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Acute pulmonary inflammation is still a frightening complication in intensive care units. In our previous study, we determined that heme oxygenase (HO)-1 had anti-inflammatory effects in pulmonary inflammation. Recent literature has emphasized a link between HO-1 and the nucleotide adenosine. Since adenosine A 2A - and A 2B -receptors play a pivotal role in pulmonary inflammation, we investigated their link to the enzyme HO-1. In a murine model of pulmonary inflammation, the activation of HO-1 by hemin significantly decreased polymorphonuclear leukocyte (PMN) migration into the lung. This anti-inflammatory reduction of PMN migration was abolished in A 2A - and A 2B -knockout mice. Administration of hemin significantly reduced chemokine levels in the BAL of wild-type animals but had no effects in A 2A -/-   and A 2B -/-   mice. Microvascular permeability was significantly attenuated in HO-1-stimulated wild-type mice, but not in A 2A -/-   and A 2B -/-   mice. The activity of HO-1 rose after LPS inhalation in wild-type animals and, surprisingly, also in A 2A -/-   and A 2B -/-   mice after the additional administration of hemin. Immunofluorescence images of animals revealed alveolar macrophages to be the major source of HO-1 activity in both knockout strains—in contrast to wild-type animals, where HO-1 was also significantly augmented in the lung tissue.  In vitro  studies on PMN migration further confirmed our  in vivo  findings. In conclusion, we linked the anti-inflammatory effects of HO-1 to functional A 2A /A 2B -receptor signaling under conditions of pulmonary inflammation. Our findings may explain why targeting HO-1 in acute pulmonary inflammation has failed to prove effective in some patients, since septic patients have altered adenosine receptor expression.

Anti-inflammatory Effects of Heme Oxygenase-1 Depend on Adenosine A2A- and A2B-Receptor Signaling in Acute Pulmonary Inflammation