Effects of temperature on ventilatory response to hypercapnia in newborn mice heterozygous for transcription factor Phox2b

Congenital central hypoventilation syndrome (CCHS) is a rare disease with variable severity, generally present from birth and chiefly characterized by impaired chemosensitivity to hypercapnia. The main cause of CCHS is a mutation in the PHOX2B gene, which encodes a transcription factor involved in the development of autonomic medullary reflex pathways. Temperature regulation is abnormal in many patients with CCHS. Here, we examined whether ambient temperature influenced CO2 sensitivity in a mouse model of CCHS. A weak response to CO2 at thermoneutrality (32°C) was noted previously in 2-day-old mice with an invalidated Phox2b allele ( Phox2b+/−), compared with wild-type littermates. We exposed Phox2b+/− pups to 8% CO2 at three ambient temperatures (TAs): 29°C, 32°C, and 35°C. We measured breathing variables and heart rate (HR) noninvasively using a novel whole body flow plethysmograph equipped with contact electrodes. Body temperature and baseline breathing increased similarly with TA in mutant and wild-type pups. The hypercapnic ventilatory response increased linearly with TA in both groups, while remaining smaller in mutant than in wild-type pups at all TAs. The differences between the absolute increases in ventilation in mutant and wild-type pups become more pronounced as temperature increased above 29°C. The ventilatory abnormalities in mutant pups were not associated with significant impairments of heart rate control. In both mutant and wild-type pups, baseline HR increased with TA. In conclusion, TA strongly influenced the hypercapnic ventilatory response in Phox2b+/− mutant mice. These findings suggest that abnormal temperature regulation may contribute to the severity of respiratory impairments in CCHS patients.

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Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factor Phox2b

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00875.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. R1691-R1696 ◽

Cited By ~ 27

Author(s):

N. Ramanantsoa ◽

V. Vaubourg ◽

S. Dauger ◽

B. Matrot ◽

G. Vardon ◽

...

Keyword(s):

Transcription Factor ◽

Ventilatory Response ◽

Minute Ventilation ◽

Whole Body ◽

Wild Type ◽

Peripheral Chemoreceptor ◽

Newborn Mice ◽

Apnea Duration ◽

Autonomic Reflex ◽

Hypoventilation Syndrome

Heterozygous mutations of the transcription factor PHOX2B have been found in most patients with central congenital hypoventilation syndrome, a rare disease characterized by sleep-related hypoventilation and impaired chemosensitivity to sustained hypercapnia and sustained hypoxia. PHOX2B is a master regulator of autonomic reflex pathways, including peripheral chemosensitive pathways. In the present study, we used hyperoxic tests to assess the strength of the peripheral chemoreceptor tonic drive in Phox2b+/− newborn mice. We exposed 69 wild-type and 67 mutant mice to two hyperoxic tests (12-min air followed by 3-min 100% O2) 2 days after birth. Breathing variables were measured noninvasively using whole body flow plethysmography. The initial minute ventilation decrease was larger in mutant pups than in wild-type pups: −37% (SD 13) and −25% (SD 18), respectively, P < 0.0001. Furthermore, minute ventilation remained depressed throughout O2 exposure in mutants, possibly because of their previously reported impaired CO2 chemosensitivity, whereas it returned rapidly to the normoxic level in wild-type pups. Hyperoxia considerably increased total apnea duration in mutant compared with wild-type pups ( P = 0.0001). A complementary experiment established that body temperature was not influenced by hyperoxia in either genotype group and, therefore, did not account for genotype-related differences in the hyperoxic ventilatory response. Thus partial loss of Phox2b function by heterozygosity did not diminish the tonic drive from peripheral chemoreceptors.

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Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00251.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. R712-R721 ◽

Cited By ~ 2

Author(s):

Maxwell S. Clayson ◽

Maiah E. M. Devereaux ◽

Matthew E. Pamenter

Keyword(s):

Substance P ◽

Network Architecture ◽

Ventilatory Response ◽

Receptor Activation ◽

Whole Body ◽

Hypercapnic Ventilatory Response ◽

Exogenous Substance ◽

Mole Rat ◽

Freely Behaving ◽

Neurokinin 1

Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%–10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40–400 μg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%–10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a “normal” HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.

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Impact of interrupted leptin pathways on ventilatory control

Journal of Applied Physiology ◽

10.1152/japplphysiol.00926.2003 ◽

2004 ◽

Vol 96 (3) ◽

pp. 991-998 ◽

Cited By ~ 48

Author(s):

Vsevolod Y. Polotsky ◽

Marc C. Smaldone ◽

Matthew T. Scharf ◽

Jianguo Li ◽

Clarke G. Tankersley ◽

...

Keyword(s):

Eye Movement ◽

Ventilatory Response ◽

Rapid Eye Movement ◽

Rapid Eye Movement Sleep ◽

Hypoxic Ventilatory Response ◽

Wild Type ◽

Hypercapnic Ventilatory Response ◽

Leptin Deficiency ◽

Significant Depression ◽

Deficient Mice

Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1) leptin deficiency affects the hypoxic ventilatory response and 2) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 ± 0.7 vs. 8.9 ± 0.7 ml·min-1·%CO2-1, P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep.

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102 Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factor Phox2b

Revue des Maladies Respiratoires ◽

10.1016/s0761-8425(05)92514-x ◽

2005 ◽

Vol 22 (5) ◽

pp. 897

Author(s):

N. Ramanantsoa ◽

V. Vaubourg ◽

S. Dauger ◽

B. Matrot ◽

G. Vardon ◽

...

Keyword(s):

Transcription Factor ◽

Ventilatory Response ◽

Newborn Mice

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Abstract 491: E-cigarette Aerosol Elevates Cardiovascular Oxidative Stress in Mice With Aldehyde Dehydrogenase 2 Deficiency

Circulation Research ◽

10.1161/res.127.suppl_1.491 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Xuan Yu ◽

Xiaocong Zeng ◽

Ri Chen ◽

Pritam Sinharoy ◽

Eric R Gross

Keyword(s):

Oxidative Stress ◽

Heart Rate ◽

Aldehyde Dehydrogenase ◽

Whole Body ◽

Protein Carbonyls ◽

Wild Type ◽

Aldehyde Dehydrogenase 2 ◽

Maximal Increase ◽

Reactive Aldehydes ◽

Reactive Aldehyde

Introduction: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein when e-cigarette is heated. Approximately 560 million people worldwide cannot efficiently metabolize aldehydes present in e-cigarette aerosol, due to a genetic deficiency in aldehyde dehydrogenase 2 enzyme (ALDH2), known as ALDH2*2. Little is known how aldehyde exposure from e-cigarettes, coupled with genetic differences in aldehyde metabolism, affects cardiovascular oxidative stress both at a physiological and cellular level. Hypothesis: E-cigarette aerosol exposure will elevate heart rate and cellular oxidative stress more substantially in ALDH2*2 knock-in mice versus wild type ALDH2 mice. Methods: To measure aldehyde levels, e-cigarette Juul aerosols were collected and quantified by selective ion flow gas mass spectrometry. Further, age-matched male wild type and homozygous ALDH2*2 mice (8-10 weeks old, ~25g) were implanted with EKG telemeters. After surgical recovery, mice were paired by genotype (one wild type ALDH2 and one ALDH2*2 mice) and exposed to either Juul aerosol or room air 4 sessions per day for 10 days. For each session, 7 puffs/min were drawn for the first two minutes (a total of 14 puffs), and the whole body exposure to Juul aerosol lasted 7 minutes, continued with 23 minutes smoking-free intervals in each session. Mice EKG waveforms were recorded daily. After 10 days of exposure, heart homogenates were subjected to biochemical assays including lipid peroxidation, 4-HNE protein adduct formation, and protein carbonylation. Results: Quantification of reactive aldehyde levels in e-cigarettes revealed that Juul aerosol contained acetaldehyde (5.3±0.32 ppm), formaldehyde (0.20±0.02 ppm), and acrolein (0.09±0.01 ppm). When exposed to Juul aerosol, ALDH2*2 mice showed a maximal increase in heart rate unlike ALDH2 wild type mice (774.6±29.5 bpm versus 678.9±32.8 bpm respectively, * p <0.01, n=8) at day 6. Furthermore, heart homogenates from ALDH2*2 mice demonstrated exacerbated oxidative stress, including higher level of 4-HNE adducts (1.5-fold), protein carbonyls (1.5-fold) and lipid peroxides (2-fold) relative to hearts from wild type ALDH2 mice, when both genotype mice were exposed to Juul e-cigarette aerosol (n=4/group). Conclusions: These findings indicate e-cigarette aerosols contain reactive aldehydes, primarily acetaldehyde. A deficiency in reactive aldehyde metabolism by having an ALDH2*2 deficiency may contribute to increases in heart rate and oxidative stress within the cardiovascular system while smoking e-cigarettes.

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Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00143.2015 ◽

2015 ◽

Vol 118 (11) ◽

pp. 1386-1395 ◽

Cited By ~ 13

Author(s):

Orlane Ballot ◽

Vincent Joseph ◽

Jorge Soliz

Keyword(s):

Ventilatory Response ◽

Minute Ventilation ◽

Whole Body ◽

Newborn Mice ◽

Male And Female ◽

Female Mice ◽

Specific Effects ◽

Respiratory Stimulant ◽

Males And Females ◽

Whole Body Plethysmography

We tested the hypothesis that endogenous brain Epo is a respiratory stimulant. Adult (3 mo) and newborn (10 days) male and female mice received an intracisternal (cisterna magna) injection of soluble Epo receptor (sEpoR; competes with EpoR to bind Epo; 50 μg/ml) or vehicle (0.1% BSA in PBS). Twenty-four hours after injection, we used whole body plethysmography to record minute ventilation (V̇e) tidal volume (VT), respiratory frequency ( fR), O2 consumption (V̇o2), and CO2 production (V̇co2) under normoxia and progressive exposure to hypoxia (12-10-6% O2; 10 min each). In adult male and female mice sEpoR decreased normoxic V̇e (−25%), due to a decrease of VT in males and fR in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O2, assessed as V̇e/V̇o2 or V̇e/V̇co2, in male but not in female mice. In newborn male and female mice sEpoR decreased V̇e (−37% in males, −59% in females) and VT (−38% in males, −47% in females) in normoxia and fR in females. During hypoxia, sEpoR decreased V̇e/V̇o2 and V̇e/V̇co2 in mice of both sexes. Upon extreme hypoxia (6% O2), the newborn mice treated with sEpoR showed respiratory depression, signs of asphyxia (gasping) and a high mortality rate in males and females. We concluded that endogenous brain Epo is a potent respiratory stimulant under normoxia and hypoxia in adult and newborn mice. Because sex-specific effects are different in newborn male and female, sex steroids secreted at different ages mice appear to modulate the effects of Epo on respiratory regulation in normoxia and in response to hypoxia.

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Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00411.2015 ◽

2015 ◽

Vol 119 (6) ◽

pp. 670-676 ◽

Cited By ~ 14

Author(s):

Saurabh K. Garg ◽

Daniel T. Lioy ◽

Sharon J. Knopp ◽

John M. Bissonnette

Keyword(s):

Transcription Factor ◽

Ventilatory Response ◽

Binding Protein ◽

Minute Ventilation ◽

Cre Recombinase ◽

Relative Increase ◽

Mecp2 Gene ◽

Hypercapnic Ventilatory Response ◽

Selective Depletion ◽

Before And After

Mice that are deficient in the transcription factor methyl-CpG-binding protein 2 (MeCP2) have a depressed hypercapnic ventilatory response (HCVR). The expression of MeCP2 can be selectively removed from astrocytes or neurons, thus offering a tool to dissect the role of this transcription factor in astrocytes from that in neurons. Studies were carried out in the progeny of mice that were a cross between those harboring a tamoxifen (TAM)-inducible Cre recombinase transgene driven by the human astrocytic glial fibrillary acidic protein (hGFAP) promoter, or Cre recombinase under control of the synapsin promoter, with mice containing a Cre-excisable exon III in the Mecp2 gene. The TAM-conditional excision of the Mecp2 exon allowed the respiratory CO2 response to be studied in the same animals before and after selective depletion of MeCP2 in astrocytes. Immunohistochemistry showed that following TAM treatment only ∼20% of GFAP-labeled cells in the retrotrapazoid nucleus and in the raphé magnus were positive for MeCP2. The slope of the relative increase in minute ventilation as a function of 1, 3, and 5% inspired CO2 was depressed in mice with depleted astrocyte MeCP2 compared with wild-type littermates. In contrast, selective depletion of MeCP2 in neurons did not significantly affect slope. While neurons which constitute the respiratory network ultimately determine the ventilatory response to CO2, this study demonstrates that loss of MeCP2 in astrocytes alone is sufficient to result in a dramatic attenuation of the HCVR. We propose that the glial contribution to HCVR is under the control of the MeCP2 gene.

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CHEMORECEPTOR REFLEXES IN THE NEWBORN INFANT: EFFECT OF COOLING ON THE RESPONSE TO HYPOXIA

PEDIATRICS ◽

10.1542/peds.37.4.556 ◽

1966 ◽

Vol 37 (4) ◽

pp. 556-564 ◽

Cited By ~ 2

Author(s):

Eliana Ceruti

Keyword(s):

Heart Rate ◽

Newborn Infant ◽

Environmental Temperature ◽

Ventilatory Response ◽

Minute Ventilation ◽

Term Infants ◽

Ambient Temperatures ◽

Thermal Environments ◽

Warm Environment ◽

Cool Environment

1. The effect of brief exposures to warm and cool environments on the newborn infant's response to hypoxia was studied in 14 healthy full-term infants. 2. In all infants studied in a cool environment minute ventilation was significantly higher while breathing 21% O2. 3. During the first week of life, hypoxia (12% O2) induced a transient hyperventilation in babies studied in a warm environment. This response was not seen when the infants were in a cool environment. The ventilatory response was the same even when the PACOACO2 was maintained constant and elevated. A decrease in ventilation and return to control levels after 21% O2 was reinstituted, occurred at both thermal environments. 4. PACOACO2 decreased during hypoxia, at both ambient temperatures. 5. Heart rate increased significantly during hypoxia and was not affected by the environmental temperature or age. 6. The ventilatory response to 3% CO2 inhalation was unaffected by temperature or age. 7. After the first week of life, a sustained hyperventilation during hypoxia occurred at both ambient temperatures.

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