Prenatal immune activation in mice induces long-term alterations in brain mitochondrial function.

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation (MIA) based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased nicotinamidadenindinucleotid (NADH)- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

Impact of High-Flow Nasal Cannula Use in Subjects With COVID-19 ARDS at High Altitudes: Clinical Presentation and Prognostic Factors.

BACKGROUND: High-flow nasal cannula (HFNC) reduces the need for intubation in adult subject with acute respiratory failure. Changes in hypobaric hypoxemia have not been studied for subject with an HFNC in ICUs at altitudes > 2,600 m above sea level. In this study, we investigated the efficacy of HFNC treatment in subjects with COVID-19 at high altitudes. We hypothesized that progressive hypoxemia and the increase in breathing frequency associated with COVID-19 in high altitudes affect the success of HFNC therapy and may also influence the performance of the traditionally used predictors of success and failure. METHODS: This was a prospective cohort study of subjects >18 y with a confirmed diagnosis of COVID-19-induced ARDS requiring HFNC who were admitted to the ICU. Subjects were followed up during the 28 d of HFNC treatment or until failure. RESULTS: One hundred and eight subjects were enrolled. At admission to the ICU, FIO2 delivery between 0.5-0.8 (odds ratio 0.38 [95% CI 0.17-0.84]) was associated with a better response to HFNC therapy than oxygen delivery on admission between 0.8-1.0 (odds ratio 3.58 [95% CI 1.56-8.22]). This relationship continued during follow-ups at 2, 6, 12, and 24 h, with a progressive increase in the risk of failure (odds ratio 24 h 13.99 [95% CI 4.32-45.26]). A new cutoff for the ratio of oxygen saturation (ROX) index (ROX ≥ 4.88) after 24 h of HFNC administration was demonstrated to be the best predictor of success (odds ratio 11.0 [95% CI 3.3-47.0]). CONCLUSIONS: High-altitude subjects treated with HFNC for COVID-19 showed a high risk of respiratory failure and progressive hypoxemia when FIO2 requirements were > 0.8 after 24 h of treatment. In these subjects, personalized management should include continuous monitoring of individual clinical conditions (such as oxygenation indices, with cutoffs adapted to those corresponding to high-altitude cities).

The ultrasound-based cardiac output monitoring is a useful tool to define baseline hemodynamic parameters in healthy permanent residents at high altitude: results of a monocentric pilot study.

Previous studies on the cardiac data of healthy permanent residents living in high-altitude regions such as Tibet and the Andes have yielded inconsistent findings and significant disparities. These discrepancies can be mainly attributed to the invasive methods conventionally used for parameter evaluation. However, with the introduction of cutting-edge ultrasound technology, there is now an innovative approach to addressing and reconciling these variations. In this pilot study, we employed an ultrasound-based cardiac output monitoring (USCOM) device to evaluate cardiac output and related hemodynamic variables in a group of 20 healthy high-altitude Andean residents (comprising 10 men and 10 women) aged between 26 and 35 years old. The monocentric study was carried out in La Paz, Bolivia, located between at an altitude of 3,600-4,000 m. A total of 60 hemodynamic measurements were evaluated, accounting for three technical replicates per subject. Our results showed strong intrasubject reproducibility and revealed important differences related to both sex and hemodynamic parameters in highlanders compared to individuals residing at sea level. We conclude that USCOM represents a highly reliable technology for performing hemodynamic measurements in high-altitude residents. Our preliminary findings underscore the need for larger studies, encompassing larger sample sizes, specifically tailored to gender considerations, and extendable to broader highland populations. These findings have special significant implications for the management of hemodynamics in intensive care and postoperative settings, warranting further comprehensive research efforts.

Malat1 deficiency prevents hypoxia-induced lung dysfunction by protecting the access to alveoli.

Hypoxia is common in lung diseases and a potent stimulator of the long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1). Herein, we investigated the impact of Malat1 on hypoxia-induced lung dysfunction in mice. Malat1-deficient mice and their wild-type littermates were tested after 8 days of normoxia or hypoxia (10% oxygen). Hypoxia decreased elastance of the lung by increasing lung volume and caused in vivo hyperresponsiveness to methacholine without altering the contraction of airway smooth muscle. Malat1 deficiency also modestly decreased lung elastance but only when tested at low lung volumes and without altering lung volume and airway smooth muscle contraction. The in vivo responsiveness to methacholine was also attenuated by Malat1 deficiency, at least when elastance, a readout sensitive to small airway closure, was used to assess the response. More impressively, in vivo hyperresponsiveness to methacholine caused by hypoxia was virtually absent in Malat1-deficient mice, especially when hysteresivity, a readout sensitive to small airway narrowing heterogeneity, was used to assess the response. Malat1 deficiency also increased the coefficient of oxygen extraction and decreased ventilation in conscious mice, suggesting improvements in gas exchange and in clinical signs of respiratory distress during natural breathing. Combined with a lower elastance at low lung volumes at baseline, as well as a decreased propensity for small airway closure and narrowing heterogeneity during a methacholine challenge, these findings represent compelling evidence suggesting that the lack of Malat1 protects the access to alveoli for air entering the lung.

Oxygen therapy limiting peripheral oxygen saturation to 89-93% is associated with a better survival prognosis for critically ill COVID-19 patients at high altitudes.

Patients admitted to the Intensive Care Unit (ICU) with acute hypoxemic respiratory failure automatically receive oxygen therapy to improve inspiratory oxygen fraction (FiO2). Supplemental oxygen is the most prescribed drug for critically ill patients regardless of altitude of residence. In high altitude dwellers (i.e. in La Paz [≈3,400 m] and El Alto [≈4,150 m] in Bolivia), a peripheral oxygen saturation (SatpO2) of 89-95% and an arterial partial pressure of oxygen (PaO2) of 50-67 mmHg (lower as altitude rises), are considered normal values ​​for arterial blood. Consequently, it has been suggested that limiting oxygen therapy to maintain SatpO2 around normoxia may help avoid episodes of hypoxemia, hyperoxemia, intermittent hypoxemia, and ultimately, mortality. In this study, we evaluated the impact of oxygen therapy on the mortality of critically ill COVID-19 patients who permanently live at high altitudes. A multicenter cross-sectional descriptive observational study was performed on 100 patients admitted to the ICU at the "Clinica Los Andes" (in La Paz city) and "Agramont" and "Del Norte" Hospitals (in El Alto city). Our results show that: 1) as expected, fatal cases were detected only in patients who required intubation and connection to invasive mechanical ventilation as a last resort to overcome their life-threatening desaturation; 2) among intubated patients, prolonged periods in normoxia are associated with survival, prolonged periods in hypoxemia are associated with death, and time spent in hyperoxemia shows no association with survival or mortality; 3) the oxygenation limits required to effectively support the intubated patients' survival in the ICU are between 89% and 93%; 4) among intubated patients with similar periods of normoxemic oxygenation, those with better SOFA scores survive; and 5) a lower frequency of observable reoxygenation events is not associated with survival. In conclusion, our findings indicate that high-altitude patients entering an ICU at altitudes of 3,400 - 4,150 m should undergo oxygen therapy to maintain oxygenation levels between 89 and 93 %.

Erythropoietin Produces a Dual Effect on Carotid Body Chemoreception in Male Rats.

Erythropoietin (EPO) regulates respiration under conditions of normoxia and hypoxia through interaction with the respiratory centers of the brainstem. Here we investigate the dose-dependent impact of EPO in the CB response to hypoxia and hypercapnia. We show, in isolated "en bloc" carotid body (CB) preparations containing the carotid sinus nerve (CSN) from adult male Sprague Dawley rats, that EPO acts as a stimulator of CSN activity in response to hypoxia at concentrations below 0.5 IU/ml. Under hypercapnic conditions, EPO did not influence the CSN response. EPO concentrations above 0.5 IU/ml decreased the response of the CSN to both hypoxia and hypercapnia, reaching complete inhibition at 2 IU/ml. The inhibitory action of high-dose EPO on the CSN activity might result from an increase in nitric oxide (NO) production. Accordingly, CB preparations were incubated with 2 IU/ml EPO and the unspecific NO synthase inhibitor (L-NAME), or the neuronal-specific NO synthase inhibitor (7NI). Both NO inhibitors fully restored the CSN activity in response to hypoxia and hypercapnia in presence of EPO. Our results show that EPO activates the CB response to hypoxia when its concentration does not exceed the threshold at which NO inhibitors masks EPO's action.

Erythropoietin promotes hippocampal mitochondrial function and enhances cognition in mice.

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.

Low serum erythropoietin levels are associated with fatal COVID-19 cases at 4,150 meters above sea level.

Previous studies suggested that erythropoietin (EPO) may protect against severe COVID-19-induced injuries, ultimately preventing mortality. This hypothesis is based on the fact that, in addition to promoting the increase in red blood cells, EPO is an anti-inflammatory, anti-apoptotic and protective factor in several non-erythropoietic tissues. Furthermore, EPO promotes nitric oxide production in the hypoxic lung and stimulates ventilation by interacting with the respiratory centers of the brainstem. Given that EPO in the blood is increased at high-altitude, we evaluated the serum levels of EPO in critical patients with COVID-19 at "Hospital Agramont" in the city of El Alto (4150 masl) in Bolivia. A total of 16 patients, 15 men, one woman, with a mean age of 55.8 ± 8.49 years, admitted to the Intensive Care Unit were studied. All patients were permanent residents of El Alto, with no travel history below 3000 masl for at least one year. Blood samples were collected upon admission to the ICU. Serum EPO concentration was assessed using an ELISA kit, and a standard technique determined hemoglobin concentration. Only half of the observed patients survived the disease. Remarkably, fatal cases showed 2.5 times lower serum EPO than survivors (2.78 ± 0.8643 mU/mL vs 7.06 ± 2.713 mU/mL; p = 0.0096), and 1.24 times lower hemoglobin levels (13.96 ± 2.56 g/dL vs 17.41 ± 1.61 g/dL; p = 0.0159). While the number of cases evaluated in this work is low, our findings strongly warrant further investigation of EPO levels in COVID-19 patients at high and low altitudes. Our results also support the hypothesis that exogenous EPO administration could help critically ill COVID-19 patients overcome the disease.

Mice and Rats Display Different Ventilatory, Hematological, and Metabolic Features of Acclimatization to Hypoxia.

Phylogeographic studies showed that house mice (Mus musculus) originated in the Himalayan region, while common rats (Rattus rattus and Rattus norvegicus) come from the lowlands of China and India. Accordingly, it has been proposed that its origins gave mice, but not rats, the ability to invade ecological niches at high altitudes (pre-adaptation). This proposal is strongly supported by the fact that house mice are distributed throughout the world, while common rats are practically absent above 2,500 m. Considering that the ability of mammals to colonize high-altitude environments (>2,500 m) is limited by their capability to tolerate reduced oxygen availability, in this work, we hypothesize that divergences in the ventilatory, hematological, and metabolic phenotypes of mice and rats establish during the process of acclimatization to hypoxia (Hx). To test this hypothesis male FVB mice and Sprague-Dawley (SD) rats were exposed to Hx (12% O2) for 0 h (normoxic controls), 6 h, 1, 7, and 21 days. We assessed changes in ventilatory [minute ventilation (VE), respiratory frequency (f R), and tidal volume (VT)], hematological (hematocrit and hemoglobin concentration), and metabolic [whole-body O2 consumption (VO2) and CO2 production (VCO2), and liver mitochondrial oxygen consumption rate (OCR) parameters]. Compared to rats, results in mice show increased ventilatory, metabolic, and mitochondrial response. In contrast, rats showed quicker and higher hematological response than mice and only minor ventilatory and metabolic adjustments. Our findings may explain, at least in part, why mice, but not rats, were able to colonize high-altitude habitats.

Decreased incidence, virus transmission capacity, and severity of COVID-19 at altitude on the American continent.

The coronavirus disease 2019 (COVID-19) outbreak in North, Central, and South America has become the epicenter of the current pandemic. We have suggested previously that the infection rate of this virus might be lower in people living at high altitude (over 2,500 m) compared to that in the lowlands. Based on data from official sources, we performed a new epidemiological analysis of the development of the pandemic in 23 countries on the American continent as of May 23, 2020. Our results confirm our previous finding, further showing that the incidence of COVID-19 on the American continent decreases significantly starting at 1,000 m above sea level (masl). Moreover, epidemiological modeling indicates that the virus transmission rate is lower in the highlands (>1,000 masl) than in the lowlands (<1,000 masl). Finally, evaluating the differences in the recovery percentage of patients, the death-to-case ratio, and the theoretical fraction of undiagnosed cases, we found that the severity of COVID-19 is also decreased above 1,000 m. We conclude that the impact of the COVID-19 decreases significantly with altitude.

Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress.

Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3-12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

Coping with hypoxemia: Could erythropoietin (EPO) be an adjuvant treatment of COVID-19?

A very recent epidemiological study provides preliminary evidence that living in habitats located at 2500 m above sea level (masl) might protect from the development of severe respiratory symptoms following infection with the novel SARS-CoV-2 virus. This epidemiological finding raises the question of whether physiological mechanisms underlying the acclimatization to high altitude identifies therapeutic targets for the effective treatment of severe acute respiratory syndrome pivotal to the reduction of global mortality during the COVID-19 pandemic. This article compares the symptoms of acute mountain sickness (AMS) with those of SARS-CoV-2 infection and explores overlapping patho-physiological mechanisms of the respiratory system including impaired oxygen transport, pulmonary gas exchange and brainstem circuits controlling respiration. In this context, we also discuss the potential impact of SARS-CoV-2 infection on oxygen sensing in the carotid body. Finally, since erythropoietin (EPO) is an effective prophylactic treatment for AMS, this article reviews the potential benefits of implementing FDA-approved erythropoietin-based (EPO) drug therapies to counteract a variety of acute respiratory and non-respiratory (e.g. excessive inflammation of vascular beds) symptoms of SARS-CoV-2 infection.

Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude?

In the present study we analyze the epidemiological data of COVID-19 of Tibet and high-altitude regions of Bolivia and Ecuador, and compare to lowland data, to test the hypothesis that high-altitude inhabitants (+2,500 m above sea-level) are less susceptible to develop severe adverse effects in acute SARS-CoV-2 virus infection. Analysis of available epidemiological data suggest that physiological acclimatization/adaptation that counterbalance the hypoxic environment in high-altitude may protect from severe impact of acute SARS-CoV-2 virus infection. Potential underlying mechanisms such as: (i) a compromised half-live of the virus caused by the high-altitude environment, and (ii) a hypoxia mediated down regulation of angiotensin-converting enzyme 2 (ACE2), which is the main binding target of SARS-CoV-2 virus in the pulmonary epithelium are discussed.

Metabolic Adaptation of Airway Smooth Muscle Cells to an SPHK2 Substrate Precedes Cytostasis.

Thickening of the airway smooth muscle is central to bronchial hyperreactivity. We have shown that the sphingosine analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) can reverse preestablished airway hyperreactivity in a chronic asthma model. Because sphingosine analogs can be metabolized by SPHK2 (sphingosine kinase 2), we investigated whether this enzyme was required for AAL-R to perturb mechanisms sustaining airway smooth muscle cell proliferation. We found that AAL-R pretreatment reduced the capacity of live airway smooth muscle cells to use oxygen for oxidative phosphorylation and increased lactate dehydrogenase activity. We also determined that SPHK2 was upregulated in airway smooth muscle cells bearing the proliferation marker Ki67 relative to their Ki67-negative counterpart. Comparing different stromal cell subsets of the lung, we found that high SPHK2 concentrations were associated with the ability of AAL-R to inhibit metabolic activity assessed by conversion of the tetrazolium dye MTT. Knockdown or pharmacological inhibition of SPHK2 reversed the effect of AAL-R on MTT conversion, indicating the essential role for this kinase in the metabolic perturbations induced by sphingosine analogs. Our results support the hypothesis that increased SPHK2 levels in proliferating airway smooth muscle cells could be exploited to counteract airway smooth muscle thickening with synthetic substrates.

Erythropoietin and caffeine exert similar protective impact against neonatal intermittent hypoxia: Apnea of prematurity and sex dimorphism.

Apnea of prematurity (AoP) is associated with severe and repeated episodes of arterial oxygen desaturation (intermittent hypoxia - IH), which in turn increases the number of apneas. So far, there is no data addressing whether IH leads to sex-specific respiratory consequences, neither if drugs targeting AoP are more effective in males or females. We used rat pups for investigating whether IH-mediated increase of apneas is sex-specific. We also tested whether caffeine (treatment of choice of AoP), erythropoietin (Epo - a neuroprotective factor and potent respiratory stimulant), and combination of both (caffeine+Epo) prevent the IH-mediated formation of apneas in a sex-dependent manner. Newborn rats exposed to IH (21% - 10% FIO2-8 h a day - 10 cycles per hour) during postnatal days (P) 3-10 were used in this work. Animals were administered drug vehicle, Epo, caffeine and Epo + caffeine (daily from P3 to P10) gavage. At P10 the frequency of apneas at rest (as an index of respiratory dysfunction induced by IH), and respiratory parameters were measured by plethysmography. Our results showed that IH significantly increases the number of apneas in male but not in female rat pups. Moreover, caffeine and Epo in males similarly prevented the increase of apneas induced by IH, and the administration of both drugs together did not provide a cumulative beneficial effect. No impact of drugs was evidenced in females. Apart from apneas, IH increased the normoxic basal ventilation (ventilation at rest) of male animals, and treatments did not prevent such alteration. Besides, no IH- nor treatment-mediated modulation of basal ventilation was found in the basal ventilation of female animals. Analysis of the activity of pro- and antioxidative molecules revealed that IH induces oxidative stress in the brainstem of male and female animals and that all tested treatments similarly prevented such oxidative imbalance in pups of both sexes. We concluded that neonatal IH and the treatments tested to prevent its respiratory consequences are sex-specific. The mechanics associated with such prevention are directly linked with the prevention of oxidative stress and the maturation of the brain. These findings are relevant to understanding better the AoP disorder and for proposing Epo as a new therapeutical tool.

Developmental expression patterns of erythropoietin and its receptor in mouse brainstem respiratory regions.

Erythropoietin (EPO) is a hypoxia-inducible hormone, classically known to enhance red blood cell production upon binding its receptor (EPOR) present on the surface of the erythroid progenitor cells. EPO and its receptor are also expressed in the central nervous system (CNS), exerting several non-hematopoietic actions. EPO also plays an important role in the control of breathing. In this review, we summarize the known physiological actions of EPO in the neural control of ventilation during postnatal development and at adulthood in rodents under normoxic and hypoxic conditions. Furthermore, we present the developmental expression patterns of EPO and EPORs in the brainstem, and with the use of in situ hybridization (ISH) and immunofluorescence techniques we provide original data showing that EPOR is abundantly present in specific brainstem nuclei associated with central chemosensitivity and control of ventilation in the ventrolateral medulla, mainly on somatostatin negative cells. Thus, we conclude that EPO signaling may act through glutamatergic neuron populations that are the primary source of rhythmic inspiratory excitatory drive. This work underlies the importance of EPO signaling in the central control of ventilation across development and adulthood and provides new insights on the expression of EPOR at the cellular level.

Brain-derived erythropoietin protects from intermittent hypoxia-induced cardiorespiratory dysfunction and oxidative stress in mice.

Study Objectives: Based on the fact that erythropoietin (Epo) administration in rodents protects against spatial learning and cognitive deficits induced by chronic intermittent hypoxia (CIH)-mediated oxidative damage, here we tested the hypothesis that Epo in the brain protects against cardiorespiratory disorders and oxidative stress induced by CIH in adult mice. Methods: Adult control and transgenic mice overexpressing Epo in the brain only (Tg21) were exposed to CIH (21%-10% O2-10 cycles/hour-8 hours/day-7 days) or room air. After CIH exposure, we used the tail cuff method to measure arterial pressure, and whole-body plethysmography to assess the frequency of apneic episodes at rest, minute ventilation, and ventilatory responses to hypoxia and hypercapnia. Finally, the activity of pro-oxidant (XO-xanthine oxidase, and NADPH) and antioxidant (super oxide dismutase) enzymes was evaluated in the cerebral cortex and brainstem. Results: Exposure of control mice to CIH significantly increased the heart rate and arterial pressure, the number of apneic events, and the ventilatory response to hypoxia and hypercapnia. Furthermore, CIH increased the ratio of pro-oxidant to antioxidant enzymes in cortex and brainstem tissues. Both physiological and molecular changes induced by CIH were prevented in transgenic Tg21 mice. Conclusions: We conclude that the neuroprotective effect of Epo prevents oxidative damage in the brain and cardiorespiratory disorders induced by CIH. Considering that Epo is used in clinics to treat chronic kidney disease and stroke, our data show convincing evidence suggesting that Epo may be a promising alternative drug to treat sleep-disorder breathing.