Hypoxia and Inflammation: Insights From High-Altitude Physiology

Abstract

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.

OxInflammation at High Altitudes: A Proof of Concept from the Himalayas

“…Hypoxia-induced inflammation impacts on the immune function and causes chronic disease and high-altitude illnesses [ 5 ]. In the same vein, redox homeostasis has been widely studied as disrupted by hypoxia conditioning [ 6 ].…”

Hypoxic and Hyperoxic Breathing as a Complement to Low-Intensity Physical Exercise Programs: A Proof-of-Principle Study

“…This prompts the development of alternative interventions to prevent and/or reduce uncontrolled inflammatory response. Although low-intensity, short-term physical activity does not cause significant changes in immunological and physiological responses [9], studies dealing with the role of exercise [10][11][12][13] and relative hypoxic stress exposure [14] demonstrated that muscle-damaging exercise triggers a delayed systemic, predominantly anti-inflammatory, acute cytokine response.…”

Correlation Between Neutrophil to Lymphocyte Ratio and Myocardial Injury in Population Exposed to High Altitude

“…When population reaches the plateau, the cardiomyocytes are subjected to prolonged hypoxic stimulation. Hypoxia will result in the disorder of energy metabolism in cardiomyocytes, accompanied by the accumulation of oxygen free radicals, thus destroying membranous permeability ( 7 ). On the other hand, ventricular hypertrophy is also a distinguishing feature of high-altitude heart disease ( 8 ).…”