Search

Previous epidemiological studies have shown that the incidence and severity of COVID-19 decrease significantly with high altitude. To date, the impact of high altitude on mortality caused by COVID-19 remains debated. This work evaluated the impact of high altitude residency on COVID-19 mortality and recovery rates in several Andean countries and México. For this purpose, a multinational ecological study of official data from Bolivia, Peru, Colombia, Ecuador, and Mexico was performed from the beginning of the pandemic until the end of 2020. The case fatality rate (CFR) of populations above 2,500 m and below 1,000 m was compared. Our results show that CFR decreases, and there is a higher recovery rate in populations located above 2,500 m in all five countries. Based on this study and multiple other references, we conclude that mortality caused by COVID-19 is lower in high-altitude Andean populations, and in the high-altitude municipalities of Mexico than in the lowlands of all these countries.

Patients admitted to the Intensive Care Unit (ICU) with acute hypoxemic respiratory failure automatically receive oxygen therapy to improve inspiratory oxygen fraction (FiO

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 (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., Robert Jacobs, Mostafa Aboouf, et al. examined the effect of erythropoietin (EPO) in hippocampal mitochondrial function and memory in two mouse models: one overexpressing EPO in the brain, and juvenile mice treated during three days with a high dose of intraperitoneal EPO. Their results suggest that erythropoietin in the neonatal brain may impact spatial memory by increasing mitochondrial content.

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.

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 capacity is lower in the highlands (>1,000 masl) than in the lowlands (HighlightsThere is a negative correlation between altitude and COVID-19 incidence on the American Continent starting from 1,000 m above sea level.The transmission rate of SARS-CoV-2 is lower in the highlands than in the lowlands.The severity of COVID-19 decreases significantly with increased altitude.

Phylogeographic studies showed that house mice (Mus musculus) originated in the Himalayan region, while common rats (Rattus rattusandRattus 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 (fR), and tidal volume (VT)], hematological (hematocrit and hemoglobin concentration), and metabolic [whole-body O2consumption (VO2) and CO2production (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.

Lower mortality due to COVID-19 in Bolivian and Peruvian highlanders compared to lowlanders.

It is increasingly evident that mitochondria are crucial in regulating neurodevelopment, brain function and cognition. Erythropoietin (EPO) has been shown to improve mitochondrial function and cognition following brain damage and in patients with neurological disorders. However, potential EPO-mediated influence(s) on hippocampal mitochondrial function during postnatal development and it corresponds to enhanced cognition is unknown. Here we show in mice, that EPO receptors (EpoR)s express postnatally in the CA1 pyramidal cells of the hippocampus reaching a zenith at puberty (postnatal (P) age 21). Constitutive neuronal EPO overexpression increases hippocampal Erk1/2 and AKT phosphorylation along with increases in cellular respiration and mitochondrial content by the third postnatal week of development. Indices of cellular oxidant balance do not appear altered by higher respiratory potentials and greater mitochondrial content. Finally, EPO overexpression also enhances hippocampal-dependent learning and memory at early adulthood (P60). Collectively, this data identifies a novel function for EPO signaling, promoting improvements in hippocampal-specific mitochondrial function and cognition during postnatal development and early adulthood.

Mitochondria play a major role in the brain. Apart from energy production, mitochondria regulate key factors in the activation of cell signaling pathways such as survival, proliferation, and differentiation. While all these processes occur during the physiological development of the brain, it is surprising that the mitochondrial functions and functioning in the brain during the postnatal development remain poorly explored. In this work, we collected samples of brainstem and cortex of mice at postnatal ages 3 (P3), 21 (P21), and at adulthood (3 months old) and evaluated the mitochondrial oxygen consumption after complex I activation. To do so, we used our oxygraph-2 K system (OROBOROS) that measures the mitochondrial bioenergetics in saponin-permeabilized tissue punches of 2 mg weight. Furthermore, as sex dimorphism in the brain occurs since very early stages of development, we performed experiments in brain samples of male and female mice. Accordingly, the mitochondrial oxygen consumption rate (OCR) was evaluated under activation of complex I (NADH-linked respiration – mitochondrial state 3), and during the inhibition of the complex V (ATP synthase) with oligomycin (mitochondrial state 4). In following, the respiratory control ratio (RCR – state 3/state4) was calculated as an index of mitochondrial oxidative-phosphorylation coupling. Our results show that the activity of the mitochondrial complex I in the brain increases along with the postnatal development in a sex- and tissue-dependent manner, with males showing higher activity than females, and with brainstem tissue showing higher activity than cortex. Our data may contribute to a better understanding of the sex-dependent maturation of the cortex and the cardiorespiratory network located in the brainstem.

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.

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.

Highlights • Epidemiological data suggests that the physiological mechanisms underlying highaltitude. • acclimatization may provide possible avenues to identify therapeutic targets for prophylaxis and treatment of COVID-19. • Acute mountain sickness (AMS) and SARS-CoV-2 virus-induced infection share striking similarities. • Erythropoietin and erythropoietin derivatives should be considered as putative adjuvants in the treatment of COVID-19., A very recent epidemiological study provides preliminary evidence that living in habitats located at 2500 m above sea level and higher 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 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. High-altitude environments of 2500 m above sea level (masl) are characterized by barometric hypoxia. Chronic exposure to hypobaric hypoxia in such extreme and adverse environments evokes short- and long-term physiologic adaptations to maintain tissue oxygen levels at high altitude in animals and humans. Recent work suggests that high altitude dewellers, in particular in American countries and Tibet (Arias-Reyes et al., 2020; Ortiz-Prado et al., 2020), may present with lower infection rates and/or less severe symptoms of COVID-19 compared to lowlanders (Arias-Reyes et al., 2020; Lei et al., 2020; Ortiz-Prado et al., 2020). This epidemiologic finding raises the question of whether physiological mechanisms underlying the acclimatization to high altitude or in turn the development of acute mountain sickness (AMS), may provide potential avenues for understanding the severity of symptoms and treatment of SARS-CoV-2 infection. Here, we provide a survey of similarities of acute mountain sickness to COVID-19 and suggest that the physiologic response to high altitude, characterized by an increase in erythropoietin (EPO), may provide a framework to develop an adjuvant therapy in COVID-19. Indeed, a recently published case study from Iran supports EPO as an effective treatment of severe COVID-19 patho-physiology (Hadadi et al., 2020).

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.

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.