2020/12/02 by Paul Robach, Carsten Lundby · 1 citation
Biochemistry, Genetics and Molecular Biology · #High Altitude and Hypoxia #Hemoglobin structure and function #Heme Oxygenase-1 and Carbon Monoxide
paper · pdf · doi:10.1113/jp281028
Exposure to high-altitude hypobaric hypoxia triggers systemic changes in respiratory, cardiovascular and haematopoietic physiology that collectively defend convective oxygen transport. With acclimatization, haematocrit and haemoglobin concentration rapidly increase so that arterial oxygen content normalizes to sea-level values. While most may associate this haemoconcentration with increases in total red blood cell volume, it is in fact primarily the result of a reduction in plasma volume (PV). While PV contraction in hypoxia is a recognized phenomenon, its underlying mechanisms remain debated. The most common explanation refers to an increased diuretic fluid loss, presumably favoured by early changes in water- and salt-regulating hormones. An alternative explanation rests on an oncotically driven fluid shift from the intra- to the extravascular space. The question of the mechanism(s) governing PV contraction in hypoxia remains a complex issue, as PV is influenced by various biological and environmental factors, such as hydration, diet, physical activity and temperature. A recent review highlighting this complexity concludes by underlining the importance of controlling experimental conditions to isolate the effect of hypoxia per se on PV (Siebenmann et al. 2017), thus providing a rationale for the study by Schlittler et al. (2021) published in this issue of The Journal of Physiology. The strength of the study resides within its experimental approach: in a cross-over design, healthy lowlanders spent two times 4 days in a hypobaric chamber, once in hypoxia equivalent to 3500 m altitude and once in normoxia, with water/food intake, exercise and temperature strictly matched between the two exposures. Comparing the effects of the two exposures thus allowed the authors to isolate the effect of hypobaric hypoxia and thereby to collect robust data that may advance our understanding of PV regulation in hypoxia. Curiously, none of the subjects developed symptoms of acute mountain sickness (AMS). This is quite an unusual response, which may partly be due to chance, but which nonetheless had the advantage of eliminating a confounding factor, AMS, known to induce fluid retention. PV was not quantified directly but derived from CO re-breathing-based assessment of total haemoglobin mass and peripheral venous haematocrit. Like any method using peripheral haematocrit to derive PV, this approach assumes that the F-cell ratio (overall-to-peripheral venous haematocrit ratio) remains constant. If not, the observed changes in haematocrit in hypoxia would reflect not only an absolute reduction in PV but also a possible redistribution of PV within the vascular system. Although the latter may be a minor phenomenon in view of the numerous studies showing PV contraction in hypoxia, it may be relevant to examine its actual contribution (presently unknown) by simultaneously assessing the F-cell ratio. As anticipated, the authors found a decrease in PV in hypoxia, which occurred primarily within the first 24 h of exposure. Although the latter finding may contrast with the additional time-dependent reduction in PV after the first 24 h, derived from a model of PV response to high altitude (Beidleman et al. 2017), the data of Schlittler et al. (2021) nonetheless highlights the rapidity of PV contraction in response to hypoxia. Contrary to hypothesis, PV contraction in hypobaric hypoxia was associated neither with an ‘altitude diuresis’ (otherwise suggested by transient hormonal changes), nor with a decrease in total body water. Together with the observation of a lower total circulating protein mass in hypoxia, these findings led the authors to the ‘alternative explanation’ for PV contraction in hypoxia, i.e. an oncotically driven fluid transfer from the intra- to the extravascular space. The demonstration that body fluid loss is not the main mechanism for PV reduction in hypoxia convincingly addresses the question of where the plasma doesn't go, at least in healthy lowlanders exposed to 3500 m without AMS symptoms. The question of where the plasma does go – presumably the extravascular space – is reasonably addressed in view of the drop in vascular oncotic pressure that must have resulted from the observed loss of circulating proteins in hypoxia. However, the latter result raises another question, namely where do the plasma proteins go, and why? Although the authors could rule out urinary excretion of the plasma proteins, they did not explore the movement of proteins between intravascular and extravascular compartments. It has previously been suggested that hypoxia facilitates protein transvascular leakage by increasing overall capillary permeability (Hansen et al. 1994). Among the mechanisms promoting such a response, the role of inflammation may be considered. Hypoxia can induce inflammation, in turn increasing the release of permeability factors favouring protein and fluid leakage from the vessels (Eltzschig & Carmeliet 2011). Indeed, the induction of inflammation in healthy subjects has been demonstrated at altitudes equivalent to the simulated altitude in the present study (Eltzschig & Carmeliet 2011). To further advance our understanding of PV regulation in hypoxia it may thus be relevant for future studies to simultaneously examine inflammation and transvascular leakage of plasma proteins in healthy individuals exposed to hypoxia. No competing interests declared. P.R.: Conception or design of the work; acquisition or analysis or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. C.L.: Conception or design of the work; acquisition or analysis or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. None.