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Adenosine receptor A2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium
Franziska M Konrad1, Esther Witte, Irene Vollmer
1Dept. of Anesthesiology and Intensive Care Medicine, Univ. of Tübingen, Tübingen, Germany.
Abstract:
Uncontrolled transmigration of polymorphonuclear leukocytes (PMNs) into the different compartments of the lungs (intravascular, interstitial, alveolar) is a critical event in the early stage of acute lung injury and acute respiratory distress syndrome. Adenosine receptor A(2b) is highly expressed in the inflamed lungs and has been suggested to mediate cell trafficking. In a murine model of LPS-induced lung inflammation, we investigated the role of A(2b) on migration of PMNs into the different compartments of the lung. In A(2b)(-/-) mice, LPS-induced accumulation of PMNs was significantly higher in the interstitium, but not in the alveolar space. In addition, pulmonary clearance of PMNs was delayed in A(2b)(-/-) mice. Using chimeric mice, we identified A(2b) on hematopoietic cells as crucial for PMN migration. A(2b) did not affect the release of relevant chemokines into the alveolar space. LPS-induced microvascular permeability was under the control of A(2b) on both hematopoietic and nonhematopoietic cells. Activation of A(2b) on endothelial cells also reduced formation of LPS-induced stress fibers, highlighting its role for endothelial integrity. A specific A(2b) agonist (BAY 60-6583) was effective in decreasing PMN migration into the lung interstitium and microvascular permeability. In addition, in vitro transmigration of human PMNs through a layer of human endothelial or epithelial cells was A(2b) dependent. Activation of A(2b) on human PMNs reduced oxidative burst activity. Together, our results demonstrate anti-inflammatory effects of A(2b) on two major characteristics of acute lung injury, with a distinct role of hematopoietic A(2b) for cell trafficking and endothelial A(2b) for microvascular permeability.
Insights
Adenosine receptor A(2b) plays a dual anti-inflammatory role in acute lung injury. It regulates polymorphonuclear leukocyte (PMN) migration and reduces microvascular permeability, offering therapeutic potential.
Area of Science:
- Immunology
- Pulmonary Medicine
- Pharmacology
Background:
- Uncontrolled polymorphonuclear leukocyte (PMN) transmigration into lung compartments is central to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
- Adenosine receptor A(2b) (A(2b)R) is upregulated in inflamed lungs and implicated in cell trafficking.
- The precise role of A(2b)R in ALI pathogenesis requires elucidation.
Purpose of the Study:
- To investigate the role of A(2b)R in regulating PMN migration and microvascular permeability in a murine model of LPS-induced lung inflammation.
- To determine the cellular source of A(2b)R mediating these effects.
- To evaluate the therapeutic potential of an A(2b)R agonist in ALI.
Main Methods:
- Utilized A(2b)R knockout (A(2b)(-/-)) and chimeric mice in an LPS-induced lung inflammation model.
- Assessed PMN accumulation in lung compartments, pulmonary PMN clearance, and microvascular permeability.
- Investigated chemokine release, endothelial cell responses, and in vitro PMN transmigration and oxidative burst.
Main Results:
- A(2b)R deficiency led to increased interstitial PMN accumulation and delayed PMN clearance in the lungs.
- A(2b)R on hematopoietic cells was critical for PMN migration, while A(2b)R on both hematopoietic and non-hematopoietic cells regulated microvascular permeability.
- A specific A(2b)R agonist reduced PMN migration and microvascular permeability, and inhibited PMN oxidative burst in vitro.
Conclusions:
- Adenosine receptor A(2b) exhibits significant anti-inflammatory effects in ALI by modulating PMN trafficking and endothelial barrier function.
- Hematopoietic A(2b)R is key for PMN migration, whereas endothelial A(2b)R controls microvascular permeability.
- Targeting A(2b)R presents a promising therapeutic strategy for ALI and ARDS.
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