Oxygenation Inhibits the Physiological Tissue-Protecting Mechanism and Thereby Exacerbates Acute Inflammatory Lung Injury

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.

Cutting Edge: Hypoxia-Inducible Factor 1α and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes

“…Another possibility is that the short isoform of HIF-1␣ may inhibit NF-B activity (e.g., by binding and retaining NF-B from nuclear translocation, or by up-regulation of expression of I B), and thereby inhibit proinflammatory transcription. We suggest that HIF-1-mediated anti-inflammatory pathway in T cells is complementary to tissue-protecting immunosuppressive signaling by extracellular adenosine (2,14,15,28,29), which is accumulated in hypoxic conditions (30,31).…”

Adenosine, an endogenous distress signal, modulates tissue damage and repair

“…74 This response was attributed to decreased levels of endogenous adenosine activating the A 2A receptors on activated immune competent cells, and could be partly mimicked by an A 2A agonist. It was therefore proposed that oxygen therapy should be combined with the administration of an adenosine A 2A agonist.…”

Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

“…In a recent study of Acute Respiratory Distress Syndrome (ARDS) and acute inflammatory lung injury, Thiel et al (16) provided evidence for the importance of hypoxic microenvironments in regulation of host immune responses. ARDS patients are normally treated with a life-saving oxygen therapy, but this therapy may have a dangerous side effect in patients with uncontrolled pulmonary inflammation.…”