Figure 4.

HH response in humans is governed by both spatial and temporal mediation of the OxS and inflammatory pathways via a series of micro and macro events. This schematic overview highlights qualitatively how pertinent relationships between crucial molecular transcription factors and both oxidative and inflammatory pathways involved in the cellular hypoxic response are mediated over time. The +, =, and − symbols refers to qualitative changes of variables during hypoxia exposure in comparison with baseline. (A) During normoxic conditions a well-balanced level of ROS cytokines and TFs mRNA turnover are present in the cells. (B) After 24 h of HH exposure HIF-1α mRNA transcription is enhanced but the level of OxS is also high, plus the existing antioxidant defenses fielded by the cell seem ineffective, results demonstrating a delayed induction of NRF2, in contrast to the immediate deleterious impact of ROS induction on key cellular biomolecules such as lipids, proteins and DNA. On the contrary, the slight increase in circulating IL-1β demonstrates an early attempt by the cell to mitigate the inflammation response. (C) After 72 h of exposure the situation is dramatically changed, showing a marked reduction of ROS production and a consequent reduction of damages on biomolecules, probably counteracted by the scavenging activity performed by antioxidant enzymes. Conversely, no significant modifications were shown by either inflammatory markers or NF-κB after 72 hours of constant, passive hypobaric hypoxic exposure.