Activation of A3 Adenosine Receptor Provides Lung Protection Against Ischemia-Reperfusion Injury Associated with Reduction in Apoptosis

Abstract

Apoptosis has been described in various models of ischemia-reperfusion (IR) injury, including lung transplantation. A 3 adenosine receptor (AR) has been linked to a variety of apoptotic processes. The effect of A 3 AR activation on lung injury and apoptosis, following IR, has not been reported to date. In a spontaneously breathing cat model, in which the left lower lobe of the lung was isolated and subjected to 2 h of ischemia and 3 h of reperfusion, we tested the effect of IB-MECA, a selective A 3 AR agonist, on lung apoptosis and injury. Significant increase in the extent of apoptosis was observed following lung reperfusion. IB-MECA, administered before IR, and before or with reperfusion, markedly (p < 0.01) attenuated indices of injury and apoptosis including the percentage of injured alveoli, wet/dry weight ratio, myeloperoxidase activity, in situ terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end-labeling (TUNEL) positive cells, and caspase 3 activity and expression. The protective effects of IB-MECA were completely blocked by pretreatment with the selective A 3 AR antagonist MRS-1191. In summary, even when given after the onset of ischemia, the A 3 AR agonist IB-MECA conferred a powerful protection against reperfusion lung injury, which was associated with decreased apoptosis. This suggests a potentially important role for A 3 AR in lung IR injury.

A3Adenosine Receptor Signaling Influences Pulmonary Inflammation and Fibrosis

“…Similar findings were reported in a study that demonstrated increased inflammation in A 3 R 2/2 mice subjected to an air-pouch model of acute inflammation (38). In addition, our observations are consistent with findings in in vivo models of injury, including lipopolysaccharide-induced endotoxemia (39), adjuvant-induced arthritis (40), colitis (41), and ischemic injury in the lung (42), where A 3 R activation has been shown to suppress inflammatory processes. Thus, our findings strengthen the notion that the A 3 R plays an important role in regulating the degree of inflammation after injury.…”

Adenosine receptors as therapeutic targets

“…In preclinical testing, the A 3 AR agonist IB-MECA was shown to protect against lung injury and apoptosis in cats after reperfusion 178 , and this protection was antagonized by MRS1191, a dihydropyridine that is a selective A AR antagonist 56 As described earlier, prominent species differences in the structure and function of ARs, especially the A 3 AR, have been observed. For example, human and rat A 3 ARs only share 72% overall identity at the amino-acid level; mast-cell degranulation is induced by the A 2B AR in dogs and humans, but by the A 3 AR in mice.…”

Sphingosine 1-Phosphate Inhibits Ischemia Reperfusion Injury Following Experimental Lung Transplantation

“…Neutrophils, in particular accelerate lung tissue damage by furthering the breakdown of the endothelial cell barrier through the production of a number of potent proteolytic enzymes and reactive oxygen species that directly lead to cell death (2). Loss of integrity of endothelial cell barrier leads to pulmonary edema and compromised blood oxygenation (3)(4)(5)(6).…”