scholarly journals Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation

2021 ◽  
Vol 12 ◽  
Author(s):  
Isato Fukushi ◽  
Kotaro Takeda ◽  
Mieczyslaw Pokorski ◽  
Yosuke Kono ◽  
Masashi Yoshizawa ◽  
...  
Keyword(s):  
Acute Hypoxia ◽  
Whole Body ◽  
High Dose ◽  
Ventilatory Responses ◽  
Adult Mice ◽  
Term Potentiation ◽  
Before And After ◽  
Whole Body Plethysmography ◽  
Hypoxic Gas Mixture

Acute hypoxia increases ventilation. After cessation of hypoxia loading, ventilation decreases but remains above the pre-exposure baseline level for a time. However, the mechanism of this post-hypoxic persistent respiratory augmentation (PHRA), which is a short-term potentiation of breathing, has not been elucidated. We aimed to test the hypothesis that astrocytes are involved in PHRA. To this end, we investigated hypoxic ventilatory responses by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas mixture (7% O2, 93% N2) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of arundic acid (AA), an astrocyte inhibitor. AA suppressed PHRA, with the high dose decreasing ventilation below the pre-hypoxic level. Further, we investigated the role of the astrocytic TRPA1 channel, a putative ventilatory hypoxia sensor, in PHRA using astrocyte-specific Trpa1 knockout (asTrpa1−/−) and floxed Trpa1 (Trpa1f/f) mice. In both Trpa1f/f and asTrpa1−/− mice, PHRA was noticeable, indicating that the astrocyte TRPA1 channel was not directly involved in PHRA. Taken together, these results indicate that astrocytes mediate the PHRA by mechanisms other than TRPA1 channels that are engaged in hypoxia sensing.

Ventilatory behavior after hypoxia in C57BL/6J and A/J mice

2001 ◽  
Vol 91 (5) ◽  
pp. 1962-1970 ◽  
Author(s):  
Fang Han ◽  
Shyam Subramanian ◽  
Thomas E. Dick ◽  
Ismail A. Dreshaj ◽  
Kingman P. Strohl
Keyword(s):  
Airway Resistance ◽  
Minute Ventilation ◽  
Genetic Effect ◽  
Strain Differences ◽  
Whole Body ◽  
Environmental Forcing ◽  
Ventilatory Responses ◽  
Term Potentiation ◽  
Genetic Mechanisms ◽  
Whole Body Plethysmography

Given the environmental forcing by extremes in hypoxia-reoxygenation, there might be no genetic effect on posthypoxic short-term potentiation of ventilation. Minute ventilation (V˙e), respiratory frequency (f), tidal volume (Vt), and the airway resistance during chemical loading were assessed in unanesthetized unrestrained C57BL/6J (B6) and A/J mice using whole body plethysmography. Static pressure-volume curves were also performed. In 12 males for each strain, after 5 min of 8% O2 exposure, B6 mice had a prominent decrease inV˙e on reoxygenation with either air (−11%) or 100% O2 (−20%), due to the decline of f. In contrast, A/J animals had no ventilatory undershoot or f decline. After 5 min of 3% CO2-10% O2 exposure, B6 exhibited significant decrease in V˙e (−28.4 vs. −38.7%, air vs. 100% O2) and f (−13.8 vs. −22.3%, air vs. 100% O2) during reoxygenation with both air and 100% O2; however, A/J mice showed significant increase inV˙e (+116%) and f (+62.2%) during air reoxygenation and significant increase in V˙e (+68.2%) during 100% O2 reoxygenation. There were no strain differences in dynamic airway resistance during gas challenges or in steady-state total respiratory compliance measured postmortem. Strain differences in ventilatory responses to reoxygenation indicate that genetic mechanisms strongly influence posthypoxic ventilatory behavior.

Role of interleukin-6 in murine airway responses to ozone

2005 ◽  
Vol 288 (2) ◽  
pp. L390-L397 ◽  
Author(s):  
Richard A. Johnston ◽  
Igor N. Schwartzman ◽  
Lesley Flynt ◽  
Stephanie A. Shore
Keyword(s):  
Interleukin 6 ◽  
Lavage Fluid ◽  
Whole Body ◽  
High Dose ◽  
Outcome Indicators ◽  
Airway Injury ◽  
Inflammatory Protein ◽  
Airway Responses ◽  
Whole Body Plethysmography

This study sought to examine the role of interleukin-6 (IL-6) in ozone (O3)-induced airway injury, inflammation, and hyperresponsiveness (AHR). Subacute (72 h) exposure to 0.3 ppm O3significantly elevated bronchoalveolar lavage fluid (BALF) protein, neutrophils, and soluble TNF receptors (sTNFR1 and sTNFR2) in wild-type C57BL/6 (IL-6+/+) mice; however, all four outcome indicators were significantly reduced in IL-6-deficient (IL-6−/−) compared with IL-6+/+mice. Acute O3exposure (2 ppm for 3 h) increased BALF protein, KC, macrophage inflammatory protein(MIP)-2, eotaxin, sTNFR1, and sTNFR2 in IL-6+/+mice. However, MIP-2 and sTNFR2 were not significantly increased following O3exposure in IL-6−/−mice. Increases in BALF neutrophils induced by O3(2 ppm for 3 h) were also significantly reduced in IL-6−/−vs. IL-6+/+mice. Airway responsiveness to methacholine was measured by whole body plethysmography before and following acute (3 h) or subacute (72 h) exposure to 0.3 ppm O3. Acute O3exposure caused AHR in both groups of mice, but there was no genotype-related difference in the magnitude of O3-induced AHR. AHR was absent in mice of either genotype exposed for 72 h. Our results indicate that IL-6 deficiency reduces airway neutrophilia, as well as the levels of BALF sTNFR1 and sTNFR2 following acute high dose and/or subacute low-dose O3exposure, but has no effect on O3-induced AHR.

scholarly journals Essential role of hemoglobin beta-93-cysteine in posthypoxia facilitation of breathing in conscious mice

2014 ◽  
Vol 116 (10) ◽  
pp. 1290-1299 ◽  
Author(s):  
Benjamin Gaston ◽  
Walter J. May ◽  
Spencer Sullivan ◽  
Sean Yemen ◽  
Nadzeya V. Marozkina ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Essential Role ◽  
Carotid Sinus ◽  
Acute Hypoxia ◽  
Carotid Sinus Nerve ◽  
Short Term ◽  
Ventilatory Responses ◽  
Term Potentiation ◽  
Β Chain

When erythrocyte hemoglobin (Hb) is fully saturated with O2, nitric oxide (NO) covalently binds to the cysteine 93 residue of the Hb β-chain (B93-CYS), forming S-nitrosohemoglobin. Binding of NO is allosterically coupled to the O2 saturation of Hb. As saturation falls, the NO group on B93-CYS is transferred to thiols in the erythrocyte, and in the plasma, forming circulating S-nitrosothiols. Here, we studied whether the changes in ventilation during and following exposure to a hypoxic challenge were dependent on erythrocytic B93-CYS. Studies were performed in conscious mice in which native murine Hb was replaced with human Hb (hB93-CYS mice) and in mice in which murine Hb was replaced with human Hb containing an alanine rather than cysteine at position 93 on the Bchain (hB93-ALA). Both strains expressed human γ-chain Hb, likely allowing a residual element of S-nitrosothiol-dependent signaling. While resting parameters and initial hypoxic (10% O2, 90% N2) ventilatory responses were similar in hB93-CYS mice and hB93-ALA mice, the excitatory ventilatory responses (short-term potentiation) that occurred once the mice were returned to room air were markedly diminished in hB93-ALA mice. Further, short-term potentiation responses were virtually absent in mice with bilateral transection of the carotid sinus nerves. These data demonstrate that hB93-CYS plays an essential role in mediating carotid sinus nerve-dependent short-term potentiation, an important mechanism for recovery from acute hypoxia.

GABA-mediated neurotransmission in the nucleus of the solitary tract alters resting ventilation following exposure to chronic hypoxia in conscious rats

2006 ◽  
Vol 291 (5) ◽  
pp. R1449-R1456 ◽  
Author(s):  
Sean Chung ◽  
Gwen O. Ivy ◽  
Stephen G. Reid
Keyword(s):  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Chronic Hypoxia ◽  
Minute Ventilation ◽  
Acute Hypoxia ◽  
Acute Exposure ◽  
Whole Body ◽  
Solitary Tract ◽  
Before And After ◽  
Whole Body Plethysmography

This study investigated whether changes in GABA-mediated neurotransmission within the nucleus of the solitary tract (NTS) contribute to the changes in breathing (resting ventilation and the acute HVR) that occur following exposure to chronic hypoxia (CH). Rats were exposed to 9 days of hypobaric hypoxia (0.5 atm) and then subjected to acute hypoxic breathing trials before and after bilateral microinjections of GABA, bicuculline (a GABAA-receptor antagonist), or bicuculline plus CGP-35348 (a GABAB receptor antagonist) into the caudal regions of the NTS. Breathing was measured using whole body plethysmography. CH caused an increase in resting ventilation when the animals were breathing 30% O2 but did not alter ventilation during acute hypoxia (10% O2). GABA alone had no effect on breathing in either the control or chronically hypoxic rats. Bicuculline and bicuculline/CGP had no effect on breathing in control rats. Following CH, bicuculline and bicuculline/CGP reduced minute ventilation (VI) during acute exposure to 30% O2 but had no effect during acute exposure to 10% O2. The bicuculline-induced reduction in VI resulted from a decrease in breathing frequency (fR) and tidal volume (VT). The bicuculline/CGP-induced reduction in VI was due to a decrease in fR with no change in VT. The results suggest that changes in GABA receptor-mediated neurotransmission, within the NTS, are involved in the increase in resting ventilation that occurs following CH.

scholarly journals Role of nitric oxide-containing factors in the ventilatory and cardiovascular responses elicited by hypoxic challenge in isoflurane-anesthetized rats

2014 ◽  
Vol 116 (11) ◽  
pp. 1371-1381 ◽  
Author(s):  
James P. Mendoza ◽  
Rachael J. Passafaro ◽  
Santhosh M. Baby ◽  
Alex P. Young ◽  
James N. Bates ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Cardiovascular Responses ◽  
Vital Role ◽  
Initial Increase ◽  
Ventilatory Responses ◽  
Arterial Blood ◽  
Anesthetized Rats ◽  
Before And After

Exposure to hypoxia elicits changes in mean arterial blood pressure (MAP), heart rate, and frequency of breathing (fr). The objective of this study was to determine the role of nitric oxide (NO) in the cardiovascular and ventilatory responses elicited by brief exposures to hypoxia in isoflurane-anesthetized rats. The rats were instrumented to record MAP, heart rate, and fr and then exposed to 90 s episodes of hypoxia (10% O2, 90% N2) before and after injection of vehicle, the NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME), or the inactive enantiomer d-NAME (both at 50 μmol/kg iv). Each episode of hypoxia elicited a decrease in MAP, bidirectional changes in heart rate (initial increase and then a decrease), and an increase in fr. These responses were similar before and after injection of vehicle or d-NAME. In contrast, the hypoxia-induced decreases in MAP were attenuated after administration of l-NAME. The initial increases in heart rate during hypoxia were amplified whereas the subsequent decreases in heart rate were attenuated in l-NAME-treated rats. Finally, the hypoxia-induced increases in fr were virtually identical before and after administration of l-NAME. These findings suggest that NO factors play a vital role in the expression of the cardiovascular but not the ventilatory responses elicited by brief episodes of hypoxia in isoflurane-anesthetized rats. Based on existing evidence that NO factors play a vital role in carotid body and central responses to hypoxia in conscious rats, our findings raise the novel possibility that isoflurane blunts this NO-dependent signaling.

Maturation of baseline breathing and of hypercapnic and hypoxic ventilatory responses in newborn mice

2001 ◽  
Vol 281 (5) ◽  
pp. R1746-R1753 ◽  
Author(s):  
Sylvain Renolleau ◽  
Stéphane Dauger ◽  
Fanny Autret ◽  
Guy Vardon ◽  
Claude Gaultier ◽  
...  
Keyword(s):  
Cesarean Section ◽  
Tidal Volume ◽  
Mammalian Species ◽  
Whole Body ◽  
Body Plethysmography ◽  
Genetic Studies ◽  
Newborn Mice ◽  
Ventilatory Responses ◽  
Neuronal Mechanisms ◽  
Whole Body Plethysmography

Breathing during the first postnatal hours has not been examined in mice, the preferred mammalian species for genetic studies. We used whole body plethysmography to measure ventilation (V˙e), breath duration (TTOT), and tidal volume (Vt) in mice delivered vaginally (VD) or by cesarean section (CS). In experiment 1, 101 VD and 100 CS pups aged 1, 6, 12, 24, or 48 h were exposed to 8% CO2 or 10% O2for 90 s. In experiment 2, 31 VD pups aged 1, 12, or 24 h were exposed to 10% O2 for 5 min. Baseline breathing maturation was delayed in CS pups, but V˙eresponses to hypercapnia and hypoxia were not significantly different between VD and CS pups [at postnatal age of 1 h (H1): 48 ± 44 and 18 ± 32%, respectively, in VD and CS pups combined]. TheV˙e increase induced by hypoxia was greater at H12 (46 ± 27%) because of TTOT response maturation. At all ages, hypoxic decline was ascribable mainly to a Vtdecrease, and posthypoxic decline was ascribable to a TTOTincrease with apneas, suggesting different underlying neuronal mechanisms.

scholarly journals Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

2020 ◽  
Author(s):  
Kevin W Gibbs ◽  
Chia-Chi Chuang Key ◽  
Lanazha Belfield ◽  
Jennifer Krall ◽  
Lina Purcell ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fatty Acid ◽  
Lung Injury ◽  
Whole Body ◽  
Acid Oxidation ◽  
Aged Mice ◽  
Protein Levels ◽  
Adult Mice ◽  
Age Related ◽  
Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

Long-term ventilatory adaptation and ventilatory response to hypoxia in plateau pika (Ochotona curzoniae): role of nNOS and dopamine

2009 ◽  
Vol 297 (4) ◽  
pp. R978-R987 ◽  
Author(s):  
Aurélien Pichon ◽  
Bai Zhenzhong ◽  
Fabrice Favret ◽  
Guoen Jin ◽  
Han Shufeng ◽  
...  
Keyword(s):  
Acute Hypoxia ◽  
Respiratory Pattern ◽  
Whole Body ◽  
Plateau Pika ◽  
Ventilatory Parameter ◽  
Species Effect ◽  
Oxide Synthase ◽  
And Control

We assessed ventilatory patterns and ventilatory responses to hypoxia (HVR) in high-altitude (HA) plateau pikas, repetitively exposed to hypoxic burrows, and control rats. We evaluated the role of neuronal nitric oxide synthase (nNOS) and dopamine by using S-methyl-l-thiocitrulline (SMTC) inhibitor and haloperidol antagonist, respectively. Ventilation (V̇i) was measured using a whole body plethysmograph in conscious pikas ( n = 9) and low-altitude (LA) rats ( n = 7) at different PiO2 (56, 80, 111, 150, and 186 mmHg) and in HA acclimatized rats ( n = 9, 8 days at 4,600 m) at two different PiO2 (56 and 80 mmHg). The effects of NaCl, SMTC, and haloperidol on ventilatory patterns were assessed in pikas at PiO2 = 56 and 80 mmHg. We observed a main species effect with larger V̇i, tidal volume (VT), inspiratory time/total time (Ti/Ttot), and a lower expiratory time in pikas than in LA rats. Pikas had also a larger VT and lower respiratory frequency compared with HA rats in hypoxia. HVR of pikas and rats were not statistically different. In pikas, SMTC induced a significant increase in V̇i and VT for a PiO2 of 56 mmHg, but had no effect for a PiO2 of 80 mmHg, i.e., the living altitude of pikas. In pikas, haloperidol injection had no effect on any ventilatory parameter. Long-term ventilatory adaptation in pikas is mainly due to an improvement in respiratory pattern (VT and Ti/Ttot) with no significant improvement in HVR. The sensitivity to severe acute hypoxia in pikas seems to be regulated by a peripheral nNOS mechanism.

Ventilatory responses to hypoxia in rats pretreated with nonpeptide NK1 receptor antagonist CP-96,345

1994 ◽  
Vol 76 (4) ◽  
pp. 1528-1532 ◽  
Author(s):  
G. T. De Sanctis ◽  
F. H. Green ◽  
X. Jiang ◽  
M. King ◽  
J. E. Remmers
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Acute Hypoxia ◽  
Frequency Component ◽  
Nk1 Receptor ◽  
Adult Rats ◽  
Nk1 Receptors ◽  
Before And After ◽  
Sites Of Action

This study reports experiments designed to evaluate the role of neurokinin-1 (NK1) receptors for substance P (SP) in the ventilatory response to acute hypoxia. Ventilation was measured by indirect plethysmography in eight unanesthetized unrestrained adult rats before and after bolus injection of 1, 5, or 10 mg/kg (ip) of CP-96,345 (Pfizer), a potent nonpeptide competitive antagonist of the SP NK1 receptor. Ventilation was measured while the rats breathed air or 8% O2–92% N2 with and without administration of SP antagonist. Pretreatment with CP-96,345 decreased the magnitude of the hypoxic response in a dose-dependent fashion. Minute ventilation in rats pretreated with CP-96,345 was reduced by 22.1% (P < 0.05) at the highest dose (10 mg/kg), largely because of an attenuation of the frequency component. Although both control and treated rats responded to hypoxia with a decrease in duration of inspiration and expiration rats pretreated with CP-96,345 displayed a smaller decrease in inspiration and expiration than control rats (P < 0.05). We have recently shown that neuropeptide-containing fibers are important for mediating the tachypnic response during acute isocapnic hypoxia in rats. The attenuation in minute ventilation at the highest dose (10 mg/kg) is comparable in magnitude to the attenuation observed with neonatal capsaicin treatment, which permanently ablates neuropeptide-containing unmyelinated fibers. Accordingly, this previously reported role of capsaicin-sensitive nerves in the hypoxic ventilatory response of rats is probably attributable to released SP acting at NK1 receptors. One of the likely sites of action of SP antagonists is the carotid body.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals BACE1 partial deletion induces synaptic plasticity deficit in adult mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sylvia Lombardo ◽  
Martina Chiacchiaretta ◽  
Andrew Tarr ◽  
WonHee Kim ◽  
Tingyi Cao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Axonal Guidance ◽  
Knock Out ◽  
App Processing ◽  
Aged Mice ◽  
Adult Mice ◽  
Term Potentiation ◽  
Partial Depletion

AbstractBACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer’s disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4–5 months (young mice) and 12–13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aβx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.

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