Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased ...high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2 release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O2 release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O2 delivery and thus new therapeutic opportunities to counteract tissue hypoxia.
Adults born preterm, regardless of whether they develop bronchopulmonary dysplasia, have underdeveloped respiratory and cardiopulmonary systems. The resulting impaired respiratory and cardiopulmonary ...systems are inadequate for the challenges imposed by aerobic exercise, which is exacerbated by the presence of bronchopulmonary dysplasia. Thus the respiratory and cardiopulmonary systems of these preterm individuals may be the most influential contributors to the significantly lower aerobic exercise capacity compared with their term born counterparts. The precise underlying cause(s) of the lower aerobic exercise capacity in adults born preterm is not entirely known but could be a number of interrelated parameters including mechanical ventilatory constraints, impaired pulmonary gas exchange efficiency, and excessive cardiopulmonary pressures. Likewise, additional aspects, such as impaired cardiovascular function and altered muscle bioenergetics, may play additional roles in limiting aerobic exercise capacity. Whether or not all or some of these aspects are present in adults born preterm and precisely how they may contribute to the lower aerobic exercise capacity are only beginning to be systematically explored. The purpose of this mini-review is to outline what is currently known about the respiratory and cardiopulmonary limitations during exercise in this population and to identify key areas where additional knowledge will help to advance this area. Additionally, where possible, we highlight the similarities and differences between obstructive lung disease resulting from preterm birth and chronic obstructive pulmonary disease (COPD) as the physiology and pathophysiology of these two forms of obstructive lung disease may not be identical.
Goss and Lovering discuss the subgroup analysis, presented by Burchert et al, from the recent Trial of Exercise to Prevent HypeRtension in young Adults (TEPHRA trial) comparing the intervention ...response between term and preterm participants. Both exercise intervention groups showed an increased estimated cardiac index at ventilatory threshold, although this appeared to be through greater increases in heart rate among preterm participants rather than greater increases in calculated stroke volume in term-born participants. Preterm participants also exhibited larger increases in minute ventilation at ventilatory threshold. The TEPHRA trial is the first to examine exercise intervention in the preterm-born adult population.
Progressive improvements in perinatal care and respiratory management of preterm infants have resulted in increased survival of newborns of extremely low gestational age over the past few decades. ...However, the incidence of bronchopulmonary dysplasia, the chronic lung disease after preterm birth, has not changed. Studies of the long‐term follow‐up of adults born preterm have shown persistent abnormalities of respiratory, cardiovascular and cardiopulmonary function, possibly leading to a lower exercise capacity. The underlying causes of these abnormalities are incompletely known, but we hypothesize that dysanapsis, i.e. discordant growth and development, in the respiratory and cardiovascular systems is a central structural feature that leads to a lower exercise capacity in young adults born preterm than those born at term. We discuss how the hypothesized system dysanapsis underscores the observed respiratory, cardiovascular and cardiopulmonary limitations. Specifically, adults born preterm have: (1) normal lung volumes but smaller airways, which causes expiratory airflow limitation and abnormal respiratory mechanics but without impacts on pulmonary gas exchange efficiency; (2) normal total cardiac size but smaller cardiac chambers; and (3) in some cases, evidence of pulmonary hypertension, particularly during exercise, suggesting a reduced pulmonary vascular capacity despite reduced cardiac output. We speculate that these underlying developmental abnormalities may accelerate the normal age‐associated decline in exercise capacity, via an accelerated decline in respiratory, cardiovascular and cardiopulmonary function. Finally, we suggest areas of future research, especially the need for longitudinal and interventional studies from infancy into adulthood to better understand how preterm birth alters exercise capacity across the lifespan.
figure legend Very preterm birth, i.e. birth occurring prior to completion of 32 weeks of gestation, creates challenges to neonatal life. The period of infancy and adolescence is characterized by abnormal development leading to pulmonary and cardiovascular dysanapsis. Various aspects of respiratory (e.g. lesser expiratory airflow, mechanical ventilatory constraints), cardiopulmonary (e.g. reduced pulmonary vascular capacity, greater pulmonary vascular pressures and resistance) and cardiovascular (e.g. reduced ventricular volumes and myocardial functional reserve) function are impaired. In combination, these aspects lead to a significantly reduced aerobic exercise capacity in adults born preterm. This topical review outlines the known and unknown physiological factors that explain the observed aerobic exercise capacity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND:High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even ...death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia.
METHODS:Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m.
RESULTS:This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation.
CONCLUSIONS:Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.
There is a growing concern for preterm birth and low birth weight population as those born preterm have an increased risk of early mortality from noncommunicable diseases but, surprisingly, not ...morbidity at ages 18-43 years. There is also evidence for an association between birthweight and risk of mortality. Thus, there is an urgent need to determine the reason(s) for the increased risk of mortality for the ever-growing population. Aerobic exercise capacity is an important predictor of all-cause mortality and morbidity in, presumably, term-born, normal birthweight men and women. However, this has not yet been established in those born preterm with very LBW (VLBW). Interestingly, there are multiple reports demonstrating reduced aerobic exercise capacity in adults born preterm, which raises the possibility that the lower aerobic exercise capacity may be the link between preterm birth and the increased mortality risk. Here, Lovering and Duke highlight the study by Yang and colleagues that provide compelling evidence in a population-based cohort that impaired respiratory and cardiovascular function is associated with reduced aerobic exercise capacity in those born preterm with VLBW.
Faster acclimatization to high altitude upon re-ascent is seen in humans; however, the molecular basis for this enhanced adaptive response is unknown. We report that in healthy lowlanders, plasma ...adenosine levels are rapidly induced by initial ascent to high altitude and achieved even higher levels upon re-ascent, a feature that is positively associated with quicker acclimatization. Erythrocyte equilibrative nucleoside transporter 1 (eENT1) levels are reduced in humans at high altitude and in mice under hypoxia. eENT1 deletion allows rapid accumulation of plasma adenosine to counteract hypoxic tissue damage in mice. Adenosine signalling via erythrocyte ADORA2B induces PKA phosphorylation, ubiquitination and proteasomal degradation of eENT1. Reduced eENT1 resulting from initial hypoxia is maintained upon re-ascent in humans or re-exposure to hypoxia in mice and accounts for erythrocyte hypoxic memory and faster acclimatization. Our findings suggest that targeting identified purinergic-signalling network would enhance the hypoxia adenosine response to counteract hypoxia-induced maladaptation.
It is classically thought that increases in hemoglobin mass (Hbmass) take several weeks to develop upon ascent to high altitude and are lost gradually following descent. However, the early time ...course of these erythropoietic adaptations has not been thoroughly investigated and data are lacking at elevations greater than 5000 m, where the hypoxic stimulus is dramatically increased. As part of the AltitudeOmics project, we examined Hbmass in healthy men and women at sea level (SL) and 5260 m following 1, 7, and 16 days of high altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260 m following descent to 1525 m for either 7 or 21 days. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7 ± 5.8% (mean ± SD; n = 20; p<0.01) at ALT7 and 7.6 ± 6.6% (n = 21; p<0.001) at ALT16. Following descent to 1525 m, Hbmass was reduced compared to ALT16 (-6.0 ± 3.7%; n = 20; p = 0.001) and not different compared to SL, with no difference in the loss in Hbmass between groups that descended for 7 (-6.3 ± 3.0%; n = 13) versus 21 days (-5.7 ± 5.0; n = 7). The loss in Hbmass following 7 days at 1525 m was correlated with an increase in serum ferritin (r = -0.64; n = 13; p<0.05), suggesting increased red blood cell destruction. Our novel findings demonstrate that Hbmass increases within 7 days of ascent to 5260 m but that the altitude-induced Hbmass adaptation is lost within 7 days of descent to 1525 m. The rapid time course of these adaptations contrasts with the classical dogma, suggesting the need to further examine mechanisms responsible for Hbmass adaptations in response to severe hypoxia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intrapulmonary arteriovenous anastomoses (IPAVA) have been known to exist in human lungs for over 60 years. The majority of the work in this area has largely focused on characterizing the conditions ...in which IPAVA blood flow (Q̇IPAVA) is either increased, e.g. during exercise, acute normobaric hypoxia, and the intravenous infusion of catecholamines, or absent/decreased, e.g. at rest and in all conditions with alveolar hyperoxia (FIO2 = 1.0). Additionally, Q̇IPAVA is present in utero and shortly after birth, but is reduced in older (>50 years) adults during exercise and with alveolar hypoxia, suggesting potential developmental origins and an effect of age. The physiological and pathophysiological roles of Q̇IPAVA are only beginning to be understood and therefore these data remain controversial. Although evidence is accumulating in support of important roles in both health and disease, including associations with pulmonary arterial pressure, and adverse neurological sequelae, there is much work that remains to be done to fully understand the physiological and pathophysiological roles of IPAVA. The development of novel approaches to studying these pathways that can overcome the limitations of the currently employed techniques will greatly help to better quantify Q̇IPAVA and identify the consequences of Q̇IPAVA on physiological and pathophysiological processes. Nevertheless, based on currently published data, our proposed working model is that Q̇IPAVA occurs due to passive recruitment under conditions of exercise and supine body posture, but can be further modified by active redistribution of pulmonary blood flow under hypoxic and hyperoxic conditions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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