Soluble erythropoietin receptor is present in the mouse brain and is required for the ventilatory acclimatization to hypoxia (original) (raw)
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The Journal of Physiology, 2005
Apart from its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischaemic injury. However, the physiological non-erythroid functions of Epo remain unclear. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate Epo's impact on ventilation upon hypoxic exposure. Tg21 mice showed improved ventilatory response to severe acute hypoxia and moreover improved ventilatory acclimatization to chronic hypoxic exposure. Furthermore, following bilateral transection of carotid sinus nerves that uncouples the brain from the carotid body, Tg21 mice adapted their ventilation to acute severe hypoxia while chemodenervated
Respiratory Physiology & Neurobiology, 2007
We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V E ) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430 mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure.V E was found to be similar in tg6 and wt mice in normoxia (FI O 2 = 0.21). Post-acclimationV E was significantly elevated in every time point in wt mice at FI O 2 = 0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase inV E throughout acute hypoxia exposure. Changes inV E are associated with adjustments in tidal volume (V T ). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V T suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.
Erythropoietin modulates the neural control of hypoxic ventilation
Cellular and Molecular Life Sciences, 2009
Numerous factors involved in general homeostasis are able to modulate ventilation. Classically, this comprises several kind of molecules, including neurotransmitters and steroids that are necessary for fine tuning ventilation under different conditions such as sleep, exercise, and acclimatization to high altitude. Recently, however, we have found that erythropoietin (Epo), the main regulator of red blood cell production, influences both central (brainstem) and peripheral (carotid bodies) respiratory centers when the organism is exposed to hypoxic conditions. Here, we summarize the effect of Epo on the respiratory control in mammals and highlight the potential implication of Epo in the ventilatory acclimatization to high altitude, as well as in the several respiratory sickness and syndromes occurring at low and high altitude. (Part of a multi-author review.)
Physiological Reports, 2014
The N-Methyl-D-Aspartate (NMDA) receptorsneuronal nitric oxide synthase (nNOS) pathway is involved in the ventilatory response to hypoxia. The objective was to assess the possible effect of erythropoietin deficiency and chronic exposure to hypoxia on this pathway during ventilatory response to acute hypoxia. Wild-type (WT) and erythropoietin-deficient (Epo-TAg h ) male mice were exposed (14 days) either to hypobaric hypoxia (Pb = 435 mmHg) or to normoxia. The ventilation was measured at 21% or 8% O 2 after injection of vehicle (NaCl), nNOS inhibitor (SMTC) or NMDA receptor antagonist (MK-801). Nitric oxide production and the expression of NMDA receptor and nNOS were assessed by real-time RT-PCR and Western blot analyses in the medulla. At rest, Epo-TAg h mice displayed normal ventilatory parameters at 21% O 2 but did not respond to acute hypoxia despite a larger expression of NMDA receptors and nNOS in the medulla. Ventilatory acclimatization to hypoxia was observed in WT but was absent in Epo-TAg h mice. nNOS inhibition blunted the hypoxic ventilatory acclimatization of WT mice without any effect in Epo-TAg h mice. Acute hypoxic ventilatory response (HVR) was increased after chronic hypoxia in WT but remained unchanged in Epo-TAg h mice. Ventilatory response to acute hypoxia was modified by MK-801 injection in WT and Epo-TAg h mice. The results confirm that adequate erythropoietin level is necessary to obtain an appropriate HVR and a significant ventilatory acclimatization to hypoxia. Furthermore, erythropoietin plays a potential catalyzing role in the NMDA-NO central pathway during the ventilatory response and acclimatization to hypoxia.
Erythropoietin and its antagonist regulate hypoxic fictive breathing in newborn mice
Respiratory Physiology & Neurobiology, 2012
Clinical use of erythropoietin in adult and newborn patients has revealed its involvement in neuroprotection, neurogenesis, and angiogenesis. More recently, we showed in adult mouse, that brain erythropoietin interacts with the major brainstem centers associated with respiration to enhance the ventilatory response to acute and chronic conditions of physiological hypoxia (e.g., as occurring at high altitude). However, whether brain erythropoietin is involved in breathing regulation in newborns remains unknown. In this study, en bloc brainstem-spinal cord preparations were obtained from mice at postnatal day 4. After various periods (30, 60, or 90 min) of incubation with 0, 25, or 250 U of erythropoietin, preparations were superfused with artificial cerebrospinal fluid bubbled with normoxic or hypoxic gas mixtures. The electrophysiological fictive breathing produced by axons at the C4 ventral root was next recorded. Our results show that erythropoietin attenuates the hypoxia-mediated decrease of the central respiratory activity and improves post-hypoxic recovery. Additional analysis revealed that the soluble erythropoietin receptor (the endogenous erythropoietin antagonist) dramatically decreases neural hypoxic respiratory activity, confirming the specific erythropoietin effect on respiratory drive. These results imply that erythropoietin exerts main modulation and maintenance of respiratory motor output during hypoxic and post-hypoxic challenges in 4-days old mice.
Erythropoietin and its antagonist regulate the hypoxic fictive breathing in newborn mice
The FASEB Journal, 2012
Clinical use of erythropoietin in adult and newborn patients has revealed its involvement in neuroprotection, neurogenesis, and angiogenesis. More recently, we showed in adult mouse, that brain erythropoietin interacts with the major brainstem centers associated with respiration to enhance the ventilatory response to acute and chronic conditions of physiological hypoxia (e.g., as occurring at high altitude). However, whether brain erythropoietin is involved in breathing regulation in newborns remains unknown. In this study, en bloc brainstem-spinal cord preparations were obtained from mice at postnatal day 4. After various periods (30, 60, or 90 min) of incubation with 0, 25, or 250 U of erythropoietin, preparations were superfused with artificial cerebrospinal fluid bubbled with normoxic or hypoxic gas mixtures. The electrophysiological fictive breathing produced by axons at the C4 ventral root was next recorded. Our results show that erythropoietin attenuates the hypoxia-mediated decrease of the central respiratory activity and improves post-hypoxic recovery. Additional analysis revealed that the soluble erythropoietin receptor (the endogenous erythropoietin antagonist) dramatically decreases neural hypoxic respiratory activity, confirming the specific erythropoietin effect on respiratory drive. These results imply that erythropoietin exerts main modulation and maintenance of respiratory motor output during hypoxic and post-hypoxic challenges in 4-days old mice.
Current Chemical Biology, 2009
Hypoxia is a decrease in tissue oxygen concentration, normally caused by a reduction in the partial pressure of atmospheric oxygen. Due to the exposition to hypoxia, reactive oxygen species (ROS) are continuously generated and, therefore, increased risks of oxidative lesions have been reported. ROS may severely damage lipids, proteins and DNA. The most important source of ROS during hypoxia is the mitochondria, which release cytochrome c following oxidative damage. Once released, cytochrome c may activate the caspase cascade, switching on the apoptotic pathway. ROS generation is typically associated with brain injury. The brain contains low activity of antioxidants enzymes, it is rich in lipids and it has high metabolic activity. The combination of these factors makes the brain particularly vulnerable to oxidative stress. Also, it has recently been demonstrated that ROS acts as a physiological signal in many cells, including neurons. A protective role of ROS in neuronal plasticity has been suggested.
Sex-dependent regulation of hypoxic ventilation in mice and humans is mediated by erythropoietin
AJP: Regulatory, Integrative and Comparative Physiology, 2009
Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia. .-The objective of the present study was to examine the impact of early stages of lung injury on ventilatory control by hypoxia and hypercapnia. Lung injury was induced with intratracheal instillation of bleomycin (BM; 1 unit) in adult, male Sprague-Dawley rats. Control animals underwent sham surgery with saline instillation. Five days after the injections, lung injury was present in BM-treated animals as evidenced by increased neutrophils and protein levels in bronchoalveolar lavage fluid, as well as by changes in lung histology and computed tomography images. There was no evidence of pulmonary fibrosis, as indicated by lung collagen content. Basal core body temperature, arterial PO2, and arterial PCO2 were comparable between both groups of animals. Ventilatory responses to hypoxia (12% O2) and hypercapnia (7% CO2) were measured by whole body plethysmography in unanesthetized animals. Baseline respiratory rate and the hypoxic ventilatory response were significantly higher in BM-injected compared with control animals (P ϭ 0.003), whereas hypercapnic ventilatory response was not statistically different. In anesthetized, spontaneously breathing animals, response to brief hyperoxia (Dejours' test, an index of peripheral chemoreceptor sensitivity) and neural hypoxic ventilatory response were augmented in BM-exposed relative to control animals, as measured by diaphragmatic electromyelograms. The enhanced hypoxic sensitivity persisted following bilateral vagotomy, but was abolished by bilateral carotid sinus nerve transection. These data demonstrate that afferent sensory input from the carotid body contributes to a selective enhancement of hypoxic ventilatory drive in early lung injury in the absence of pulmonary fibrosis and arterial hypoxemia.