Adenosine receptor A3 is a critical mediator in LPS-induced pulmonary inflammation.
American journal of physiology. Lung cellular and molecular physiology 2010 Jul 16; In press
Wagner R, Ngamsri K KC, Stark S, Vollmer I, Reutershan J
1University Hospital Tübingen.
Adenosine receptor A3 (A3) regulates directed movement of polymorphonuclear cells (PMNs) to sites of inflammation and has been implicated as a relevant mediator in models of inflammatory diseases. Here, we sought to characterize the role of A3 in a murine model of lung inflammation. Initial studies revealed that pulmonary A3 transcript levels were elevated following LPS exposure in vivo. In addition, inhalation of LPS increased the accumulation of PMNs in wildtype and A3-/- mice in all lung compartments. Pretreatment with the specific A3-agonist Cl-IB-MECA significantly decreased migration of PMNs into lung interstitium and alveolar airspace of wildtype mice but not of A3-/- mice. Lower PMN counts were associated with reduced levels of TNFalpha and IL-6 in the alveolar space of wildtype mice that received Cl-IB-MECA. In addition, Cl-IB-MECA attenuated LPS-induced microvascular permeability in wildtype mice as assessed by the extravasation of Evans blue. In pulmonary microvascular endothelial cells, Cl-IB-MECA reduced LPS-induced cytoskeletal remodeling and cell retraction, consistent with a specific role of A3 for maintaining endothelial integrity. Migratory activity of human PMNs across an endothelial or epithelial monolayer was reduced when A3 was activated on PMNs. Studies in chimeric mice, however, revealed that Cl-IB-MECA required A3 on both hematopoietic and non-hematopoietic cells to reduce transmigration in vivo. Together, our results shed new light on the role of adenosine receptor A3 in LPS-induced PMN trafficking in the lung and suggest pharmacologic modulation of A3-dependent pathways as a promising approach in lung inflammation.
Keywords: Adenosine A3 pulmonary inflammation