Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury

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.