Abstract
Acute respiratory distress syndrome (ARDS) usually requires symptomatic supportive therapy by intubation and mechanical ventilation with the supplemental use of high oxygen concentrations. Although oxygen therapy represents a life-saving measure, the recent discovery of a critical tissue-protecting mechanism predicts that administration of oxygen to ARDS patients with uncontrolled pulmonary inflammation also may have dangerous side effects. Oxygenation may weaken the local tissue hypoxia-driven and adenosine A2A receptor (A2AR)-mediated anti-inflammatory mechanism and thereby further exacerbate lung injury. Here we report experiments with wild-type and adenosine A2AR-deficient mice that confirm the predicted effects of oxygen. These results also suggest the possibility of iatrogenic exacerbation of acute lung injury upon oxygen administration due to the oxygenation-associated elimination of A2AR-mediated lung tissue-protecting pathway. We show that this potential complication of clinically widely used oxygenation procedures could be completely prevented by intratracheal injection of a selective A2AR agonist to compensate for the oxygenation-related loss of the lung tissue-protecting endogenous adenosine. The identification of a major iatrogenic complication of oxygen therapy in conditions of acute lung inflammation attracts attention to the need for clinical and epidemiological studies of ARDS patients who require oxygen therapy. It is proposed that oxygen therapy in patients with ARDS and other causes of lung inflammation should be combined with anti-inflammatory measures, e.g., with inhalative application of A2AR agonists. The reported observations may also answer the long-standing question as to why the lungs are the most susceptible to inflammatory injury and why lung failure usually precedes multiple organ failure.
Highlights
Many clinical conditions, including aspiration, trauma, and hemorrhagic shock, are frequently followed by pulmonary and systemic infectious and septic complications that lead to pulmonary dysfunction and subsequent lung failure
Five times more mice with inflamed lungs died after exposure to 100% oxygen than those left at 21% ambient oxygen tension (Figure 1). This was further confirmed by a much more pronounced increase in the alveolocapillary permeability and severe overall impairment of lung gas exchange, as evidenced by the increase in the amount of protein recovered from the alveolar space by bronchoalveolar lavage (BAL), as well as by the decrease in arterial oxygen partial pressure values of previously oxygen-exposed mice when returned to normal atmosphere (Figure 2A)
While the majority of wild-type mice survived, all of the A2A receptor (A2AR) gene-deficient mice died, indicating that expression of A2AR is required for survival of hypoxic lung inflammation; this experiment mimics the clinical situation in which lung inflammation increases to such severity that hypoxia occurs
Summary
Many clinical conditions, including aspiration, trauma, and hemorrhagic shock, are frequently followed by pulmonary and systemic infectious and septic complications that lead to pulmonary dysfunction and subsequent lung failure. Intubation with mechanical ventilation represent one of the most widely used prophylactic and therapeutic clinical interventions to counteract the insufficient pulmonary oxygen-delivering capacity in patients who suffer from severe lung inflammation. Since the magnitude and duration of lung inflammation has been shown to determine the final outcome of ARDS patients [3], it is important to carefully evaluate the possible adverse effects of oxygen on inflammatory processes. We assumed that lung tissues are protected from overactive immune cells by the same hypoxia-driven mechanism and immunosuppressive adenosine A2A receptor (A2AR)-mediated mechanism that was recently shown to play a critical role in the down-regulation of inflammation and tissue damage in different models [4,5,6,7].
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