Respiratory Physiology & Neurobiology

Published by Elsevier BV

Print ISSN: 1569-9048


Figure 1. Breathing behavior is compromised in Pet-1 −/− mice during the early postnatal period. (A) Plethysmographic recordings of resting ventilation in wild-type (+/+) and Pet-1 null (−/−) mice made within 12 hrs of birth (P0.5) and on postnatal day 4.5 (P4.5) while breathing 21% O 2 . The −/− recordings reflect the finding that the prolonged respiratory pauses occurred predominantly during inspiration. (B,C) Comparison of the incidence of prolonged (≥1 sec duration) respiratory pauses in wild type (+/+) and Pet-1 mutant (−/−) mice on the day of birth (B; +/+, 4.7 ± 0.78/min, n = 13 vs −/−, 8.5 ± 4.1/min, n = 13, P=0.0114) and on postnatal day 4.5 (C; +/+, 0.27 ± 0.13/min, n = 19 vs −/−, 0.88 ± 0.27/min, n = 10, P=0.0288). Values are means ± SE. *P<0.05. Scale bars: horizontal, 2 sec; vertical, 50 μL.
Fig. 2. Comparison of mean inspiratory (T I ) and expiratory (T E ) time, breathing frequency (f) and the coefficients of variation (CV = S.D./mean × 100) of these parameters, respectively, on the day of birth (P0.5; A-C) and on postnatal day 4.5 (D-F). Values are means ± S.D. * P < 0.05; ** P < 0.01. See Table 2A and B for sample sizes and P values.
Figure 3. Breathing deficits improve in Pet-1 −/− mice with increasing postnatal age. (A) Plethysmographic recordings of resting ventilation in a wild type (+/+) and Pet-1 mutant (−/ −) mouse breathing 21% O 2 on postnatal day 9.5. Recordings are from the same P4.5 animals presented in Fig. 1. (B,C,D) Comparison of mean inspiratory (T I ) and expiratory (T E ) time (B), breathing frequency (f; panel C), and the coefficients of variation (CV=SD/mean x 100) of these parameters (D) between genotypes on P9.5. At this age prolonged respiratory pauses were rarely seen in the serotonin-deficient mice. Values are means ± SD. *P<0.05; **P<0.01. See Table 2C for sample sizes and P values.
Figure 4. Disorder of central respiratory rhythm may contribute to the breathing deficits of Pet-1 null mutant mice. (A) In vitro recording arrangement. Output from the central respiratory rhythm generator was assessed via recordings from hypoglossal nerve (nXII) rootlets arising from neurons in the hypoglossal nucleus (XII). (B) XII th nerve recordings from wild type (+/+, left panel) and Pet-1 −/− (−/−, right panel) medullary slices at two different levels of extracellular potassium (5 and 8 mM K + ). No significant differences in either burst duration or burst area were detected. Above each set of recordings are representative Poincaré plots (see Materials and Methods) of interburst intervals (analogous to T E in vivo) derived from recordings in +/+ and −/− slices at 8 mM K + . Each cross (+) represents a single nerve discharge. If interburst intervals were identical for every fictive breath, the graph would reduce to a single point representing that identical time between two discharges. (C) Comparison of mean interburst interval of XII th nerve discharges from +/+ and −/− brainstem slices exposed to either 5 or 8 mM potassium. (D) Comparison of interval entropy values derived from XII th nerve discharges in +/+ and −/−brainstem slices exposed to two different levels of extracellular potassium. For both panels (C) and (D): +/+: n=13 at 5 mM, n=19 at 8 mM; −/−: n=13 at 5 mM, n=15 at 8 mM. All values are means ± SD. *P<0.05.
Fig. 5. The severity of breathing abnormalities in Pet-1 −/− mice can be influenced by environmental conditions. (A-C) Comparison of inspiratory (T I ) and expiratory (T E ) time (A), breathing frequency (B) and the coefficients of variation of these ventilatory parameters (C) in P4.5 wild type (+/+, dark bars) and Pet-1 null mutant (−/−, light bars) mice reared in either a pathogen-exposed (PE) or pathogen-free (PF) environment. (D-F) Direct comparison of inspiratory (T I ) and expiratory (T E ) time (D), breathing frequency (E) and the coefficients of variation of these ventilatory parameters (F) in P4.5 +/+ mice from the PE and PF colonies. (G-I) Direct comparison of inspiratory (T I ) and expiratory (T E ) time (G), breathing frequency (H) and the coefficients of variation of these ventilatory parameters (I) in P4.5 Pet-1 −/− mice from the PE and PF colonies. (J) Pet-1 −/− mice from the PF colony also suffered an increased incidence of prolonged respiratory pauses, relative to wild type littermates (compare with Fig. 1C). Values are means ± S.D. * P < 0.05; ** P < 0.01. See Tables 2B and 3 for sample sizes and P values.


Erickson JT, Shafer G, Rossetti MD, Wilson CG, Deneris ES. Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges. Respir Physiol Neurobiol 159: 85-101
  • Article
  • Full-text available

November 2007


114 Reads


Geoffrey Shafer


Michael D Rossetti




Evan S Deneris
Serotonin (5HT) is a powerful modulator of respiratory circuitry in vitro but its role in the development of breathing behavior in vivo is poorly understood. Here we show, using 5HT neuron-deficient Pet-1 (Pet-1(-/-)) neonates, that serotonergic function is required for the normal timing of postnatal respiratory maturation. Plethysmographic recordings reveal that Pet-1(-/-) mice are born with a depressed breathing frequency and a higher incidence of spontaneous and prolonged respiratory pauses relative to wild type littermates. The wild type breathing pattern stabilizes by postnatal day 4.5, while breathing remains depressed, highly irregular and interrupted more frequently by respiratory pauses in Pet-1(-/-) mice. Analysis of in vitro hypoglossal nerve discharge indicates that instabilities in the central respiratory rhythm generator contribute to the abnormal Pet-1(-/-) breathing behavior. In addition, the breathing pattern in Pet-1(-/-) neonates is susceptible to environmental conditions, and can be further destabilized by brief exposure to hypoxia. By postnatal day 9.5, however, breathing frequency in Pet-1(-/-) animals is only slightly depressed compared to wild type, and prolonged respiratory pauses are rare, indicating that the abnormalities seen earlier in the Pet-1(-/-) mice are transient. Our findings provide unexpected insight into the development of breathing behavior by demonstrating that defects in 5HT neuron development can extend and exacerbate the period of breathing instability that occurs immediately after birth during which respiratory homeostasis is vulnerable to environmental challenges.

Phorbol 12,13-dibutyrate-mediated contraction of the stimulated bronchial smooth muscles of mice

September 2010


23 Reads

Increasing evidence suggests that protein kinase C (PKC) is involved in the Ca(2+) sensitization of various smooth muscle contractions. However, the exact role of PKC on bronchial smooth muscle (BSM) contraction is still unclear. In the present study, to determine the role of PKC activation in the BSM contraction, the effects of phorbol 12,13-dibutyrate (PDBu) on BSM tone were examined in the absence and presence of contractile stimulation. Although PDBu had no effect on the basal tone, the contraction induced by acetylcholine, high K(+) depolarization or Ca(2+) ionophore A23187 was significantly augmented by PDBu. Western blot analyses also revealed that the increase in the level of phosphorylated myosin light chain (MLC) induced by high K(+) depolarization was significantly augmented by PDBu treatment. Interestingly, neither high K(+) depolarization alone nor PDBu alone caused CPI-17 phosphorylation, but a significant phosphorylation of CPI-17 was observed when BSMs were co-stimulated by high K(+) and PDBu. Thus, a certain level of intracellular Ca(2+) might be needed both for an activation of CPI-17 and an induction of contraction induced by PDBu in mouse BSMs.

Priming of Beta-2agonist and antimuscarinic induced physiological responses induced by 1200mg/day NAC in moderate to severe COPD patients: A pilot study.

November 2013


49 Reads

This study evaluated antioxidant modulations of lung physiological-responses to beta-2-agonist and antimuscarinic bronchodilators with 1200mg/day n-acetyl-cysteine (NAC) in a placebo-controlled, randomised, double-blind, parallel-group study, in moderate-very severe COPD patients. 15 COPD patients received NAC treatment, while 9 COPD patients received placebo treatment, for 15 days. Pre-and-post salbutamol and ipratopium-bromide lung-physiology responses were measured using body-plethysmography, Impulse-oscillometry (IOS) and spirometry before-and-after study treatments. Compared to pre-treatment, the NAC-treatment significantly enhanced the potential of Ipratopium-bromide to reduce functional-residual-capacity (FRC) by nearly 3-folds (mean% FRC-response: pre-NAC: -5.51%±10.42% versus post-NAC: -17.89%±12.94%, p=0.02; mean-absolute FRC-response: pre-NAC: -300ml±450ml versus post-NAC:-770ml±550ml, p=0.02), which was superior to placebo-treatment. The increase in total-lung-capacity response to ipratopium-bromide, although insignificant, was superior with post-NAC treatment versus post-placebo treatment (p=0.049). The salbutamol-response remained unaltered with either treatment. The treatment with 1200mg/day NAC has potential to enhance the bronchodilator ability of antimuscarinic-agents but not beta-2-agonist. However, its clinical application has to be established in large sample-size studies for longer-duration.

Do genes on rat chromosomes 9, 13, 16, 18, and 20 contribute to regulation of breathing?

May 2003


46 Reads

As part of a large scale, high through-put physiologic genomics study, we sought to determine whether genes on rat chromosomes 9, 13, 16, 18, and 20 contribute to phenotypic differences in the control of breathing between two inbred rat strains (SS/Mcw and BN/Mcw). Through a chromosomal substitution breeding strategy, we created 5 consomic rat strains (SS.BN9, SS.BN13, SS.BN16, SS.BN18, and SS.BN20), which were BN/Mcw homozygous at only one chromosome and SS/Mcw homozygous at all other chromosomes. Standard plethsmography was used to assess eupneic breathing and ventilatory responses to CO(2) (FI(CO(2))=0.07) and hypoxia (FI(CO(2))=0.12), and Pa(CO(2)) during treadmill exercises provided the index of the exercise hyperpnea. There were no robust differences in eupneic breathing between any strains. The ventilatory response to CO(2) was 150% greater (P<0.001) in the SS/Mcw rats than in the BN/Mcw rats and all consomic strains had the SS/Mcw phenotype. Hyperventilation during hypoxia did not differ between the parental and the consomic strains, but ventilation during hypoxia was greater (P<0.001) in the SS/Mcw than in the BN/Mcw, and the SS.BN9, and SS.BN18 appeared to acquire this BN/Mcw phenotype. The hyperventilation during treadmill walking was greater (P<0.006) in the BN/Mcw and the SS.BN18 rats than in the SS/Mcw rats. Finally, the duration of the apnea following an augmented breath (post sigh apnea, PSA) was greater (P<0.001) in the BN/Mcw and the SS.BN9 rats than all other strains. We conclude that the robust difference between the parental strains in ventilatory CO(2) sensitivity is not due to genotypic differences on the 5 chromosomes studied to date, but genotypic differences on chromosomes 9 and 18 contribute to differences in ventilatory responses to hypoxia, exercise, and/or to the differences in the PSA.

Jansen GF, Kagenaar DA, Basnyat B, Odoom JABasilar artery blood flow velocity and the ventilatory response to acute hypoxia in mountaineers. Respir Physiol Neurobiol 133:65-74

October 2002


29 Reads

Hypoxic ventilatory response is higher in successful extreme-altitude climbers than in controls. We hypothesized that these climbers have lower brainstem blood flow secondary to hypoxia which may possibly cause retention of medullary CO(2) and greater ventilatory drive. Using transcranial Doppler, basilar artery blood flow velocity (Vba) was measured at sea level in 7 extreme-altitude climbers and 10 controls in response to 10 min sequential exposures to inspired oxygen fractions (FI(O(2))) of 0.21 (baseline), 0.13, 0.11, 0.10, 0.09, 0.08 and 0.07. Sa(O(2)) was higher in climbers at FI(O(2)) of 0.11 (P<0.05), 0.08 and 0.07 (both P<0.0001). Expired ventilation (VE) increased more (n.s.), and PET(CO(2)) decreased more (n.s.) in the climbers than in controls. Vba did not significantly change in both groups at FI(O(2)) of 0.13-0.09. At FI(O(2)) of 0.08 and 0.07, Vba decreased 21% (P<0.03) and 27% (P<0.01), respectively, in climbers, and increased 29% (P<0.01) and 27% (P<0.01), respectively, in controls. The conflicting effects of hypoxia and hypocapnia on both medullary blood flow and ventilatory drive thus balance out, giving climbers a greater drive and higher Sa(O(2)), despite lower PET(CO(2)) and lower brain stem blood flow.

The composition of pulmonary surfactant from diving mammals. Respir Physiol Neurobiol 152(2):152-168

July 2006


349 Reads

Maintaining a functional pulmonary surfactant system at depth is critical for diving mammals to ensure that inspiration is possible upon re-emergence. The lipid and protein composition of lavage extracts from three pinniped species (California sea lion, Northern elephant seal and Ringed seal) were compared to several terrestrial species. Lavage samples were purified using a NaBr discontinuous gradient. Concentrations of phospholipid classes and molecular species were measured using electrospray ionisation mass spectrometry, cholesterol was measured using high-performance liquid chromatography, surfactant protein A (SP-A) and SP-B were measured using enzyme-linked immunosorbent assays. There were small differences in phospholipid classes, with a lower level of anionic surfactant phospholipids, PG and PI, between diving and terrestrial mammals. There were no differences in PL saturation or SP-A levels between species. PC16:0/14:0, PC16:0/16:1, PC16:0/16:0, long chain PI species and the total concentrations of alkyl-acyl species of PC and PG as a ratio of diacyl species were increased in diving mammals, whereas concentrations of PC16:0/18:1, PG16:0/16:0 and PG16:0/18:1 were decreased. Cholesterol levels were very variable between species and SP-B was very low in diving mammals. These differences may explain the very poor surface activity of pinniped surfactant that we have previously described [Miller, N.J., Daniels, C.B., Schürch, S., Schoel, W.M., Orgeig, S., 2005. The surface activity of pulmonary surfactant from diving mammals. Respir. Physiol. Neurobiol. 150 (2006) 220-232], supporting the hypothesis that pinniped surfactant has primarily an anti-adhesive function to meet the challenges of regularly collapsing lungs.

Button, B. & Boucher, R. C. Role of mechanical stress in regulating airway surface hydration and mucus clearance rates. Respir. Physiol. Neurobiol. 163, 189-201

July 2008


85 Reads

Effective clearance of mucus is a critical innate airway defense mechanism, and under appropriate conditions, can be stimulated to enhance clearance of inhaled pathogens. It has become increasingly clear that extracellular nucleotides (ATP and UTP) and nucleosides (adenosine) are important regulators of mucus clearance in the airways as a result of their ability to stimulate fluid secretion, mucus hydration, and cilia beat frequency (CBF). One ubiquitous mechanism to stimulate ATP release is through external mechanical stress. This article addresses the role of physiologically relevant mechanical forces in the lung and their effects on regulating mucociliary clearance (MCC). The effects of mechanical forces on the stimulating ATP release, fluid secretion, CBF, and MCC are discussed. Also discussed is evidence suggesting that airway hydration and stimulation of MCC by stress-mediated ATP release may play a role in several therapeutic strategies directed at improving mucus clearance in patients with obstructive lung diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).

Congenital central hypoventilation syndrome and desogestrel: A call for caution. Addendum to "C. Straus, H. Trang, M.H. Becquemin, P. Touraine, T. Similowski, Chemosensitivity recovery in ondine's curse syndrome under treatment with desogestrel" [Respir. Physiol. Neurobiol. 171 (2010) 171-174]

July 2011


115 Reads

Patients suffering from congenital central hypoventilation syndrome (CCHS) depend on mechanical ventilation during sleep, from birth and throughout life. They lack CO₂-chemosensitivity. Hope has recently been raised by serendipitous observations of chemosensitivity recovery under treatment by desogestrel, a very potent progestin (Straus et al., 2010). Caution is however needed, because this effect could depend on dose, idiosyncrasies, or be transient. Desogestrel should not be prescribed to CCHS patients with a respiratory purpose until the results of a pending clinical trial ( NCT01243697) are available.

Decreased H2O2 in exhaled breath condensate during pregnancy-Feasible effect of 17β-estradiol

June 2008


44 Reads

Since pregnancy is known to favor systemic generation of reactive oxygen species, this study was designed to assess the levels of exhaled hydrogen peroxide (eH2O2), serum progesterone (PG), 17beta-estradiol (E2) and systemic oxidative parameters in 20 pregnant women between 15th and 28th gestation week and 23 healthy, eumenorrheic women. Exhaled breath condensate H2O2 was assessed fluorometrically with homovanillic acid. Exhaled H2O2 levels were lowered in pregnancy (median Me 0.13 microM) compared with follicular (Me 0.29 microM) or luteal phase (Me 0.26 microM; p<0.05 vs. both). The follicular H2O2 tended to exceed luteal phase. Whole blood chemiluminescence was increased approximately ten fold in pregnancy. E2 markedly decreased chemiluminescence of isolated polymorphonuclear leukocytes. In vitro ferric reducing ability of plasma and 2,2-diphenyl-1-picryl-hydrazyl scavenging assay were not affected by E2 or PG. Decreased exhaled H2O2 during pregnancy, despite of the increased oxidative capacity of peripheral phagocytes, might be ascribed to the magnitude of increased 17beta-estradiol levels.

Diffusion-weighted F-19-MRI of lung periphery: Influence of pressure and air-SF6 composition on apparent diffusion coefficients

September 2005


38 Reads

Lung functional magnetic resonance imaging (MRI) has become a reality using different inert hyperpolarized gases, such as 3He and 129Xe, which have provided an extraordinary boost in lung imaging and has also attracted interest to other chemically inert gaseous contrast agents. In this context, we have recently demonstrated the first diffusion-weighted images using thermally polarized inhaled sulfur hexafluoride (SF6) in small animals. The aim of this study was to evaluate whether or not the diffusion coefficient of this fluorinated gas is sensitive to pulmonary structure, gas concentration and air pressure in the airways. Diffusion coefficients of SF6 (both pure and in air mixtures) measured in vitro at different pressures and 20 degrees C showed an excellent agreement with theoretical values. Measurements of diffusion coefficients were also performed in vivo and post-mortem on healthy rats, achieving satisfactory signal-to-noise ratios (SNRs), and SF6 gas was found to be in an almost completely restricted diffusion regime in the lung, i.e., the transport by molecular diffusion is delayed by collisions with barriers such as the alveolar septa. This observed low diffusivity means that this gas will be less sensitive to structural changes in the lungs than other magnetic resonance sensitive gas such as 3He, particularly at human scale. However, it is still possible that SF6 plays a role since it opens a new structural window. Thus, the interest of researchers in delimiting the important limiting technical factors that makes this process very challenging is obvious. Among them, T2 relaxation is very fast, so gradient systems with very fast switching rate and probably large radiofrequency (RF) power and high field systems will be needed for hexafluoride to be used in human studies.

Interleukin-1β depresses hypoxic gasping and autoresuscitation in neonatal DBA/1lacJ mice

May 2005


93 Reads

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) has been proposed to act as an important mediator between infection and apnea in neonates. In this study, respiration and the ability to survive anoxic challenge were investigated between 70 and 95 min after intraperitoneal injection of IL-1beta (10 microg/kg) or NaCl in 9-day-old DBA/1lacJ mice. Using flow plethysmography, we show that mice given IL-1beta exhibited a decreased tidal volume (V(T)) and minute ventilation (V(E)) during normoxia compared to control animals. Hyperoxic challenge revealed functioning peripheral chemoreceptors in all animals, suggesting a central mechanism underlying the ventilatory effects of IL-1beta. In response to anoxia (100% N2), all animals irrespective of treatment displayed a biphasic ventilatory pattern. Mice given IL-1beta exhibited fewer gasps and were unable to sustain gasping efforts for as long as control animals. Additionally, they were less able to autoresuscitate and survive following severe hypoxic apnea. These findings indicate that infection may adversely affect central respiratory control in newborn mice via interleukin-1beta.

Expression of HIF-1α, VEGF and VEGF receptors in the carotid body of chronically hypoxic rat

December 2003


20 Reads

We examined the protein expression and localization of HIF-1alpha, VEGF, VEGF receptors in the carotid body (CB) of rats breathing 10% inspired oxygen for up to 4 weeks. The immunoreactivity (IR) of HIF-1alpha was distributed numerously in the nuclei of glomus (type-I) and other cells since hypoxia for 1 day, but was faint and scattered in the normoxic CBs. Cytoplasmic staining of the VEGF was intense in glomus cells of the hypoxic but not the normoxic group. The IR levels of HIF-1alpha and VEGF reached plateau at 4 weeks, and the IRs of VEGFR-1 and VEGFR-2 were strongly positive in the hypoxic group. Yet, the expression of VEGFR-1-IR was mild, whereas the VEGFR-2-IR was intense in normoxic CBs, suggesting an upregulation of VEGFR-1 but not VEGFR-2 in hypoxia. Hence, HIF-1 may activate the expression of VEGF and VEGFR-1 in the CB and the expression of VEGF in the chemoreceptors may play a paracrine role in the vascular remodeling during chronic hypoxia.

Fig. 1. Hypoxia inducible factor-1 ␣ mRNA (HIF-1 ␣ mRNA) in leukocytes before (baseline) and after the acute hypoxic test, before (PRE) and after (POST) 18 days of “living high–training low” (hypoxic group: HG) or “living low–training low” (control group: CG). HIF-1 ␣ mRNA is expressed as a percentage of variation from baseline. The grey dashed line represents PRE and the black solid line represents POST. Values are means for six subjects in both CG and HG. * P < 0.05 vs. baseline. 
Fig. 2. Relationship between the changes in the acute hypoxic ventilatory response ( AHVR) during exercise and protein oxidation ( AOPP) during the acute hypoxic response test between before (PRE) and after (POST) 18 days of “living high–training low” ( n = 12). The black circles represent subjects of the hypoxic group ( n = 6) and the open circles represent subjects of the control group ( n = 6). 
Oxidative stress and HIF-1α modulate hypoxic ventilatory responses after hypoxic training on athletes

May 2009


311 Reads

We investigated the strength of the association between oxidative stress, hypoxia inducible factor 1 (HIF-1 alpha) and acute hypoxic ventilatory response (AHVR) after hypoxic training in elite runners. Six elite runners were submitted to 18-day of "living high-training low" (LHTL) and six performed the same training in normoxia. AHVR was measured during an acute hypoxic test before and after training. Plasma levels of protein oxidation (AOPP), malondialdehydes and (HIF-1 alpha) mRNA in the leukocytes were measured before and after the acute hypoxic test. LHTL increased AHVR and amplified the responses of HIF-1 alpha mRNA and AOPP (Delta(AOPP)) to the acute hypoxic test. Furthermore, between PRE and POST, the changes in Delta(AOPP) were correlated with the changes in AHVR (r=0.69, P=0.01). The ventilatory acclimatization to hypoxia occurring in athletes after LHTL seems to be modulated by oxidative stress. Furthermore, LHTL induced a higher sensitivity of HIF-1 alpha mRNA to acute hypoxia in elite athletes.

Fig. 2. Effects of iron chelator, ciclopirox olamine (CPX-5 M) on rat glomus cell. (A) Representative recordings of CPX and CPX + FeSO 4 (200 M) effects on the whole cell outward K + currents. Holding potential was −85 mV, voltage ramps from −80 to +60 mV with 10 mV increment. All recordings were from the same patch. Membrane K + current during normoxia was suppressed by CPX within <1 min and the effect was reversed by FeSO 4. (B) I-V curves from (A). (C) CPX-induced shift of the reversal potential ( * P < 0.05). (D) Glomus cell E m depolarized by CPX.
Fig. 3. Effects of iron chelators on glomus cell [Ca 2+ ] i (as measured by Fura-2 ratio). (A, B and C) Iron chelators CPX (5 M), PIH (300 M) and NIH (300 M), all stimulated glomus cell [Ca 2+ ] i and the effects are promptly reversed by exogenous FeSO 4 (200 M). (D) Shows the summary data indicating that CPX significantly stimulated glomus cell [Ca 2+ ] i (P < 0.001; t-tests), that is reversed by exogenous iron.
Fig. 4. Effect of iron chelator CPX on CB dopamine current (I DA in picoamperes) measured in vitro from isolated whole CB. (A) CB perfused with buffer containing CPX increased DA current, indicating release of DA from the CB. In presence of FeSO 4 the DA current is reversed. (B) Summary data showing temporal changes in the DA current which is significantly increased within 10 s and reached maximum within 40 s (P < 0.001, t-test) in presence of CPX. The effect of CPX is always reversed significantly by FeSO 4. A. Effect of CPX B. Effect of PIH. C. Effect of NIH. D. Summary of [Ca 2+ ] i rise by CPX and reversal by FeSO 4 .
Fig. 7. Effects of Fe 2+ chelation on glomus cells.
Fig. 8. (A) Effects of extracellular [K + ] 0 (4.7-20 mM) on CSN discharge during normoxia; 4.7 to 15 mM [K + ] stimulated the discharge; 20 mM inhibited the discharge-there is a depolarization block. Hypoxia (40 Torr) stimulated the discharge rate during 15 mM [K + ] administration; Hypoxia with 20 mM [K + ] did not elicit any response. (B) [K + ] 0 concentration in normoxia did not have any effect on the expression of HIF-1 in glomus cells, but hypoxia elicited a strong expression independent of [K + ] 0 concentrations.
Effects of iron-chelators on ion-channels and HIF-1α in the carotid body

August 2004


140 Reads

Acute hypoxia instantaneously increases the chemosensory discharge from the carotid body, increasing ventilation mostly by inhibiting the oxygen sensitive ion channels and exciting the mitochondrial functions in the glomus cells. On the other hand, Fe2+-chelation mimics hypoxia by inhibiting the prolyl hydroxylases and the degradation of HIF-1alpha in non-excitable cells. Whether Fe2+-chelation can inhibit the ion channels giving rise to the sensory responses in excitable cells was the question. We characterized the responses to Fe2+-chelators on excitable glomus cells of the rat, and found that they instantaneously blocked the ion-channels, exciting the chemosensory discharge, and later causing a gradual accumulation of HIF-1alpha. Although initiated by the same stimuli, the two effects (on ion channels and cytosolic HIF-1alpha) possibly occurred by two different mechanisms.

Oxygen and life span: Chronic hypoxia as a model for studying HIF-1α, VEGF and NOS during aging

June 2005


43 Reads

To test if oxygen sensitive mechanisms are affected by hypoxia, we studied hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) expression by immunohistochemical analysis in young and old rat carotid bodies (CBs) using hypoxia as a model for modulating aging. Four groups of male age-matched Wistar rats (3 and 24 months) were used. Two groups were kept in room air, and two groups were kept under chronic intermittent hypoxia for 12 days. In aged carotid body and in hypoxia the increased expression of HIF-1alpha, VEGF, iNOS is less evident as compared to the young one. Electron microscopy sections showed a reduced mitochondrial number and area in the aged CBs and during hypoxia. Less responsiveness to hypoxia could be evidenced in the aged rats as compared to the young rats, suggesting an age dependency of the oxygen sensitive mechanisms.

Lung inflammation induces IL-1β expression in hypoglossal neurons in rat brainstem

May 2013


80 Reads

Perinatal inflammation is associated with respiratory morbidity. Immune modulation of brainstem respiratory control centers may provide a link for this pathobiology. We exposed 11-day old rats to intratracheal lipopolysaccharide (LPS, 0.5μg/g) to test the hypothesis that intrapulmonary inflammation increases expression of the pro-inflammatory cytokine IL-1β within respiratory-related brainstem regions. Intratracheal LPS resulted in a 32% increase in IL-1β protein expression in the medulla oblongata. In situ hybridization showed increased intensity of IL-1β mRNA but no change in neuronal numbers. Co-localization experiments showed that hypoglossal neurons express IL-1β mRNA and immunostaining showed a 43% increase in IL-1β protein-expressing cells after LPS exposure. LPS treatment also significantly increased microglial cell numbers though they did not express IL-1β mRNA. LPS-induced brainstem expression of neuronal IL-1β mRNA and protein may have implications for our understanding of the vulnerability of neonatal respiratory control in response to a peripheral pro-inflammatory stimulus.

IL-1β acutely increases pulmonary SP and permeability without associated changes in airway resistance and ventilation in anesthetized rats

January 2011


16 Reads

Bronchopulmonary C-fibers (PCFs), when activated, promote substance P (SP) release, increase microvascular leak, and produce bronchoconstriction and apnea. IL-1β administered systemically or locally into the pulmonary parenchyma stimulates PCFs. Thus, we tested whether right atrial bolus injection or aerosol inhalation of IL-1β, to mainly stimulate PCFs, would acutely affect pulmonary SP level and vascular permeability, airway resistance (R(L)), and ventilation in anesthetized rats. Our results showed that 30min after IL-1β injection (2-6 μg kg⁻¹), SP levels and Evans blue extravasation in bronchoalveolar lavage fluid were markedly increased and these responses were eliminated or largely reduced in neonatal capsaicin-treated rats. In contrast, neither injection nor inhalation of IL-1β (5-15 μg ml⁻¹) significantly altered R(L) and ventilation. Additionally, the capsaicin-evoked (4 μg kg⁻¹, i.v.) apneic response was unaffected by IL-1β treatment. Our data suggest that IL-1β, as administered in this study, can acutely increase pulmonary SP and vascular permeability, likely via stimulating PCFs, with little impact on R(L) and ventilation.

Three fatal cases of pandemic 2009 influenza A virus infection in Shenzhen are associated with cytokine storm

November 2010


56 Reads

China had taken strict measures for pandemic 2009 H1N1 infection with enhanced surveillance and hospital isolation since April 2009. In Shenzhen, over 1200 confirmed cases of H1N1 infection were identified. Three young patients died of severe pneumonia. Among them, two boys developed neurological complications. Cytokine storm seemed an important cause.

Inhibition of pre-B cell colony-enhancing factor attenuates inflammation and apoptosis induced by pandemic H1N1 2009 in lung endothelium

June 2011


26 Reads

The recent pandemic influenza A (H1N1 2009) virus infection has caused acute lung injury in susceptible population resulting in high mortality in ICU patients. In this report, we observed the effect of pre-B cell colony-enhancing factor (PBEF) on the inflammation and apoptosis in H1N1-infected human pulmonary microvascular endothelial cells (HPMECs). We constructed an in vitro HPMEC monolayer model. The results showed that H1N1 2009 induced the increased expression of inflammatory cytokines (IL-6/IL-8/TNF-α/IP-10) and apoptosis factors (FasL/TRAIL) in infected HPMECs. However, PBEF silencing with siRNA inhibited the expression of some inflammatory cytokines and decreased the apoptosis mediated by FasL. We conclude that PBEF might be partially responsible for the localized inflammatory response to H1N1 2009 in the lung microvascular endothelium and the H1N1-induced endothelial cell apoptosis probably through the FasL-mediated pathway.

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