Abstract
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 A2A- and A2B-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 A2A- and A2B-knockout mice. Administration of hemin significantly reduced chemokine levels in the BAL of wild-type animals but had no effects in A2A-/- and A2B-/- mice. Microvascular permeability was significantly attenuated in HO-1-stimulated wild-type mice, but not in A2A-/- and A2B-/- mice. The activity of HO-1 rose after LPS inhalation in wild-type animals and, surprisingly, also in A2A-/- and A2B-/- 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 A2A/A2B-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.
Highlights
Acute pulmonary inflammation and its more severe form acute respiratory distress syndrome, are life-threatening complications in intensive care units (ICU) with a high mortality of 40% [1]
Neither inflammation nor heme oxygenase (HO)-1 activation by hemin changed the expression of HO-1 in
We demonstrated that HO-1 activation in A2B−/− mice had no effect on microvascular permeability, highlighting the pivotal role of A2A−/− and A2B−/− receptor signaling in conjunction with the enzyme HO-1 in the appearance of the second hallmark of acute pulmonary inflammation
Summary
Acute pulmonary inflammation and its more severe form acute respiratory distress syndrome, are life-threatening complications in intensive care units (ICU) with a high mortality of 40% [1]. Acute pulmonary inflammation can be caused either by direct lung injury, such as pneumonia, or indirect injury, such as sepsis or trauma. These different etiological factors might be the reason why, despite decades of research, no single treatment. In the case of acute pulmonary inflammation, PMNs excessively migrate from the intravascular compartment through an endothelial barrier into the lung interstitium, followed by a transepithelial migration into the alveolar space. These migration steps underlay different regulation [4] and destroy the lung architecture
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