The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

SUMMARYAnimals reared in hypoxic environments frequently exhibit smaller body sizes than when reared under normal atmospheric oxygen concentrations. The mechanisms responsible for this widely documented pattern of body size plasticity are poorly known. We studied the ontogeny of responses of Drosophila melanogaster adult body size to hypoxic exposure. We hypothesized that there may be critical oxygen-sensitive periods during D. melanogaster development that are primarily responsive to body size regulation. Instead, our results showed that exposure to hypoxia (an atmospheric partial pressure of oxygen of 10kPa) during any developmental stage (embryo, larvae and pupae) leads to smaller adult size. However, short hypoxic exposures during the late larval and early pupal stages had the greatest effects on adult size. We then investigated whether the observed reductions in size induced by hypoxia at various developmental stages were the result of a decrease in cell size or cell number. Abdominal epithelial cells of flies reared continuously in hypoxia were smaller in mean diameter and were size-limited compared with cells of flies reared in normoxia. Flies reared in hypoxia during the embryonic, larval or pupal stage, or during their entire development, had smaller wing areas than flies reared in normoxia. Flies reared during the pupal stage, or throughout development in hypoxia had smaller wing cells, even after controlling for the effect of wing size. These results suggest that hypoxia effects on the body size of D. melanogaster probably occur by multiple mechanisms operating at various developmental stages.

Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO 2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O 2 ) improved daytime feelings of confusion (ASV: p < 0.01; O 2 : p < 0.05) and fatigue (ASV: p < 0.01; O 2 : p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization.

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