Abstract
Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils into the different compartments of the lung. Recent studies showed evidence that the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 influence migration of immune cells and their activity was linked to adenosine concentrations. We investigated the particular role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A2B-receptor, which plays an important anti-inflammatory role in the lung. After LPS-inhalation for 45 minutes, administration of the CXCR4-inhibitor (AMD3100) decreased transendothelial and transepithelial migration, whereas CXCR7-antagonism influenced epithelial migration exclusively. In A2B−/− mice, no anti-inflammatory effects were detectible through either one of the agents. Using chimeric mice, we identified A2B on hematopoietic cells to be crucial for these anti-inflammatory effects of CXCR4/7-inhibition. Both inhibitors decreased TNFα, IL6, CXCL1 and CXCL2/3 levels in the bronchoalveolar lavage of wild type mice, while not influencing the chemokine release in A2B−/− mice. Inflammation augmented the expression of both receptors and their inhibition increased A2B-levels upon inflammation. In vitro assays with human epithelium/endothelium confirmed our in vivo findings. During inflammation, inhibition of CXCR4- and CXCR7-receptors prevented microvascular permeability in wild type but not in A2B−/− mice, highlighting the pivotal role of an active A2B-receptor in this setting. The combination of both inhibitors had a synergistic effect in preventing capillary leakage. In conclusion, we determined the pivotal role of CXCR4- and CXCR7-inhibition in acute pulmonary inflammation, which depended on A2B-receptor signalling.
Highlights
Acute pulmonary inflammation and its more severe form acute respiratory distress syndrome still have a high mortality around 40%1 and the surviving patients commonly have residual physical limitations and a poor quality of life.[2]
We investigated the particular role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A2B-receptor, which plays an important antiinflammatory role in the lung
stromal cell-derived factor (SDF)-1 (CXCL12 in the systematic nomenclature) has two receptors: CXCR4 and CXCR7.7 These receptors seem to play a role in lung emphysema and chronic obstructive pulmonary disease.[8]
Summary
Acute pulmonary inflammation and its more severe form acute respiratory distress syndrome still have a high mortality around 40%1 and the surviving patients commonly have residual physical limitations and a poor quality of life.[2]. Stromal cell-derived factor (SDF)-1 is a chemokine that mediates hematopoietic stem cell mobilization and migration of leukocytes.[4,5] SDF-1 is naturally highly expressed in the bone marrow and acts as a retention factor for neutrophils. The concentration of SDF-1 in the bone marrow decreases and PMNs enter the circulation from where they can migrate to the site of inflammation.[6]. SDF-1 (CXCL12 in the systematic nomenclature) has two receptors: CXCR4 and CXCR7.7 These receptors seem to play a role in lung emphysema and chronic obstructive pulmonary disease.[8]. Four different adenosine receptors exist, whereby the A2B-receptor plays a predominant role in terms of pulmonary inflammation.[9,10] A connection between the A2B-receptor and CXCR4-expression was found in terms of protection against vascular injury.[11]
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