Protective effect of purinergic agonist ATPγS against acute lung injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of acute respiratory failure associated with high morbidity and mortality. Although ALI/ARDS pathogenesis is only partly understood, pulmonary endothelium plays a major role by regulating lung fluid balance and pulmonary edema formation. Consequently, endothelium-targeted therapies may have beneficial effects in ALI/ARDS. Recently, attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface P2Y receptors. We previously described ATP-induced endothelial cell (EC) barrier enhancement via a complex cell signaling and hypothesized endothelial purinoreceptors activation to exert anti-inflammatory barrier-protective effects. To test this hypothesis, we used a murine model of ALI induced by intratracheal administration of endotoxin/lipopolysaccharide (LPS) and cultured pulmonary EC. The nonhydrolyzed ATP analog ATP␥S (50 -100 M final blood concentration) attenuated inflammatory response with decreased accumulation of cells (48%, P Ͻ 0.01) and proteins (57%, P Ͻ 0.01) in bronchoalveolar lavage and reduced neutrophil infiltration and extravasation of Evans blue albumin dye into lung tissue. In cell culture model, ATP␥S inhibited junctional permeability induced by LPS. These findings suggest that purinergic receptor stimulation exerts a protective role against ALI by preserving integrity of endothelial cell-cell junctions.endotoxin/lipopolysaccharide; mice; inflammation; endothelial barrier THE ENDOTHELIAL LINING of blood vessels forms a selective barrier between plasma and interstitial spaces. In the course of acute lung injury (ALI), the endothelial barrier of the pulmonary microvasculature becomes compromised, leading to pulmonary edema, a characteristic feature of ALI. It is widely accepted that endothelial cell (EC) barrier dysfunction is initiated by agonist-induced cytoskeletal remodeling, which leads to disruption of cell-cell contacts and formation of paracellular gaps, allowing penetration of protein-rich fluid and inflammatory cells. Little is known about processes that determine barrier enhancement or protection. Recently, it has been shown that extracellular ATP stabilizes barrier function of endothelial monolayers (15,18,21) and attenuates barrier disruption caused by thrombin (12) and reperfusion (13). Extracellular purines (adenosine, ADP, and ATP) are important signaling molecules that mediate diverse biological effects via cellsurface receptors. Purinergic receptors are divided into two classes: P1 or adenosine receptors, and P2, which recognize primarily extracellular ATP, ADP, UTP, and UDP (26). The P2 receptors are further subdivided into two subclasses. P2X receptors are ATP-gated calcium-permeable nonselective cation channels. The P2Y receptors are coupled...

Purinergic Signaling in the Airways

“…In a recent study, it was shown that short-term exposure to low concentrations of sodium arsenide reduced the ability of lung epithelial cells to respond to wound-induced purinergic signaling via both P2X and P2Y receptors (Sherwood et al, 2011). The P2 receptor agonist ATP␥S had a protective effect against acute lung injury induced in a murine model by the bacterial endotoxin LPS (Kolosova et al, 2008). ATP released during mechanical ventilation caused lung injury via P2Y receptors (Matsuyama et al, 2008).…”

The Effects ofPortulaca oleraceaon Hypoxia-Induced Pulmonary Edema in Mice

“…The vascular permeability assays were performed as previously described (Kolosova et al, 2008). Evans Blue dye at a dose of 20 mg/kg (body weight) was injected into the mice via the caudal vein 30 min before tissue collection.…”

Critical Role of S1PR1 and Integrin β4 in HGF/c-Met-mediated Increases in Vascular Integrity

“…Therefore, agents that protect vascular endothelial cell (EC) 2 barrier properties and vascular integrity may have important therapeutic implications. In prior studies, we detailed the barrier-enhancing effects of bioregulatory molecules such as sphingosine 1-phosphate (S1P) (2,3,4,5,6), hepatocyte growth factor (HGF) (7,1), HMW HA (high molecular weight hyaluronic acid; 8), ATP (9,10), and APC (activated protein C) (11,12,13) via ligation of their cognate receptors resulting in restoration of EC barrier integrity and reduced permeability. HGF promotes angiogenesis and EC barrier function via ligation of c-Met, a cell surface receptor tyrosine kinase, as well as Rac1-dependent cytoskeleton rearrangement (7,1).…”