-
[show abstract]
[hide abstract]
ABSTRACT: Mometasone furoate (MF)/formoterol fumarate (F) combination is a new inhaIed corticosteroid/long-acting β₂-adrenergic agonist (ICS/LABA). The purpose of this study was to evaluate the effects of different dose combinations of MF/F on a variety of late-phase responses to aerosolized antigen challenge in ovalbumin sensitized Brown Norway rats. Late-phase responses were assessed by reductions in lung function, measured by forced vital capacity (FVC) and increased numbers of inflammatory cells and pro-inflammatory cytokines in the bronchoalveolar lavage (BAL) fluid of ovalbumin challenged rats. Intratracheal administration of MF/F 5 h before aerosolized ovalbumin challenge inhibited the increase in inflammatory cells, including eosinophils and levels of interleukin (IL)-4, IL-5, IL-13 and tumour necrosis factor-α (TNF-α) appearing in the bronchoalveolar lavage fluid 24 h after the antigen challenge. The combination index for inhibition of both inflammatory cells and cytokines was consistently <1 suggesting a synergistic interaction between MF and F. Intratracheal MF/F given 24 h after the aerosolized ovalbumin challenge reversed the reduction in FVC with statistically significant effects seen over a 24 h period after drug whereas MF and F alone reversed the antigen-induced reduction in FVC at selected times only. At 5 h after drug administration, when both MF and F were partially active, the combination index for MF/F was <1 suggesting a synergistic interaction between MF and F for reversal of the lung function. These results demonstrate that MF/F combination inhibits a variety of late-phase responses induced by allergen challenge and it is likely that MF/F will have a significant benefit in clinical asthma to suppress lung inflammation and improve lung function.
Pulmonary Pharmacology & Therapeutics 10/2010; 24(1):67-73. · 2.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The proximal and distal portions of the lungs may respond differently to antigen challenge and bronchodilator treatment. This difference may contribute to differences in actual and perceived efficacy of therapies. In this study we used the forced oscillation technique (FOT) to measure impedance in the pulmonary system and discern the effects of antigen challenge on proximal (large airway) and distal (small airway and lung parenchyma) portions of the lung. In addition we treated the animals with two i.m. injections of either a saline control or dexamethasone (0.5 mg/kg) 18 and 1 hour(s) before the antigen challenge. The FOT technique was used to measure indices of proximal airway status, Newtonian airway resistance (R(N)), and distal airway status, including tissue damping (G) and tissue elastance (H). Challenging the animals with Ascaris Suum antigen caused a significant increase in both the proximal and distal lung measures. Pretreatment with dexamethasone significantly reduced the peak increase in R(N) but not G or H. In addition, the area under the curve (AUC) of the FOT response over 60 minutes was significantly reduced for the R(N) but again, G and H were not significantly reduced. These data indicate that, using the FOT, we can dissociate the response of proximal and distal airways to an antigen challenge. Moreover, steroid pre-treatment can reduce the bronchoconstrictor response to inhaled antigen but this effect is primarily via effects on the proximal airways with little effect on the distal airways and parenchymal component of pulmonary impedance. These data may help to provide a mechanism for evaluation of novel therapies for small airway dysfunction.
Journal of Asthma 07/2008; 45(5):377-81. · 1.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Since sleep is known to influence respiratory activity we studied whether the sleep state would affect the complexity value of the respiratory network output. Specifically, we tested the hypothesis that the complexity values of the diaphragm EMG (EMGdia) activity would be lower during REM compared to NREM. Furthermore, since REM is primarily generated by a homogeneous population of neurons in the medulla, the possibility that REM-related respiratory output would be less complex than that of the awake state was also considered. Additionally, in order to examine the influence of neuron vulnerabilities within the rostral ventral medulla (RVM) on the complexity of the respiratory network output, we inhibited respiratory neurons in the RVM by microdialysis of GABA(A) receptor agonist muscimol. Diaphragm EMG, nuchal EMG, EEG, EOG as well as other physiological signals (tracheal pressure, blood pressure and respiratory volume) were recorded from five unanesthetized chronically instrumented intact piglets (3-10 days old). Complexity of the diaphragm EMG (EMGdia) signal during wakefulness, NREM and REM was evaluated using the approximate entropy method (ApEn). ApEn values of the EMGdia during NREM and REM sleep were found significantly (p < 0.05 and p < 0.001, respectively) lower than those of awake EMGdia after muscimol inhibition. In the absence of muscimol, only the differences between REM and wakefulness ApEn values were found to be significantly different.
Journal of Neural Engineering 07/2008; 5(2):254-61. · 3.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The laryngeal chemoreflex exists in infants as a primary sensory mechanism for defending the airway from the aspiration of liquids. Previous studies have hypothesized that prolonged apnea associated with this reflex may be life threatening and might be a cause of sudden infant death syndrome.
In this study we quantified the output of the respiratory neural network, the diaphragm EMG signal, during the laryngeal chemoreflex and eupnea in early postnatal (3-10 days) piglets. We tested the hypothesis that diaphragm EMG activity corresponding to reflex-related events involved in clearance (restorative) mechanisms such as cough and swallow exhibit lower complexity, suggesting that a synchronized homogeneous group of neurons in the central respiratory network are active during these events. Nonlinear dynamic analysis was performed using the approximate entropy to asses the complexity of respiratory patterns.
Diaphragm EMG, genioglossal activity EMG, as well as other physiological signals (tracheal pressure, blood pressure and respiratory volume) were recorded from 5 unanesthetized chronically instrumented intact piglets. Approximate entropy values of the EMG during cough and swallow were found significantly (p < 0.05 and p < 0.01 respectively) lower than those of eupneic EMG.
Reduced complexity values of the respiratory neural network output corresponding to coughs and swallows suggest synchronous neural activity of a homogeneous group of neurons. The higher complexity values exhibited by eupneic respiratory activity are the result of a more random behaviour, which is the outcome of the integrated action of several groups of neurons involved in the respiratory neural network.
Journal of NeuroEngineering and Rehabilitation 02/2008; 5:17. · 3.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Inhibition of neurones in the ventral medulla accentuates the respiratory inhibition associated with acute blood pressure elevation in piglets. Activation of presynaptic 5-HT(1A) receptors inhibits serotonergic neurones in the ventral medulla and caudal raphé, and we tested the hypothesis that administration of 8-hydroxydipropylaminotetralin (8-OH-DPAT), a 5-HT(1A) agonist, within the rostroventral medulla and caudal raphé would enhance baroreceptor-mediated inhibition of respiratory activity in decerebrate, neonatal piglets. Baroreceptor stimulation was achieved by inflating a balloon in the distal aorta to elevate carotid blood pressure. After two to four control trials of baroreceptor stimulation, each piglet was given either a single intravenous (i.v.) dose of 10 microg kg(-1) 8-OH-DPAT or treated by adding 10 or 30 mm 8-OH-DPAT to the dialysate for approximately 10 min to inhibit serotonergic neurones, after which the baroreceptor stimulation trials were repeated. Baroreceptor stimulation reduced respiratory activity, particularly the respiratory frequency, which diminished from 35.7 +/- 3.3 to 33.8 +/- 3.1 breaths min(-1) (P < 0.02) and, following i.v. 8-OH-DPAT, baroreceptor-mediated inhibition of respiratory output was significantly accentuated (P < 0.05); the respiratory frequency declined from 34.5 +/- 3.6 to 26.5 +/- 2.9 breaths min(-1). Increasing aortic blood pressure reduced the respiratory frequency (P < 0.01), but focal dialysis of 10 or 30 mm 8-OH-DPAT had, on average, no effect on the ventilatory inhibition associated with an acute elevation of blood pressure. We conclude that activation of 5-HT(1A) receptors after systemic administration of 8-OH-DPAT enhanced baroreflex-mediated inhibition of ventilation, but this effect cannot be attributed to 5-HT(1A) receptor activation within the rostroventral medulla and caudal raphé.
Experimental Physiology 07/2007; 92(4):757-67. · 3.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We tested the hypothesis that inhibition of neurons within the rostral ventral medulla (RVM) would prolong the laryngeal chemoreflex (LCR), a putative stimulus in the sudden infant death syndrome (SIDS). We studied the LCR in 19 piglets, age 3-16 days, by injecting 0.05 ml of saline or water into the larynx during wakefulness, non-rapid eye movement (NREM) sleep, and REM sleep, before and after 1 or 10 mM muscimol dialysis in the RVM. Muscimol prolonged the LCR (P < 0.05), and the prolongation was greater when the LCR was stimulated with water compared with saline (P < 0.02). The LCR was longer during NREM sleep than during wakefulness and longest during REM sleep (REM compared with wakefulness). Muscimol had no effect on the likelihood of arousal from sleep after LCR stimulation. We conclude that the RVM provides a tonic facilitatory drive to ventilation that limits the duration of the LCR, and loss of this drive may contribute to the SIDS when combined with stimuli that inhibit respiration.
Journal of Applied Physiology 05/2003; 94(5):1883-95. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The rostral ventral medulla (RVM) may be important in the control of cardiorespiratory interactions. We hypothesized that inhibition of the RVM would enhance inhibition of breathing associated with transient blood pressure elevations. In 25 piglets 3-16 days of age, we studied the effect of acutely increasing blood pressure, by systemic infusion of phenylephrine, on respiratory activity before and after inhibition of neural activity in the RVM by dialysis of 10 mM muscimol, a GABA(A)-receptor agonist. Muscimol dialysis through probes that were placed along the ventral medullary surface from approximately 1 mm rostral to the facial nucleus to approximately 0.5 mm caudal to the facial nucleus augmented the respiratory inhibition associated with acute increases in blood pressure. No similar enhancement of respiratory inhibition after phenylephrine treatment was seen in six control animals that did not receive muscimol dialysis. We conclude that the piglet RVM participates in cardiorespiratory interactions and that dysfunction of homologous regions in the human infant could lead to cardiorespiratory instability and may be involved in the pathogenesis of sudden infant death syndrome.
Journal of Applied Physiology 07/2002; 92(6):2554-64. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Microdialysis is a technique used to study the extracellular environment or to deliver minute quantities of drugs into the central nervous system and other tissues in physiological experiments. It may have an expanding role in clinical studies. It can be used to study the microenvironment or to study the systemic effects of extremely localized pharmacological interventions, without interpretation of the results being confounded by systemic distribution of circulating drug. Proper interpretation of experimental results, however, depends on precise histological localization of the site of microdialysis or microinjection. This paper describes a simple method using potassium permanganate in 1% filtered aqueous solution to mark the site of experimental microdialysis or microinjection in brain tissue. Potassium permanganate reacts with brain tissue to produce insoluble, tar-like organic manganese dioxide reaction products that make a more visible mark than staining with either 5% neutral red or 5% fast green. Subsequent tissue processing and histological staining with cresyl violet or hematoxylin, eosin, and Luxol fast blue did not obscure the mark. (The J Histotechnol 23:151, 2000)
Journal of histotechnology 05/2000; · 0.10 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Developmental abnormalities have been described in the arcuate nucleus of sudden infant death syndrome (SIDS) victims. The arcuate nucleus has putative homologues in chemosensitive areas of the ventral medulla in animals. We refer to some of these areas collectively as the rostral ventral medulla (RVM). In the RVM of decerebrate piglets 2–15 days of age, we studied the effects of electrolytic lesions (n=7) or microdialysis of muscimol (n=15), a GABAa receptor agonist, on ventilatory output and the response to hypercapnia. Lesions caused a 66.7±17.3% reduction in eupneic phrenic minute activity (MA) and abolished the response to hypercapnia. Muscimol dialysis caused a 32.4±10.4% reduction in MA with a significant downward displacement of the response to hypercapnia with no significant effect on the slope. We conclude that the piglet RVM contains neurons of vital importance in the maintenance of normal breathing and the response to systemic CO2. We hypothesize that dysfunction of homologous regions in the human infant could lead to impaired ability to respond to hypercapnia and could potentially be involved in the pathogenesis of SIDS.
Respiration Physiology.
