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1.  Recent advances in alveolar biology: Evolution and function of alveolar proteins☆ 
This review is focused on the evolution and function of alveolar proteins. The lung faces physical and environmental challenges, due to changing pressures/volumes and foreign pathogens, respectively. The pulmonary surfactant system is integral in protecting the lung from these challenges via two groups of surfactant proteins – the small molecular weight hydrophobic SPs, SP-B and -C, that regulate interfacial adsorption of the lipids, and the large hydrophilic SPs, SP-A and -D, which are surfactant collectins capable of inhibiting foreign pathogens. Further aiding pulmonary host defence are non-surfactant collectins and antimicrobial peptides that are expressed across the biological kingdoms. Linking to the first symposium session, which emphasised molecular structure and biophysical function of surfactant lipids and proteins, this review begins with a discussion of the role of temperature and hydrostatic pressure in shaping the evolution of SP-C in mammals. Transitioning to the role of the alveolus in innate host defence we discuss the structure, function and regulation of antimicrobial peptides, the defensins and cathelicidins. We describe the recent discovery of novel avian collectins and provide evidence for their role in preventing influenza infection. This is followed by discussions of the roles of SP-A and SP-D in mediating host defence at the alveolar surface and in mediating inflammation and the allergic response of the airways. Finally we discuss the use of animal models of lung disease including knockouts to develop an understanding of the role of these proteins in initiating and/or perpetuating disease with the aim of developing new therapeutic strategies.
doi:10.1016/j.resp.2010.04.023
PMCID: PMC4097100  PMID: 20433956
Surfactant proteins; SP-A; SP-C; SP-D; Binding affinity; Oligomerization; Deficiency; Alveolar proteins; Collectins; Cathelicidins; Defensins; Innate host defence; Hemagglutination inhibition activity; Bacterial aggregation; Pro-inflammatory response; Anti-inflammatory response; Airways; Allergic response; Sensitization; Surfactant homeostasis; Alveolar lipoproteinosis; Type II cell hypertrophy and hyperplasia; Lamellar body size and number
2.  Effects of nitrate supplementation via beetroot juice on contracting rat skeletal muscle microvascular oxygen pressure dynamics 
NO3− supplementation via beetroot juice (BR) augments exercising skeletal muscle blood flow subsequent to its reduction to NO2− then NO. We tested the hypothesis that enhanced vascular control following BR would elevate the skeletal muscle O2 delivery/O2 utilization ratio (microvascular PO2, PmvO2) and raise the PmvO2 during the rest-contractions transition. Rats were administered BR (~0.8 mmol/kg/day, n=10) or water (control, n=10) for 5 days. PmvO2 was measured during 180 s of electrically-induced (1 Hz) twitch spinotrapezius muscle contractions. There were no changes in resting or contracting steady-state PmvO2. However, BR slowed the PmvO2 fall following contractions onset such that time to reach 63% of the initial PmvO2 fall increased (MRT1; control: 16.8±1.9, BR: 24.4±2.7 s, p<0.05) and there was a slower relative rate of PmvO2 fall (Δ1PmvO2/τ1; control: 1.9±0.3, BR: 1.2±0.2 mmHg/s, p<0.05). Despite no significant changes in contracting steady state PmvO2, BR supplementation elevated the O2 driving pressure during the crucial rest-contractions transients thereby providing a potential mechanism by which BR supplementation may improve metabolic control.
doi:10.1016/j.resp.2013.04.001
PMCID: PMC3753182  PMID: 23584049
exercise; blood flow; nitrite; nitric oxide
3.  Chronic nicotine and ethanol exposure both disrupt central ventilatory responses to hypoxia in bullfrog tadpoles 
The central hypoxic ventilatory response (HVR) comprises a reduction in ventilatory activity that follows a peripherally mediated ventilatory augmentation. Chronic early developmental exposure to nicotine or ethanol are both known to impair the peripherally mediated HVR, and nicotine impairs the central HVR, but the effect of ethanol on the central HVR has not been investigated. Additionally, chronic nicotine and ethanol exposure are known to impair ventilatory responses to hypercapnia in bullfrog tadpoles but HVRs have not been tested. Here early and late metamorphic tadpoles were exposed to either 30 µg/L nicotine or 0.15 – 0.05 g/dL ethanol for 10 wk. Tadpole brainstems were then isolated and the neurocorrelates of ventilation were monitored in vitro over 180 min of hypoxia (PO2 = 5.05 ± 1.04 kPa). Both nicotine and ethanol exposure disrupted central HVRs. Nicotine impairments were dependent on development. Central HVRs were impaired only in early metamorphic nicotine-exposed tadpoles. Both early and late metamorphic ethanol-exposed tadpoles failed to exhibit central HVRs. Thus, central HVRs are impaired following both nicotine and ethanol exposure. Such failure to decrease ventilatory activity during hypoxia indicates that central hypoxic ventilatory depression is an active suppression of neural activity in response to hypoxia rather than a metabolic consequence of O2 limitation, and that exposure to ethanol (across development) or nicotine (during early development) disrupts mechanisms that normally induce active ventilatory depression.
doi:10.1016/j.resp.2013.04.004
PMCID: PMC3791079  PMID: 23590824
control of breathing; development; alcohol
4.  Mechanisms of Intrinsic Force in Small Human Airways 
We quantified the magnitude and investigated mechanisms regulating intrinsic force (IF) in human airway smooth muscle (hASM). IF was identified by reducing extracellular calcium (Ca2+) concentration to nominally zero in freshly isolated isometrically mounted 2 mm human bronchi. Our results show: (1) the magnitude of IF is ~ 50% of the maximal total force elicited by acetylcholine (10-5 M) and is epithelial-independent, (2) IF can also be revealed by β-adrenergic activation (isoproterenol), non-specific cationic channel blockade (La3+) or L-type voltage gated Ca2+ channel blockade (nifedipine), (3) atropine, indomethacin, AA– 861, or pyrilamine did not affect IF, (4) IF was reduced by the intracellular Ca2+ ([Ca2+]i) chelating agent BAPTA-AM, (5) ω-conotoxin had no effect on IF. In studies in cultured hASM cells nominally zero Ca2+ buffer and BAPTA-AM reduced [Ca2+]i but isoproterenol and nifedipine did not. Taken together these results indicate that rapid reduction of [Ca2+]i reveals a permissive relationship between extracellular Ca2+, [Ca2+]i and IF. However IF can be dissipated by mechanisms effecting Ca2+ sensitivity. We speculate that an increase of IF, a fundamental property of ASM, could be related to human airway clinical hyperresponsiveness and must be accounted for in in vitro studies of hASM.
doi:10.1016/j.resp.2012.01.011
PMCID: PMC4066449  PMID: 22322114
Intrinsic force; human; airway smooth muscle; asthma; intracellular calcium concentration [Ca2+]i
5.  Leptin Integrates Vertebrate Evolution: from Oxygen to the Blood-Gas Barrier 
The following are the proceedings of a symposium held at the Second International Congress for Respiratory Science in Bad Honnef, Germany. The goals of the symposium were to delineate the blood-gas barrier phenotype across vertebrate species; to delineate the interrelationship between the evolution of the blood-gas barrier, locomotion and metabolism; to introduce the selection pressures for the evolution of the surfactant system as a key to understanding the physiology of the blood-gas barrier; to introduce the lung lipofibroblast and its product, leptin, which coordinately regulates pulmonary surfactant, type IV collagen in the basement membrane and host defense, as the cell-molecular site of selection pressure for the blood-gas barrier; to drill down to the gene regulatory network(s) involved in leptin signaling and the blood-gas barrier phenotype; to extend the relationship between leptin and the blood-gas-barrier to diving mammals.
doi:10.1016/j.resp.2010.01.007
PMCID: PMC4059502  PMID: 20096383
6.  Effect of Supine Posture on Airway Blood Flow and Pulmonary Function in Stable Heart Failure 
Background
The aim of this study was to determine the relationship between body position, pulmonary function (PF) and bronchial blood flow (Qaw) in a group of heart failure (HF) and control subjects.
Methods
Thirty-six subjects were studied: 24 stable, ambulatory HF patients (HF: LVEF=27±6%, age=65±9yr) and 12 age- and sex-matched controls (CTRL: LVEF=60±7%, age=62±8yr). Measures of Q̇aw (soluble gas method) and PF were collected upright and following 30 min in the supine position.
Results
Q̇aw was similar between groups and remained unchanged with body position. Declines in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) with the supine position were observed in both groups; declines in forced expiratory flow 25–75% (FEF25–75) and FEF 75% (FEF75) with the supine position were observed in the HF group only. Changes in Q̇aw were related to changes in PF only in the HF patient groups (ΔFVC, %predicted, r=−0.45, p<0.04, ΔFEV1 r=−0.61, p<0.01, ΔFEV1 %predicted, r=−0.45, p<0.04).
Conclusion
These data demonstrate that relationships between postural changes in Q̇aw and PF exist only in the HF population and that the bronchial circulation may contribute to postural PF decline in HF.
doi:10.1016/j.resp.2011.06.021
PMCID: PMC4033692  PMID: 21741500
Upright and Supine Position; Bronchial Blood Flow; Left Ventricular Systolic Dysfunction
7.  Respiratory muscles and motoneurons ✩ 
doi:10.1016/j.resp.2011.06.027
PMCID: PMC4019334  PMID: 21762791
8.  Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats 
The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO2 sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO2 sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7 % CO2 exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10 mg/kg/day) in adult male BN and SD rats. Fluoxetine had minimal effects on room air breathing in BN and SD rats (p>0.05), although tidal volume (VT) was reduced in BN rats (p<0.05). There were also minimal effects of fluoxetine on CO2 sensitivity in SD rats, but fluoxetine increased minute ventilation, breathing frequency and VT during hypercapnia in BN rats (p<0.05). The augmented CO2 response was reversible upon withdrawal of fluoxetine. Brain levels of biogenic amines were largely unaffected, but 5-HIAA and the ratio of 5-HIAA/5-HT were reduced (p<0.05) consistent with selective and effective 5-HT reuptake inhibition. Thus, fluoxetine increases ventilatory CO2 sensitivity in BN but not SD rats, further suggesting altered 5-HT system function may contribute to the inherently low CO2 sensitivity in the BN rat.
doi:10.1016/j.resp.2013.02.020
PMCID: PMC4014076  PMID: 23454023
CO2 chemoreception; SSRI; control of breathing
9.  Prenatal nicotine exposure alters medullary nicotinic and AMPA-mediated control of respiratory frequency in vitro 
Prenatal nicotine exposure (PNE) is correlated with breathing abnormalities in humans and other animals. Despite evidence that this relationship results from alterations in nicotinic acetylcholine receptors (nAChRs), the mechanisms are poorly understood. Here, we hypothesize that PNE blunts nAChR-mediated respiratory-related motor output. We also hypothesize that the PNE-induced changes in nAChRs leads to secondary alterations in glutamatergic neurotransmission. To test these hypotheses, we used an in vitro brainstem-spinal cord preparation and recorded C4 ventral root (C4 VR) nerve bursts from 0 to 4-day-old rats that were exposed to either nicotine (6 mg kg−1 day−1) or saline (control) in utero. Nicotine bitartrate, nAChR antagonists, NMDA and AMPA were applied to the brainstem compartment of a “split-bath” configuration, which physically separated the medulla from the spinal cord. Nicotine (0.2 or 0.5 μM) increased peak C4 VR burst frequency by over 230% in control pups, but only 140% in PNE animals. The application of nAChR antagonists showed that these effects were mediated by the α4β2 nAChR subtype with no effect on α7 nAChRs in either group. We also show that AMPA-mediated excitatory neurotransmission is enhanced by PNE, but NMDA-mediated neurotransmission is unaltered. These data and the work of others suggest that the PNE may functionally desensitize α4β2 nAChRs located on the presynaptic terminals of glutamatergic neurons leading to less neurotransmitter release, which in turn up-regulates AMPA receptors on rhythm generating neurons.
doi:10.1016/j.resp.2009.07.022
PMCID: PMC4011194  PMID: 19651248
Nicotinic receptor; Control of breathing; Nicotine; Prenatal nicotine exposure; Respiratory rhythm generation
10.  Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: implications for peripheral vascular control 
Neuronal nitric oxide (NO) synthase (nNOS) inhibition with systemically-administered S-methyl-L-thiocitrulline (SMTC) elevates mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle and renal blood flow. We tested the hypothesis that those SMTC-induced cardiovascular effects resulted, in part, from increased sympathetic nerve discharge (SND). MAP, HR, and lumbar and renal SND (direct nerve recordings) were measured in 9 baroreceptor (sino-aortic)-denervated rats for 20 minutes each following both saline and SMTC (0.56 mg/kg i.v.). SMTC increased MAP (peak Δ MAP: 50±8 mmHg, p<0.01) compared to saline. Lumbar and renal SND were not different between saline and SMTC conditions at any time (p>0.05). The Δ SND between saline and SMTC conditions for the lumbar and renal nerves were not different from zero (peak Δ SND, lumbar: 2.0±6.8%; renal: 9.7±9.0%, p>0.05 versus zero for both). These data support that SMTC-induced reductions in skeletal muscle and renal blood flow reported previously reflect peripheral nNOS-derived NO vascular control as opposed to increased sympathetic vasoconstriction.
doi:10.1016/j.resp.2013.02.021
PMCID: PMC3999663  PMID: 23454026
sympathetic nervous system; blood pressure; heart rate
11.  Variability of respiratory mechanics during sleep in overweight and obese subjects with and without asthma 
Variability of respiration may provide information regarding disease states. We sought to characterize variability of ventilation and resistance in healthy and asthma, to determine how respiratory control may be altered in sleep and with bi-level positive airway pressure (BPAP). Overweight and obese subjects with and without asthma were studied during sleep at baseline and with BPAP, while measuring respiratory system resistance (Rrs) continuously. Stable periods (>20min) of wake, NREM, and REM sleep were identified and correlation metrics of respiratory parameters were calculated, including coefficient of variation (CV). Variability of Rrs was also characterized over short time scales (20 breaths) during sleep and defined as either “leading to arousal” or “not leading to arousal”. Data from 10 control and 10 subjects with asthma were analyzed. CV of Rrs was decreased in asthma at baseline (p<0.001) and decreased on BPAP as compared to baseline (p<0.001). Long time scale correlations were found in respiratory parameters, but the degree of correlations was decreased from wake to sleep (p<0.05). The variance and CV of Rrs was increased preceding an arousal from sleep at baseline; however, during BPAP, the CV was decreased and was not increased preceding arousals. At baseline, resistance was greater in those with asthma, but variability was smaller. BPAP reduced both resistance and overall variability. We conclude that the BPAP-induced decrease in variability may indicate that those with asthma are more likely to remain in a low resistance state, and that low resistance variability may reduce arousals from sleep.
doi:10.1016/j.resp.2013.02.026
PMCID: PMC3659817  PMID: 23473922
Variability; resistance; arousals; ventilation; asthma
12.  Clinical challenges to ventilatory control✩ 
doi:10.1016/j.resp.2013.09.006
PMCID: PMC3988782  PMID: 24056024
13.  Sleep-disordered breathing and oxidative stress in preclinical chronic mountain sickness (excessive erythrocytosis) 
Chronic mountain sickness (CMS) is considered to be a loss of ventilatory acclimatization to high altitude (>2500 m) resulting in marked arterial hypoxemia and polycythemia. This case-control study explores the possibility that sleep-disordered breathing (SBD) and associated oxidative stress contribute to the etiology of CMS. Nocturnal respiratory and SaO2 patterns were measured using standard polysomnography techniques and compared between male high-altitude residents (aged 18–25) with preclinical CMS ([excessive erythrocytosis (EE)], n=20) and controls (n=19). Measures of oxidative stress and antioxidant status included isoprostanes (8-iso-PGF2 alpha), superoxide dismutase and ascorbic acid. EE cases had a greater apnea-hypopnea index, a higher frequency of apneas (central and obstructive) and hypopneas during REM sleep, and lower nocturnal SaO2 compared to controls. 8-iso-PGF2alpha was greater in EE than controls, negatively associated with nocturnal SaO2, and positively associated with hemoglobin concentration. Mild sleep-disordered breathing and oxidative stress are evident in preclinical CMS, suggesting that the resolution of nocturnal hypoxemia or antioxidant treatment may prevent disease progression.
doi:10.1016/j.resp.2013.01.016
PMCID: PMC3615034  PMID: 23380170
polycythemia; sleep-disordered breathing; altitude; oxidative stress
14.  Serotonergic mechanisms are necessary for central respiratory chemoresponsiveness in situ 
Evidence from in vivo and in vitro experiments conclude that serotonin (5-HT) neurons are involved in and play an important role in central respiratory CO2/H+ chemosensitivity. This study was designed to assess the importance of 5-HT neurons and 5-HT receptor activation in the frequency and amplitude components of the hypercapnic response of the respiratory network in the unanesthetized perfused in situ juvenile rat brainstem preparation that exhibits patterns of phrenic nerve discharge similar to breathing in vivo. Exposure to a hypercapnic perfusate increased phrenic burst frequency and/or amplitude, the neural correlates of breathing frequency and tidal volume in vivo. Hypercapnic responses were also assessed during exposure to ketanserin (5-HT2 receptor antagonist), and 8-OH-DPAT (inhibiting 5-HT neurons via 5-HT1A autoreceptors). Neither of these drugs substantially altered baseline activity, however, both abolished hypercapnic responses of the respiratory network. These data illustrate that 5-HT neurons and 5-HT receptor activation are not required for respiratory rhythm generation per se, but are critical for CO2 responses in situ, supporting the hypothesis that 5-HT neurons play an important role in central ventilatory chemosensitivity in vivo.
doi:10.1016/j.resp.2013.02.015
PMCID: PMC3645885  PMID: 23454177
hypercapnia; perfused in situ brainstem preparation; ketanserin
15.  Respiration and heart rate complexity: Effects of age and gender assessed by band-limited transfer entropy 
Respiratory physiology & neurobiology  2013;189(1):10.1016/j.resp.2013.06.016.
Aging and disease are accompanied with a reduction of complex variability in the temporal patterns of heart rate. This reduction has been attributed to a break down of the underlying regulatory feedback mechanisms that maintain a homeodynamic state. Previous work has established the utility of entropy as an index of disorder, for quantification of changes in heart rate complexity. However, questions remain regarding the origin of heart rate complexity and the mechanisms involved in its reduction with aging and disease. In this work we use a newly developed technique based on the concept of band-limited transfer entropy to assess the aging-related changes in contribution of respiration and blood pressure to entropy of heart rate at different frequency bands. Noninvasive measurements of heart beat interval, respiration, and systolic blood pressure were recorded from 20 young (21–34 years) and 20 older (68–85 years) healthy adults. Band-limited transfer entropy analysis revealed a reduction in high-frequency contribution of respiration to heart rate complexity (p < 0.001) with normal aging, particularly in men. These results have the potential for dissecting the relative contributions of respiration and blood pressure-related reflexes to heart rate complexity and their degeneration with normal aging.
doi:10.1016/j.resp.2013.06.016
PMCID: PMC3821922  PMID: 23811194
Heart rate variability; Respiratory sinus arrhythmia; Aging; Entropy
16.  Influence of age, body temperature, GABAA receptor inhibition and caffeine on the Hering-Breuer inflation reflex in unanesthetized rat pups 
We measured the duration of apnea induced by sustained end-inspiratory lung inflation (the Hering Breuer Reflex; HBR) in unanesthetized infant rat pups aged 4 days (P4) to P20 at body temperatures of 32°C and 36°C. The expiratory prolongation elicited by the HBR lasted longer in the younger pups and lasted longer at the higher body temperature. Blockade of adenosine receptors by caffeine following injection into the cisterna magna (ICM) significantly blunted the thermal prolongation of the HBR. Blockade of gama-amino-butyric acid A (GABAA) receptors by pre-treatment with ICM bicuculline had no effect on the HBR duration at either body temperature. To test the hypothesis that developmental maturation of GABAergic inhibition of breathing was modifying the response to bicuculline, we pretreated rat pups with systemically administered bumetanide to lower the intracellular chloride concentration, and repeated the bicuculline studies. Bicuculline still did not alter the HBR at either temperature after bumetanide treatment. We administered PSB-36, a selective adenosine A1 receptor antagonist, and this drug treatment did not modify the HBR. We conclude that caffeine blunts the thermal prolongation of the HBR, probably by blocking adenosine A2a receptors. The thermally-sensitive adenosinergic prolongation of the HBR in these intact animals does not seem to depend on GABAA receptors
doi:10.1016/j.resp.2013.01.002
PMCID: PMC3602215  PMID: 23318703
Lung inflation; reflex apnea; body temperature; rat pups; bicuculline; bumetanide; caffeine
17.  Spinal Pathways Mediating Phrenic Activation during High Frequency Spinal Cord Stimulation 
High frequency spinal cord stimulation (HF-SCS) is a method of inspiratory muscle activation resulting in phrenic motoneuron activation via stimulation of spinal cord pathways. The specific pathways mediating this response, however, are unknown. The aim of this study was to assess the potential role of upper cervical (C1–C4) pre-phrenic interneurons (UCI) and localize the pathways in the thoracic spinal cord mediating activation of phrenic motoneurons during HF-SCS. In 7 anesthetized, spinalized (C1 level) dogs, HF-SCS was applied at the T2 level. Diaphragm EMG, inspired volume and airway pressure generation were monitored before and following sequential spinal cord sections at the C4 and C8 levels. Section at the C4 level and dorsal columns at C8 resulted in no significant changes. However, lateral funiculi section (C8 level) resulted in significant reductions in each parameter. We conclude that during upper thoracic HF-SCS, the phrenic motoneuron pools are activated via spinal pathways located in the lateral funiculus but UCI are not involved.
doi:10.1016/j.resp.2012.12.003
PMCID: PMC3602409  PMID: 23261850
spinal cord stimulation; inspiratory muscles; spinal cord injury
18.  Laryngeal reflex apnea in neonates: effects of CO2 and the complex influence of hypoxia 
We have examined influence of hypocapnia, mild hypercapnia and hypoxia on the durations of fictive apnea and respiratory disruption elicited by injection of 0.1 ml of water into the laryngeal lumen—the laryngeal chemoreflex (LCR)—in 20 unanesthetized, decerebrate, vagotomized piglets aged 4 to 10 days that were paralyzed and ventilated with a constant frequency and tidal volume. The LCR was enhanced by hypocapnia and attenuated by hypercapnia as reported by others. The responses to laryngeal stimulation during hypoxia were varied and complex: some animals showed abbreviated responses during the tachypnea of early hypoxia, followed after 10-15 min by more prolonged apnea and respiratory disruption accompanying the reduction in ventilatory activity that commonly occurs during sustained hypoxia in neonates. We speculate that this later hypoxic enhancement of the LCR may be due to accumulation of adenosine in the brain stem.
doi:10.1016/j.resp.2013.01.004
PMCID: PMC3604991  PMID: 23348024
Laryngeal chemoreflex; Sudden Infant Death Syndrome; Hypocapnia; Hypercapnia; Hypoxia; Piglet
19.  Mechanism of augmented exercise hyperpnea in chronic heart failure and dead space loading 
Patients with chronic heart failure (CHF) suffer increased alveolar VD/VT (dead-space-to-tidal-volume ratio), yet they demonstrate augmented pulmonary ventilation such that arterial PCO2 (PaCO2) remains remarkably normal from rest to moderate exercise. This paradoxical effect suggests that the control law governing exercise hyperpnea is not merely determined by metabolic CO2 production (V̇CO2) per se but is responsive to an apparent (real-feel) metabolic CO2 load (V˙CO2o) that also incorporates the adverse effect of physiological VD/VT on pulmonary CO2 elimination. By contrast, healthy individuals subjected to dead space loading also experience augmented ventilation at rest and during exercise as with increased alveolar VD/VT in CHF, but the resultant response is hypercapnic instead of eucapnic, as with CO2 breathing. The ventilatory effects of dead space loading are therefore similar to those of increased alveolar VD/VT and CO2 breathing combined. These observations are consistent with the hypothesis that the increased series VD/VT in dead space loading adds to V˙CO2o as with increased alveolar VD/VT in CHF, but this is through rebreathing of CO2 in dead space gas thus creating a virtual (illusory) airway CO2 load within each inspiration, as opposed to a true airway CO2 load during CO2 breathing that clogs the mechanism for CO2 elimination through pulmonary ventilation. Thus, the chemosensing mechanism at the respiratory controller may be responsive to putative drive signals mediated by within-breath PaCO2 oscillations independent of breath-to-breath fluctuations of the mean PaCO2 level. Skeletal muscle afferents feedback, while important for early-phase exercise cardioventilatory dynamics, appears inconsequential for late-phase exercise hyperpnea.
doi:10.1016/j.resp.2012.12.004
PMCID: PMC3889173  PMID: 23274121
Chronic heart failure; Physiological dead space; Dead space loading; Alveolar dead space; Anatomical dead space; Series dead space; Parallel dead space; Whipp’s law; Comroe’s law; Fenn–Craig diagram; Exercise hyperpnea; Metabolic CO2 load; Airway CO2 load; CO2 breathing; Arterial PCO2 oscillations; Cognition; Perception
20.  Firing patterns of muscle sympathetic neurons during short-term use of continuous positive airway pressure in healthy subjects and in chronic heart failure patients 
The current study tested the hypothesis that modification in central hemodynamics during short-term continuous positive airway pressure (CPAP) application was accompanied by altered firing patterns of sympathetic nerve activity in CHF patients and healthy subjects.
Muscle sympathetic nerve activity (MSNA), hemodynamic and ventilatory parameters were obtained from 8 healthy middle aged subjects and 7 CHF patients. Action potentials (APs) were extracted from MSNA neurograms, quantified as AP frequency and classified into different sized clusters. While on CPAP at 10 cm H2O, multi-unit MSNA, AP frequency and mean burst area/min increased in healthy middle aged subjects (p < 0.05) whereas CPAP had no effect on these variables in CHF patients. In conclusion, the impact of CPAP on central hemodynamics in healthy individuals elicited a moderate activation of sympathetic neurons through increased AP firing frequency, whereas in CHF patients both hemodynamics and MSNA remained unaltered.
doi:10.1016/j.resp.2013.03.003
PMCID: PMC3919512  PMID: 23541507
Action potential detection; Microneurography; End-expiratory positive pressure; Human
21.  Isoflurane and Ketamine Anesthesia have Different Effects on Ventilatory Pattern Variability in Rats 
We hypothesize that isoflurane and ketamine impact ventilatory pattern variability (VPV) differently. Adult Sprague-Dawley rats were recorded in a whole-body plethysmograph before, during and after deep anesthesia. VPV was quantified from 60-s epochs using a complementary set of analytic techniques that included constructing surrogate data sets that preserved the linear structure but disrupted nonlinear deterministic properties of the original data. Even though isoflurane decreased and ketamine increased respiratory rate, VPV as quantified by the coefficient of variation decreased for both anesthetics. Further, mutual information increased and sample entropy decreased and the nonlinear complexity index (NLCI) increased during anesthesia despite qualitative differences in the shape and period of the waveform. Surprisingly mutual information and sample entropy did not change in the surrogate sets constructed from isoflurane data, but in those constructed from ketamine data, mutual information increased and sample entropy decreased significantly in the surrogate segments constructed from anesthetized relative to unanesthetized epochs. These data suggest that separate mechanisms modulate linear and nonlinear variability of breathing.
doi:10.1016/j.resp.2012.12.001
PMCID: PMC3563719  PMID: 23246800
22.  Hypoxia-induced ventilatory responses in conscious mice: Gender differences in ventilatory roll-off and facilitation 
The aim of this study was to compare the ventilatory responses of C57BL6 female and male mice during a 15 min exposure to a hypoxic-hypercapnic (H-H) or a hypoxic (10% O2, 90% N2) challenge and subsequent return to room air. The ventilatory responses to H-H were similar in males and females whereas there were pronounced gender differences in the ventilatory responses during and following hypoxic challenge. In males, the hypoxic response included initial increases in minute volume via increases in tidal volume and frequency of breathing. These responses declined substantially (roll-off) during hypoxic exposure. Upon return to room-air, relatively sustained increases in these ventilatory parameters (short-term potentiation) were observed. In females, the initial responses to hypoxia were similar to those in males whereas roll-off was greater and post-hypoxia facilitation was smaller than in males. The marked differences in ventilatory roll-off and post-hypoxia facilitation between female and male C57BL6 mice provide evidence that gender is of vital importance to ventilatory control.
doi:10.1016/j.resp.2012.11.010
PMCID: PMC3593587  PMID: 23183420
Hypoxia; hypercapnia; minute ventilation; male and female mice
23.  Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase 
Exposure to a hypoxic challenge increases ventilation in wild-type (WT) mice that diminish during the challenge (roll-off) whereas return to room air causes an increase in ventilation (short-term facilitation, STF). Since plasma and tissue levels of ventilatory excitant S-nitrosothiols such as S-nitrosoglutathione (GSNO) increase during hypoxia, this study examined whether (1) the initial increase in ventilation is due to generation of GSNO, (2) roll-off is due to increased activity of the GSNO degrading enzyme, GSNO reductase (GSNOR), and (3) STF is limited by GSNOR activity. Initial ventilatory responses to hypoxic challenge (10% O2, 90% N2) were similar in WT, GSNO+/− and GSNO−/− mice. These responses diminished markedly during hypoxic challenge in WT mice whereas there was minimal roll-off in GSNOR+/− and GSNOR−/− mice. Finally, STF was greater in GSNOR+/− and GSNOR−/− mice than WT mice (especially females). This study suggests that GSNOR degradation of GSNO is a vital step in the expression of ventilatory roll-off and that GSNOR suppresses STF.
doi:10.1016/j.resp.2012.11.009
PMCID: PMC3593598  PMID: 23183419
hypoxia; ventilatory responses; S-nitrosoglutathione reductase; S-nitrosothiols; mice
24.  Dynamics of neuromodulatory feedback determines frequency modulation in a reduced respiratory network: A computational study 
Neuromodulators, such as amines and neuropeptides, alter the activity of neurons and neuronal networks. In this work, we investigate how neuromodulators, which activate Gq-protein second messenger systems, can modulate the bursting frequency of neurons in a critical portion of the respiratory neural network, the pre-Bötzinger complex (preBötC). These neurons are a vital part of the ponto-medullary neuronal network, which generates a stable respiratory rhythm whose frequency is regulated by neuromodulator release from the nearby Raphe nucleus. Using a simulated 50-cell network of excitatory preBötC neurons with a heterogeneous distribution of persistent sodium conductance and Ca2+, we determined conditions for frequency modulation in such a network by simulating interaction between Raphe and preBötC nuclei. We found that the positive feedback between the Raphe excitability and preBötC activity induces frequency modulation in the preBötC neurons. In addition, the frequency of the respiratory rhythm can be regulated via phasic release of excitatory neuromodulators from the Raphe nucleus. We predict that the application of a Gq antagonist will eliminate this frequency modulation by the Raphe and keep the network frequency constant and low. In contrast, application of a Gq agonist will result in a high frequency for all levels of Raphe stimulation. Our modeling results also suggest that high [K+] requirement in respiratory brain slice experiments may serve as a compensatory mechanism for low neuromodulatory tone.
doi:10.1016/j.resp.2012.11.013
PMCID: PMC3647346  PMID: 23202052
Central pattern generator; Endogenous bursting; Pre-Bötzinger complex; preBötC
25.  Spinal vascular endothelial growth factor (VEGF) and erythropoietin (EPO) induced phrenic motor facilitation after repetitive acute intermittent hypoxia 
Respiratory physiology & neurobiology  2012;185(3):10.1016/j.resp.2012.10.014.
Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) exert neurotrophic and neuroprotective effects in the CNS. We recently demonstrated that VEGF, EPO and their receptors (VEGF-R2, EPO-R) are expressed in phrenic motor neurons, and that cervical spinal VEGF-R2 and EPO-R activation elicit long-lasting phrenic motor facilitation (pMF). Since VEGF, VEGF-R, EPO, and EPO-R are hypoxia-regulated genes, and repetitive exposure to acute intermittent hypoxia (rAIH) up-regulates these molecules in phrenic motor neurons, we tested the hypothesis that 4 weeks of rAIH (10 episodes per day, 3 days per week) enhances VEGF- or EPO- induced pMF. We confirm that cervical spinal VEGF and EPO injections elicit pMF. However, neither VEGF- nor EPO-induced pMF was affected by rAIH pre-conditioning (4 wks). Although our data confirm that spinal VEGF and EPO may play an important role in respiratory plasticity, we provide no evidence that rAIH amplifies their impact. Further experiments with more robust protocols are warranted.
doi:10.1016/j.resp.2012.10.014
PMCID: PMC3832191  PMID: 23128070
VEGF; EPO; phrenic motor facilitation; intermittent hypoxia; respiratory plasticity; spinal cord

Results 1-25 (304)