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1.  Dalhousie dyspnea and perceived exertion scales: psychophysical properties in children and adolescents 
Children and adolescents vary widely in their perception of, or capacity to rate, sensations during exercise using the Borg scale. We sought to measure sensory-perceptual responses obtained using Dalhousie Dyspnea and Perceived Exertion Scales in 79 pediatric subjects during maximal exercise challenge and to determine the psychophysical function relationship(s). Concurrent validity was assessed by canonical plots of mean ratings on either scale, which showed showing very good correlations for perceived leg exertion vs work, and dyspnea vs ventilation. Both scales yielded similar results with respect to goodness of fit regardless of whether data was fitted to a power or quadratic function provided a delay term was included. The quadratic model fixed the exponent of the power law at 2 but, unlike a power model, allowed characterization of individual responses that increased and then plateaued. Dalhousie Dyspnea and Perceived Exertion Scales offer an alternative to Borg scale during exercise in pediatric populations.
doi:10.1016/j.resp.2014.04.003
PMCID: PMC4116154  PMID: 24793132
adolescents; children; exercise; dyspnea; perceived exertion
2.  Foreword☆ 
doi:10.1016/j.resp.2013.07.012
PMCID: PMC4500530  PMID: 23876742
3.  CHRONOTROPIC INCOMPETENCE PREDICTS MORTALITY IN SEVERE OBSTRUCTIVE PULMONARY DISEASE 
We evaluated the prevalence of chronotropic incompetence (CI), a marker of autonomic dysfunction, and its prognostic value in patients with chronic obstructive pulmonary disease (COPD). We performed a retrospective analysis of 449 patients with severe COPD who underwent a cardiopulmonary exercise test, after excluding patients with lung volume reduction surgery, left ventricular dysfunction and those not in sinus rhythm. CI was defined as percent predicted heart rate reserve (%HRR). Events were defined as death or lung transplant during a median follow-up of 68 months. Median age was 61 years; median percent predicted forced expiratory volume in one second (%FEV1) of 25% and median %HRR of 33%. The hazard ratio for an event in the lowest quartile of %HRR, taking the highest quartile as reference, was of 3.2 (95% Confidence Interval: 2.1–4.8; p<0.001). In a multivariate regression model, %HRR was an independent predictor of events. In conclusion, CI was an independent and powerful outcome predictor in patients with severe COPD.
doi:10.1016/j.resp.2013.05.002
PMCID: PMC4495898  PMID: 23669496
Chronic obstructive pulmonary disease; Chronotropic incompetence; Heart rate reserve
4.  Postnatal development of eupneic ventilation and metabolism in rats chronically exposed to moderate hyperoxia 
Newborn rats chronically exposed to moderate hyperoxia (60% O2) exhibit abnormal respiratory control, including decreased eupneic ventilation. To further characterize this plasticity and explore its proximate mechanisms, rats were exposed to either 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until studied at 3 – 14 days of age (P3 – P14). Normoxic ventilation was reduced in Hyperoxia rats when studied at P3, P4, and P6-7 and this was reflected in diminished arterial O2 saturations; eupneic ventilation spontaneously recovered by P13-14 despite continuous hyperoxia, or within 24 h when Hyperoxia rats were returned to room air. Normoxic metabolism was also reduced in Hyperoxia rats but could be increased by raising inspired O2 levels (to 60% O2) or by uncoupling oxidative phosphorylation within the mitochondrion (2, 4-dinitrophenol). In contrast, moderate increases in inspired O2 had no effect on sustained ventilation which indicates that hypoventilation can be dissociated from hypometabolism. The ventilatory response to abrupt O2 inhalation was diminished in Hyperoxia rats at P4 and P6-7, consistent with smaller contributions of peripheral chemoreceptors to eupneic ventilation at these ages. Finally, the spontaneous respiratory rhythm generated in isolated brainstem-spinal cord preparations was significantly slower and more variable in P3-4 Hyperoxia rats than in age-matched Controls. We conclude that developmental hyperoxia impairs both peripheral and central components of eupneic ventilatory drive. Although developmental hyperoxia diminishes metabolism as well, this appears to be a regulated hypometabolism and contributes little to the observed changes in ventilation.
doi:10.1016/j.resp.2014.03.010
PMCID: PMC4066817  PMID: 24703970
developmental plasticity; control of breathing; hypometabolism; perinatal hyperoxia; brainstem-spinal cord preparation
5.  Breathing hot humid air induces airway irritation and cough in patients with allergic rhinitis 
We studied the respiratory responses to an increase in airway temperature in patients with allergic rhinitis (AR). Responses to isocapnic hyperventilation (40% of maximal voluntary ventilation) for 4 minutes of humidified hot air (HA; 49 °C) and room air (RA: 21 °C) were compared between AR patients (n=7) and healthy subjects (n=6). In AR patients, cough frequency increased pronouncedly from 0.10±0.07 before to 2.37±0.73 during, and 1.80±0.79 coughs/min for the first 8 minutes after the HA challenge, but not during the RA challenge. In contrast, neither HA nor RA had any significant tussive effect in healthy subjects. The HA challenge also caused respiratory discomfort (mainly throat irritation) measured by the handgrip dynamometry in AR patients, but not in healthy subjects. Bronchoconstriction was not detected after the HA challenge in either group of subjects. In conclusion, hyperventilation of HA triggered vigorous cough response and throat irritation in AR patients, indicating the involvement of sensory nerves innervating upper airways.
doi:10.1016/j.resp.2014.03.013
PMCID: PMC4104521  PMID: 24709444
cough; allergic rhinitis; airway irritation; TRPV1; laryngeal
6.  Role of chemoreceptors in mediating dyspnea 
Dyspnea, or the uncomfortable awareness of respiratory distress, is a common symptom experienced by most people at some point during their lifetime. It is commonly encountered in individuals with pulmonary disease, such as chronic obstructive pulmonary disease (COPD), but can also be seen in healthy individuals after strenuous exercise, at altitude or in response to psychological stress. Dyspnea is a multifactorial sensation involving the brainstem, cortex, and limbic system, as well as mechanoreceptors, irritant receptors and chemoreceptors. Chemoreceptors appear to contribute to the sensation of dyspnea in two ways. They stimulate the respiratory control system in response to hypoxia and/or hypercapnia, and the resultant increase respiratory motor output can be consciously perceived as unpleasant. They also can induce the sensation of dyspnea through an as yet undetermined mechanism–potentially via direct ascending connections to the limbic system and cortex. The goal of this article is to briefly review how changes in blood gases reach conscious awareness and how chemoreceptors are involved in dyspnea.
doi:10.1016/j.resp.2008.12.002
PMCID: PMC4486073  PMID: 19118647
Hypercapnia; Hypoxia; Serotonin; 5-HT; Raphe; Dyspnea; Chemoreceptors; Breathing
7.  Neither Serotonin nor Adenosine-dependent Mechanisms Preserve Ventilatory Capacity in ALS rats 
In rats over-expressing SOD1G93A, ventilation is preserved despite significant loss of respiratory motor neurons. Thus, unknown forms of compensatory respiratory plasticity may offset respiratory motor neuron cell death. Although mechanisms of such compensation are unknown, other models of respiratory motor plasticity may provide a conceptual guide. Multiple cellular mechanisms give rise to phrenic motor facilitation; one mechanism requires spinal serotonin receptor and NADPH oxidase activity whereas another requires spinal adenosine receptor activation. Here, we studied whether these mechanisms contribute to compensatory respiratory plasticity in SOD1G93A rats. Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: 1) serotonin depletion with parachlorophenylalanine (PCPA), 2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, 3) NADPH oxidase inhibition (apocynin), and 4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. Possible mechanisms giving rise to enhanced breathing capacity with combined treatment in end-stage SOD1G93A rats are discussed.
doi:10.1016/j.resp.2014.03.005
PMCID: PMC4022482  PMID: 24681328
plethysmography; compensatory plasticity; respiration; facilitation
8.  Sudden unexpected death in epilepsy: Fatal post-ictal respiratory and arousal mechanisms 
Sudden unexplained death in epilepsy (SUDEP) is the cause of premature death of up to 17% of all patients with epilepsy and as many as 50% with chronic refractory epilepsy. However, SUDEP is not widely recognized to exist. The etiology of SUDEP remains unclear, but growing evidence points to peri-ictal respiratory, cardiac, or autonomic nervous system dysfunction. How seizures affect these systems remains uncertain. Here we focus on respiratory mechanisms believed to underlie SUDEP. We highlight clinical evidence that indicates peri-ictal hypoxemia occurs in a large percentage of patients due to central apnea, and identify the proposed anatomical regions of the brain governing these responses. In addition, we discuss animal models used to study peri-ictal respiratory depression. We highlight the role 5-HT neurons play in respiratory control, chemoreception, and arousal. Finally, we discuss the evidence that 5-HT deficits contribute to SUDEP and sudden infant death syndrome and the striking similarities between the two.
doi:10.1016/j.resp.2013.05.010
PMCID: PMC4467545  PMID: 23707877
9.  Morphological differences of the carotid body among C57/BL6 (B6), A/J, and CSS B6A1 mouse strains 
The C57/BL6 (B6) mouse strain exhibits post-hypoxic frequency decline and periodic breathing, as well as greater amount of irregular breathing during rest in comparison to the A/J and to the B6a1, a chromosomal substitution strain whereby the A/J chromosome 1 is bred onto the B6 background (Han et al., 2002; Yamauchi et al., 2008a,b). The hypothesis was that morphological differences in the carotid body would associate with such trait variations. After confirming strain differences in post-hypoxic ventilatory behavior, histological examination (n = 8 in each group) using hematoxylin and eosin (H&E) staining revealed equivalent, well-defined tissue structure at the bifurcation of the carotid arteries, an active secretory parenchyma (type I cells) from the supportive stromal tissue, and clustering of type I cells in all three strains. Tyrosine hydroxylase (TH) immunohistochemical staining revealed a typical organization of type I cells and neurovascular components into glomeruli in all three strains. Image analysis from 5 μm sections from each strain generated a series of cytological metrics. The percent carotid body composition of TH+ type I cells in the A/J, B6 and B6a1 was 20 ± 4%, 39 ± 3%, and 44 ± 3%, respectively (p = 0.00004). However, cellular organization in terms of density and ultrastructure in the B6a1 is more similar to the B6 than to the A/J. These findings indicate that genetic mechanisms that produce strain differences in ventilatory function do not associate with carotid body structure or tyrosine hydroxylase morphology, and that A/J chromosome 1 does not contribute much to B6 carotid body morphology.
doi:10.1016/j.resp.2011.04.021
PMCID: PMC4455900  PMID: 21555000
Hypoxia; Carotid body; Murine breathing; Type I cell; Chromosomal substitution strain
10.  Co-activation of μ- and δ-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite 
We determined whether pretreatment with (1) the μ-/δ-opioid receptor (μ-/δ-OR) antagonist, naloxone, (2) the δ1,2-OR antagonist, naltrindole, or (3) the peroxynitrite scavenger, D-penicillamine, affects the development of tolerance to the ventilatory depressant effects of morphine in rats. The injection of morphine in vehicle-pretreated rats decreased minute ventilation predominantly via decreases in tidal volume. Pretreatment with naloxone blunted the responses to morphine whereas pretreatment with naltrindole or D-penicillamine did not. A second injection of morphine, given one day later, elicited markedly smaller responses in vehicle rats whereas it elicited pronounced ventilatory depression in rats that were pretreated with naloxone, naltrindole or D-penicillamine (prior to morphine) the day before. Moreover, the ventilatory responses elicited by subsequent exposure to a hypoxic-hypercapnic challenge were markedly depressed in naloxone- or D-penicillamine-pretreated rats compared to vehicle-pretreated rats. These findings suggest that activation of μ- and δ-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite.
doi:10.1016/j.resp.2013.02.028
PMCID: PMC4451624  PMID: 23473921
morphine; ventilatory depression; tolerance; opiate receptors; peroxynitrite; rats
11.  β-hydroxy-β-methylbutyrate (HMB) Prevents Sepsis-Induced Diaphragm Dysfunction in Mice 
Infections induce severe respiratory muscle weakness. Currently there are no treatments for this important clinical problem. We tested the hypothesis that β-hydroxy-β-methylbutyrate (HMB) would prevent sepsis-induced diaphragm weakness. Four groups of adult male mice were studied: controls (saline-injected), sepsis (intraperitoneal lipopolysaccharide), sepsis+HMB (injected intravenously), and HMB. Diaphragm force generation and indices of caspase 3, calpain, 20S proteasomal subunit, and double-stranded RNA-dependent protein kinase (PKR) activation were assessed after 24 hours. Sepsis elicited large reductions in diaphragm specific force generation at all stimulation frequencies. Endotoxin also activated caspase 3, calpain, the 20S proteasomal subunit and PKR in the diaphragm. HMB blocked sepsis-induced caspase 3, 20S proteasomal and PKR activation, but did not prevent calpain activation. Most importantly, HMB administration significantly attenuated sepsis-induced diaphragm weakness, preserving muscle force generation at all stimulation frequencies (p<0.01). We speculate that HMB may prove to be an important therapy in infected patients, with the potential to increase diaphragm strength, to reduce the duration of mechanical ventilation and to decrease mortality in this patient population
doi:10.1016/j.resp.2014.02.015
PMCID: PMC4049168  PMID: 24632527
Diaphragm; sepsis; caspase 3; PKR; β-hydroxy-β-methylbutyrate (HMB); proteolysis
12.  Expression of neuronal nicotinic acetylcholine receptors in rat vagal pulmonary sensory neurons 
It has been known that cigarette smoke inhalation causes airway irritation and cough, and the effect is caused by both direct and indirect stimulatory effects of nicotine on bronchopulmonary sensory nerves. However, little is known about the expression of nicotinic acetylcholine receptors (nAChRs) in these afferents. In the present study, whole-cell patch-clamp recording and RT-PCR were carried out to examine the expression and function of nAChRs in isolated rat vagal pulmonary sensory neurons that were identified by retrograde labeling with a fluorescent tracer. Patch-clamp recordings demonstrated that application of acetylcholine concentration-dependently evoked an inward current in a subset of pulmonary sensory neurons, which was inhibited by hexamethonium. Application of nicotine or 1,1-dimethyl-4-phenylpiperazinium (DMPP) also activated these neurons, evoking an inward current in voltage-clamp configuration and causing depolarization and action potential in current-clamp recordings. RT-PCR analysis further demonstrated the expression of mRNA encoding for the nAChR subunits α4, α5, α6, α7, β2, β3 and β4, but not α2 and α3 in these neurons.
doi:10.1016/j.resp.2007.11.006
PMCID: PMC4445079  PMID: 18206429
nicotinic acetylcholine receptor; pulmonary sensory neuron; airway irritation; cough
13.  Prostaglandin E2 Enhances the Sensitizing Effect of Hyperthermia on Pulmonary C Fibers in Rats 
This study was carried out to investigate whether the pulmonary C-fiber hypersensitivity induced by hyperthermia is altered by prostaglandin E2 (PGE2). Single-unit afferent activities of pulmonary C-fibers were recorded in anesthetized, artificially ventilated rats when the intrathoracic temperature (Tit) was maintained at normal (N; ~36°C) and hyperthermia levels (H; ~41°C) by perfusion of heated saline into the thoracic chamber for 3 min. After ~20 min of recovery, the fiber activities were recorded again during infusion of PGE2 at both N and H levels of Tit. Our study showed: 1) The baseline fiber activity and responses to lung inflation, right atrial injection of capsaicin and adenosine were all increased by increasing Tit from N to H, and these hyperthermia-induced increases in sensitivities were also significantly augmented by PGE2. 2) These enhanced sensitivities induced by PGE2 were abolished by pretreatment with AH6809 and AH23848, selective antagonists of EP2 and EP4 prostanoid receptors, respectively. In conclusion, the hyperthermia-induced hypersensitivity of vagal pulmonary C-fibers is potentiated by PGE2, and this effect is mediated through activation of EP2 and EP4 prostanoid receptors.
doi:10.1016/j.resp.2006.11.003
PMCID: PMC4445127  PMID: 17161661
Prostaglandin E2; Hyperthermia; Pulmonary C fibers; Airway inflammation
14.  L-Cysteine ethyl ester reverses the deleterious effects of morphine on arterial blood-gas chemistry in tracheotomized rats 
Summary
This study determined whether the membrane-permeable ventilatory stimulant, L-cysteine ethylester (L-CYSee), reversed the deleterious actions of morphine on arterial blood-gas chemistry in isoflurane-anesthetized rats. Morphine (2 mg/kg, i.v.) elicited sustained decreases in arterial blood pH, pO2 and sO2, and increases in pCO2 (all responses indicative of hypoventilation) and Alveolar-arterial gradient (indicative of ventilation-perfusion mismatch). Injections of L-CYSee (100 μmol/kg, i.v.) reversed the effects of morphine in tracheotomized rats but were minimally active in non-tracheotomized rats. L-cysteine or L-serine ethylester (100 μmol/kg, i.v.) were without effect. It is evident that L-CYSee can reverse the negative effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient but that this positive activity is negated by increases in upper-airway resistance. Since L-cysteine and L-serine ethylester were ineffective, it is evident that cell penetrability and the sulfur moiety of L-CYSee are essential for activity. Due to its ready penetrability into the lungs, chest wall muscle and brain, the effects of L-CYSee on morphine-induced changes in arterial blood-gas chemistry are likely to involve both central and peripheral sites of action.
doi:10.1016/j.resp.2013.07.007
PMCID: PMC4430552  PMID: 23892097
morphine; L-cysteine ethylester; arterial blood-gas chemistry; halothane-anesthetized rats
15.  Effects of modulators of AMP-activated protein kinase on TASK-1/3 and intracellular Ca2+ concentration in rat carotid body glomus cells 
Acute hypoxia depolarizes carotid body chemoreceptor (glomus) cells and elevates intracellular Ca2+ concentration ([Ca2+]i). Recent studies suggest that AMP-activated protein kinase (AMPK) mediates these effects of hypoxia by inhibiting the background K+ channels such as TASK. Here we studied the effects of modulators of AMPK on TASK activity in cell-attached patches. Activators of AMPK (1 mM AICAR and 0.1–0.5 mM A769662) did not inhibit TASK activity or cause depolarization during acute (10 min) or prolonged (2–3 hr) exposure. Hypoxia inhibited TASK activity by ~70% in cells pretreated with AICAR or A769662. Both AICAR and A769662 (15–40 min) failed to increase [Ca2+]i in glomus cells. Compound C (40 µM), an inhibitor of AMPK, showed no effect on hypoxia-induced inhibition of TASK. AICAR and A769662 phosphorylated AMPKα in PC12 cells, and Compound C blocked the phosphorylation. Our results suggest that AMPK does not affect TASK activity and is not involved in hypoxia-induced elevation of intracellular [Ca2+] in isolated rat carotid body glomus cells.
doi:10.1016/j.resp.2014.01.020
PMCID: PMC3998119  PMID: 24530802
Hypoxia; Carotid body; Chemoreceptors; AMP kinase; Background K+ channels
16.  Serotonin transporter null male mouse pups have lower ventilation in air and 5% CO2 at postnatal ages P15 and P25 
In Wild Type (WT) and serotonin transporter (5HTT) null mice, we studied oxygen consumption, ventilation and heart rate in air and 5% CO2 at postnatal (P) days P5, P15, and P25 using either a head-out (younger mice) or whole body plethysmograph (older mice). Body weight and temperature did not differ between the groups. Oxygen consumption differed significantly only in females at P15 when it was reduced in 5HTT nulls (P < 0.01). Heart rate similarly differed only in female 5HTT nulls at P15 being decreased in both air and CO2 (P < 0.01). Ventilation in air and 5% CO2 was significant reduced via an effect on tidal volume at P15 (P < 0.02) and P25 (P < 0.05) but only in males. Ventilation in air and 5% CO2 was greater in 5HTT null females at P25. We conclude that the gender specific effect (male predominant) on the CO2 response reported in 5HTT null adult mice (Li and Nattie, 2008, J. Physiol. 586.9, 2321–2329, 2008) appears to have origins in early postnatal life (P15) when ventilation in both air and 5% CO2 is reduced.
doi:10.1016/j.resp.2011.02.006
PMCID: PMC4394861  PMID: 21333760
17.  Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats 
This study determined the effects of the peripherally restricted µ-opiate receptor (µ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25 µg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5 mg/kg of NLXmi but was attenuated by a 5.0 mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5 mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5 mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral µ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient.
doi:10.1016/j.resp.2013.11.005
PMCID: PMC4391496  PMID: 24284037
Fentanyl; Naloxone methiodide; Ventilation; Arterial blood gases; Analgesia; Rats
18.  Carotid chemoafferent activity is not necessary for all phrenic long-term facilitation following acute intermittent hypoxia 
Phrenic long-term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH) or episodic carotid chemoafferent neuron activation. Surprisingly, residual pLTF is expressed in carotid denervated rats. However, since carotid denervation eliminates baroreceptor feedback and causes profound hypotension during hypoxia in anesthetized rats, potential contributions of these uncontrolled factors or residual chemoafferent neuron activity to residual pLTF cannot be ruled out. Since ATP is necessary for hypoxic carotid chemotransduction, we tested the hypothesis that functional peripheral chemoreceptor denervation (with intact baroreceptors) via systemic P2X receptor antagonism blocks hypoxic phrenic responses and AIH-induced pLTF in anesthetized rats. Pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 100 mg/kg i.v.), a non-selective P2X receptor antagonist, was administered to anesthetized, vagotomized, paralyzed and ventilated male Sprague–Dawley rats prior to AIH (3, 5 min episodes of 10% O2; 5 min intervals). Although PPADS strongly attenuated the short-term hypoxic phrenic response (20±4% vs. 113±15% baseline; P < 0.001), pLTF was reduced but not eliminated 60 min post-AIH (25±4% vs. 51±11% baseline; n = 8 and 7, respectively; P < 0.002). Thus, AIH initiates residual pLTF out of proportion to the diminished hypoxic phrenic response and chemoafferent neuron activation. Although the mechanism of residual pLTF following functional chemo-denervation remains unclear, possible mechanisms involving direct effects of hypoxia on the CNS are discussed.
doi:10.1016/j.resp.2010.11.006
PMCID: PMC4374991  PMID: 21093615
Long-term facilitation; Intermittent hypoxia; PPADS; ATP receptor; Carotid chemoreceptor; Plasticity; Motor neuron
19.  Ventilatory Control in ALS 
Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease. ALS selectively causes degeneration in upper and lower (spinal) motor neurons, leading to muscle weakness, paralysis and death by ventilatory failure. Although ventilatory failure is generally the cause of death in ALS, little is known concerning the impact of this disorder on respiratory motor neurons, the consequences of respiratory motor neuron cell death, or the ability of the respiratory control system to “fight back” via mechanisms of compensatory respiratory plasticity. Here we review known effects of ALS on breathing, including possible effects on rhythm generation, respiratory motor neurons, and their target organs: the respiratory muscles. We consider evidence for spontaneous compensatory plasticity, preserving breathing well into disease progression despite dramatic loss of spinal respiratory motor neurons. Finally, we review current and potential therapeutic approaches directed toward preserving the capacity to breathe in ALS patients.
doi:10.1016/j.resp.2013.05.016
PMCID: PMC4361018  PMID: 23692930
breathing; neurodegenerative disease; motor neuron disease; compensation; plasticity; ventilatory control
20.  On locating the obstruction in the upper airway via numerical simulation 
The fluid dynamical properties of the air flow in the upper airway (UA) are not fully understood at present due to the three-dimensional (3D) patient-specific complex geometry of the airway, flow transition from laminar to turbulent and flow-structure interaction during the breathing cycle. It is quite difficult at present to experimentally measure the instantaneous velocity and pressure at specific points in the human airway. On the other hand, direct numerical simulation (DNS) can predict all the flow properties and resolve all its relevant length- and time-scales. We developed a DNS solver with the state-of-the-art lattice Boltzmann method (LBM), and used it to investigate the flow in two patient-specific UAs reconstructed from CT scan data. Inspiration and expiration flows through these two airways are studied. The time-averaged first spatial derivative of pressure (pressure gradient), ∂p/∂z, is used to locate the region of the UA obstruction. But the time-averaged second spatial derivative, ∂2p/∂z2, is used to pinpoint the exact location of the obstruction. The present results show that the DNS-LBM solver can be used to obtain accurate flow details in the UA and is a powerful tool to locate its obstruction.
doi:10.1016/j.resp.2013.12.009
PMCID: PMC4037816  PMID: 24389271
Upper airway; Obstruction; Lattice Boltzmann; Direct numerical simulation; Turbulent; First derivative; Second derivative
21.  Subjective evaluation of experimental dyspnoea – Effects of isocapnia and repeated exposure 
Highlights
•Functional neuroimaging is poised to understand brain processing of dyspnoea.•Experimental dyspnoea alters PaCO2, which confounds FMRI contrast.•Experimentally stabilizing CO2 had minimal effects on perception of respiratory loads.•No perceptual habituation to resistive loads occurred over four experimental sessions.
Resistive respiratory loading is an established stimulus for the induction of experimental dyspnoea. In comparison to unloaded breathing, resistive loaded breathing alters end-tidal CO2 (PETCO2), which has independent physiological effects (e.g. upon cerebral blood flow). We investigated the subjective effects of resistive loaded breathing with stabilized PETCO2 (isocapnia) during manual control of inspired gases on varying baseline levels of mild hypercapnia (increased PETCO2). Furthermore, to investigate whether perceptual habituation to dyspnoea stimuli occurs, the study was repeated over four experimental sessions. Isocapnic hypercapnia did not affect dyspnoea unpleasantness during resistive loading. A post hoc analysis revealed a small increase of respiratory unpleasantness during unloaded breathing at +0.6 kPa, the level that reliably induced isocapnia. We did not observe perceptual habituation over the four sessions. We conclude that isocapnic respiratory loading allows stable induction of respiratory unpleasantness, making it a good stimulus for multi-session studies of dyspnoea.
doi:10.1016/j.resp.2014.12.019
PMCID: PMC4347539  PMID: 25578628
Dyspnoea; FMRI; Habituation; Isocapnia; Perception; Respiratory loading
22.  Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column 
Reverse dialysis of the muscarinic receptor antagonist, atropine (ATR, 50 mM), into the pre-Bötzinger Complex region of the ventral respiratory column (VRC) of awake and sleeping goats increases breathing frequency and serotonin (5-HT), substance P (SP), glycine, and GABA concentrations in the effluent dialysate. Herein, we report data from goats in which we reverse dialyzed 5 mM ATR or specific antagonists of M2 or M3 muscarinic receptors into the VRC. The effects on frequency of all three antagonists were not significantly different from time control studies. 5 mM ATR and the M3 antagonist increased SP seven-fold less than 50 mM ATR. The antagonists had no effect on 5-HT, glycine, and/or GABA, suggesting that the increases in glycine and GABA with 50 mM ATR were secondary to the larger increases in 5-HT and/or SP. These data are suggestive of neuromodulator interdependence, whereby attenuation of one neuromodulator is compensated for by local changes in other neuromodulators to stabilize breathing.
doi:10.1016/j.resp.2014.09.010
PMCID: PMC4341919  PMID: 25262584
neuromodulator interdependence; muscarinic receptor; control of breathing
23.  Contributions of the Kölliker–Fuse nucleus to coordination of breathing and swallowing 
Herein we compare the effects of perturbations in the Kölliker–Fuse nucleus (KFN) and the lateral (LPBN) and medial (MPBN) parabrachial nuclei on the coordination of breathing and swallowing. Cannula was chronically implanted in goats through which ibotenic acid (IA) was injected while awake. Swallows in late expiration (E) always reset while swallows in early inspiration (I) never reset the respiratory rhythm. Before cannula implantation, all other E and I swallows did not reset the respiratory rhythm, and had small effects on E and I duration and tidal volume (VT). However, after cannula implantation in the MPBN and KFN, E and I swallows reset the respiratory rhythm and increased the effects on I and E duration and VT. Subsequent injection of IA into the KFN eliminated the respiratory phase resetting of swallows but exacerbated the effects on I and E duration and VT. We conclude that the KFN and to a lesser extent the MPBN contribute to coordination of breathing and swallowing.
doi:10.1016/j.resp.2013.06.003
PMCID: PMC4338573  PMID: 23774145
24.  Clinical consequences of altered chemoreflex control 
Control of ventilation dictates various breathing patterns. The respiratory control system consists of a central pattern generator and several feedback mechanisms that act to maintain ventilation at optimal levels. The concept of loop gain has been employed to describe its stability and variability. Synthesizing all interactions under a general model that could account for every behavior has been challenging. Recent insight into the importance of these feedback systems may unveil therapeutic strategies for common ventilatory disturbances. In this review we will address the major mechanisms that have been proposed as mediators of some of the breathing patterns in health and disease that have raised controversies and discussion on ventilatory control over the years.
doi:10.1016/j.resp.2013.04.020
PMCID: PMC4336771  PMID: 23681082
Exercise hyperpnea; High altitude; Sleep apnea; Loop gain; Cheyne–Stokes; Oxygen induced hypercapnia; Lung
25.  Effect of oxygen in obstructive sleep apnea: Role of loop gain 
We compared the effect of oxygen on the apnea-hypopnea index (AHI) in 6 obstructive sleep apnea patients with a relatively high loop gain (LG) and 6 with a low LG. LG is a measure of ventilatory control stability. In the high LG group (unstable ventilatory control system), oxygen reduced the LG from 0.69 ± 0.18 to 0.34 ± 0.04 (p < 0.001) and lowered the AHI by 53 ± 33 percent (p = 0.04 compared to the percent reduction in the low LG group). In the low LG group (stable ventilatory control system), oxygen had no effect on LG (0.24 ± 0.04 on room air, 0.29 ± 0.07 on oxygen, p = 0.73) and very little effect on AHI (8 ± 27 percent reduction with oxygen). These data suggest that ventilatory instability is an important mechanism causing obstructive sleep apnea in some patients (those with a relatively high LG), since lowering LG with oxygen in these patients significantly reduces AHI.
doi:10.1016/j.resp.2008.05.019
PMCID: PMC4332598  PMID: 18577470

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