Anti-inflammatory Effects of Heme Oxygenase-1 Depend on Adenosine A _2A- and A _2B-Receptor Signaling in Acute Pulmonary Inflammation

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.