The adenosinergic system also has an impact on the lung response to hypoxia. An upregulation of A
1R was observed during experimental hypoxia in rats
[36][19]. Lungs are also threatened during altitude hypoxia in humans. High-altitude pulmonary edema (HAPE) is a life-threatening disorder that can occur in healthy unacclimatized individuals. HAPE is a noncardiogenic pulmonary edema. The key pathogenic mechanism is exaggerated pulmonary hypertension induced by hypoxia. Contributing factors such as inflammation, endothelial dysfunction, sympathetic overactivity, and fluid retention were cited
[37][20].
1.3. Chronic Hypoxia: Life at Altitude
Prolonged exposure to altitude hypoxia is known to result in the development of an acclimatization phenomenon. In a human study, Song et al.
[14] reported that the adenosinergic-signaling network enhanced the hypoxia adenosine response to counteract hypoxia-induced maladaptation. They measured APLs and soluble CD73 activity in healthy subjects at sea level and during a stay at high altitudes (5260 m). The volunteers returned for several days (from 7–21 days) at 1525 m, and a further blood sample was collected upon re-ascent at 5260 m. The
autscho
lars found that APLs and CD73 activity were significantly higher upon re-ascent to 5260 m for 1 day, after spending several days at 1525 m, compared with the first hypoxia exposure. Consequently, the first stay at high altitude can enhance the defense response to hypoxia through an increase in APLs and CD73 activity.
Although adenosine production is activated during prolonged stays at high altitudes, its action on the artery decreases. Calbet et al.
[40][21] reported that short-term residence at altitude (between 8 and 12 days at 4554 m) induced an increase in resting blood pressure. Vasodilatory responses secondary to exogenous adenosine infusion were impaired by alteration in endothelial function. Thus, chronic or acute exposures to a high endogenous adenosine extracellular concentration may have different effects on the cardiovascular system.
2. Hyperoxia
In hyperbaric conditions, subjects breathe a mixture of high-pressure gases through a regulator. Most frequently, diving tanks contain compressed air (filtered and dehumidified), i.e., 78% nitrogen, 20.9% oxygen, and small proportions of trace gases. The increase in ambient pressure generates an increase in the partial pressures of oxygen and nitrogen. Furthermore, the gas density is increased. Some divers inhale oxygen-enriched gas mixtures to decrease the nitrogen content of tissues and blood at the time of decompression and to limit the occurrence of decompression sickness. For an air dive, the partial pressure of O
2 is 40 KPa at 10 m depth and 60 KPa at 20 m depth. In the particular case of military diving, the use of pure oxygen through a closed-circuit self-contained underwater breathing apparatus (SCUBA) allows better self-sufficiency (the exhaled gas is reused after the CO
2 is extracted by lime) and discretion (no bubbles). Consequently, hyperoxia is a constant stressor for healthy subjects working in hyperbaria, such as SCUBA divers or professional workers in a tunnel boring machine hyperbaric chamber.
2.1. Cardio-Vascular Changes
Hyperoxic exposure has a major impact on cardiovascular function in healthy subjects. Numerous studies have shown that cardiovascular responses to acute hyperoxia include a decrease in cardiac output related to the simultaneous decreases in heart rate and stroke volume
[41,42,43][22][23][24]. Increases in mean blood pressure and systemic vascular resistance, and a decrease in arterial compliance, have been documented in resting healthy volunteers breathing pure oxygen
[41,44,45][22][25][26]. Such an effect of oxygen appears to be related to its vasoconstrictive action on the peripheral vascular system. The exact mechanism by which hyperoxia induces vasoconstriction is not fully understood. The increase in partial pressure of O
2 and the production of reactive oxygen species can contribute to arterial vasoconstriction through an alteration in endothelial function or a direct effect on the vascular smooth muscle
[46,47][27][28].
2.2. Oxygen Toxicity
Retinal toxicity is one of the first indicators of hyperoxia
[51][29]. From this perspective, the lack of A
1R reduced hyperoxia-induced retinal toxicity in mice
[52][30], suggesting that A
1R activation did not protect against hyperoxia-induced retinal toxicity.
Brain oxygen toxicity is linked to oxidative stress induced by hyperoxia. Damage is secondary to increased production of reactive oxygen species (ROS) and/or reactive nitrogen species and lipid peroxidation, which impair cell membranes
[53][31]. Clinical disorders include disturbances of vision (tunnel vision), headache, nausea, muscle twitching, and convulsions similar to epileptic seizures with loss of consciousness
[54][32].
It has long been known that prolonged exposure to hyperoxia can lead to lung damage (Lorrain-Smith effect)
[59][33]. Pulmonary disorders consist of three successive phases, i.e., inflammatory, proliferative-reparative, and fibrotic. The severity is positively correlated with the duration of exposure and the level of partial pressure of O
2. Hyperoxia can disrupt the structure and function of the pulmonary epithelial barrier through the destruction of the pulmonary epithelial tight junction structures (see
Figure 2).
Figure 2. Schematic presentation of the protective action of the adenosine system in pulmonary oxygen toxicity. Prolonged exposure to high oxygen partial pressure leads to an impairment in pulmonary barrier function through inflammation and disruption of the tight junction via a downregulation of tight junction proteins such as occludin, zonula occludens-1, and claudin-4. The increase in adenosine is mainly due to the activation of CD73, which converts AMP into adenosine, while other nucleotidases such as CD39 (NTDPase1) or NTDPase2 may also participate in the modulation of extracellular adenosine levels.
3. Conclusions
Adenosine concentration and adenosine receptor activity are altered by changes in ambient oxygen pressure experienced by healthy subjects during professional or leisurely activities such as climbing or diving. When climbing at a high altitude, the increase in adenosine concentration can contribute to improved tolerance to hypoxia. In contrast, the increase in the expression of A
2AR can promote neurological disorders involved in mountain illness. During hyperoxic exposure, changes in the adenosinergic system lead to vasoconstriction and may decrease the risk of cerebral oxygen toxicity. The adenosinergic system is also recognized as a protector against the lung toxicity of oxygen. Finally, acute and chronic exposures to a high endogenous adenosine extracellular concentration lead to different adaptation mechanisms. Because the involvement of the adenosinergic system seems decisive in some diseases induced by major changes in the partial pressure of O
2, the use of drugs that modulate this system may be of interest to treating or prevent clinical disorders.