoxic environments of ≥5% CO 2 + ≤15% O 2 . [ABSTRACT FROM AUTHOR]

DLCO measured in hypoxia must be corrected due to the higher affinity (increase in coefficient θ ) of CO with Hb. We propose an adjustment accounting for individual changes in the equation relating DLCO to subcomponents Dm (membrane diffusive capacity) and Vc (lung capillary volume): 1/ DLCO = 1/ Dm + 1/ θVc . We adjusted the individual DLCO measured in hypoxia (HA, 3269m) by interpolating the 1/ DLCO to the sea level (SL) 1/ θ value. Nineteen healthy subjects were studied at SL and HA. Based on the proposed adjustment, DLCO increased in HA in 53% of subjects, reflecting the increase in Dm that largely overruled the decrease in Vc . We hypothesize that a decrease in Vc (buffering microvascular filtration) and the increase in Dm (possibly resulting from a decrease in thickness of the air-blood barrier) represent the anti-edemagenic adaptation of the lung to hypoxia exposure. The efficiency of this adaptation varied among subjects as DLCO did not change in 31% of subjects and decreased in 16%. [ABSTRACT FROM AUTHOR]

We tested the hypotheses that: (1) carotid body size can be measured by computed tomographic angiography (CTA) with high inter-observer agreement, and (2) patients with sleep apnea exhibit larger carotid bodies than those without sleep apnea. A chart review was conducted from patients who underwent neck CTA and polysomnography at the Mayo Clinic between January 2000 and February 2015. Widest axial measurements of the carotid bodies, performed independently by two radiologists, were possible in 81% of patients. Intra-class correlation coefficients ranged from 0.93 to 0.95 (Right carotid body: 0.93; Left: 0.94; Average: 0.95). Widest axial measurements of the carotid bodies were greater in patients with sleep apnea (n = 32) compared to controls (n = 46, P -value range 0.02–0.04). After adjusting for age, no differences in carotid body size were observed between the patient groups ( P -value range 0.45–0.59). We conclude carotid body size can be detected by CTA with high inter-observer agreement; however, carotid body size is not increased in patients with sleep apnea. [ABSTRACT FROM AUTHOR]

We measured the effects of adding CO 2 to an inhaled hypoxic gas mixture on cardio-respiratory parameters during maximal exercise. Eight young males performed four incremental maximal exercise tests on cycle under ambient air, hypoxia (FIO 2 0.125), inhaled CO 2 (FICO 2 0.045), and combination of hypoxia and inhaled CO 2 . The highest ventilation (VE) and VE/CO 2 output were recorded in CO 2 inhalation and combined treatments. Arterial O 2 partial pressure was higher in combined than in hypoxia treatment, but the difference between the treatments narrowed from rest to end-exercise, at least partly because the magnitude of the increase in VE (%) at exercise was smaller in combined treatment than in hypoxia. Arterial O 2 content was higher in combined treatment than in hypoxia at rest, but no more at maximal exercise. Cardiac output was higher and O 2 extraction lower when breathing O 2 -poor gas mixtures than under the two other treatments. For a given oxygen consumption, hypoxia and combined treatment showed similar cardiac output and O 2 extraction. [ABSTRACT FROM AUTHOR]

Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin. [ABSTRACT FROM AUTHOR]

Development of the capacity to mitigate potential disturbances to blood physiology in bird embryos is incompletely understood. We investigated regulation of acid-base and hematology in day 15 chicken embryos exposed to graded intrinsic hypercapnic hypoxia created by varying degrees of water submersion. Metabolic acidosis with additional respiratory or metabolic acidosis occurred at 2 h according to magnitude of submersion. Acid-base disturbance was partially compensated by metabolic alkalosis at 6 h, but compensatory metabolic alkalosis was absent at 24 h. Following submersion with only air cell exposed to air, both hypercapnic respiratory acidosis and metabolic acidosis occurred within 10 min. Subsequently, both forms of acidosis created lethal levels of [HCO 3 -] at ∼120 min. Blood hematology showed small but significant effects associated with induced acid-base disturbance. Increased Hct occurring during partial egg submersion lasting 24 h was attributed to an increase in MCV. By day 15 of development chicken embryos are able to partially compensate for and withstand all but severe induced internal hypoxic hypercapnia. [Display omitted] • Graded levels of internal hypoxia and hypercapnia were induced in Day 15 chicken embryos using water submergence. • Embryos withstand all but severe induced internal hypoxic hypercapnia, indicating presence of acid-base regulation abilities. • Hypoxic hypercapnia had little effect on blood hematology (e.g. hematocrit, red blood cell and hemoglobin concentrations). [ABSTRACT FROM AUTHOR]