atl-146e and Inflammation

We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A(2A)-receptor (A(2A)R) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A(2A)R agonists in a chronic model of renal injury. We hypothesized that A(2A) agonists mediate renal tissue protection in diabetic nephropathy by reducing glomerular inflammation. Diabetes was induced with single intravenous injection of streptozotocin in Sprague-Dawley rats (50 mg/kg). Increases in urinary albumin excretion (UAE) and plasma creatinine at week 6 in the diabetes group (26- and 6-fold over control, respectively) were markedly reduced by continuous subcutaneous administration of ATL146e (10 ng x kg(-1) x min(-1)), a selective A(2A) agonist. The increase in UAE in the diabetes group was associated with a significant reduction in the expression of slit diaphragm-associated molecules compared with control (nephrin; P < 0.05 and podocin; P < 0.005) that was reversed by ATL146e treatment. Diabetes led to an increase in urinary excretion of monocyte chemoattractant protein-1 (705% of control), TNF-alpha (1,586% of control), IFN-gamma (298% of control), kidney fibronectin mRNA (457% of control), and glomerular infiltration of macrophages (764% of control), effects significantly reduced by ATL146e treatment. Mesangial expansion and basement membrane thickness were reduced with ATL146e. To further confirm the selectivity of ATL146e, we used wild-type (WT) or A(2A)knockout (A(2A)-KO) mice. Four weeks after diabetes, UAE increased significantly in both WT and A(2A)-KO diabetic mice (3.0- and 3.3-fold over control). A(2A) agonist treatment blocked the increase in UAE in WT diabetic mice (P < 0.001), whereas it had no effect on the A(2A)-KO diabetic mice. These results demonstrate that chronic A(2A)R activation in diabetic rats 1) ameliorates histological and functional changes in kidneys induced by diabetes and 2) causes reduced inflammation associated with diabetic nephropathy.

Topics: Adenosine A2 Receptor Agonists; Albuminuria; Animals; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Inflammation; Kidney; Mice; Mice, Knockout; Purines; Rats; Rats, Sprague-Dawley; Receptors, Adenosine A2

Renal interstitial inflammation is a consequence of unilateral ureteral obstruction (UUO). Following ischemia/reperfusion, adenosine reduces renal inflammation and injury, effects which are potentiated by type 4 phosphodiesterase inhibitors. We therefore studied the effects of A2A adenosine receptor agonist (ATL146e), and PDE4 inhibitor (rolipram) in mice subjected to UUO.. Mice were subjected to UUO or sham operation, and received either vehicle or ATL146e + rolipram by osmotic minipump for 1 or 7 days. At 1, 3, 7, or 14 days after operation, renal macrophage infiltration, apoptosis, proliferation, tubular atrophy, and interstitial fibrosis were quantitated, and expressions of IL-6 and TGF-beta mRNA were determined.. ATL146e + rolipram reduced macrophage infiltration by 40% after 3 days UUO (p < 0.05). Tubular apoptosis, tubular atrophy, and interstitial fibrosis were increased by 7 or 14 days UUO, but were unaffected by ATL146e + rolipram. However, cellular proliferation was increased by ATL146e + rolipram in the obstructed kidney. ATL146e + rolipram had no effect on the renal expression of IL-6 and TGF-beta mRNA.. A2A receptor activation and PDE4 inhibition transiently reduce renal macrophage infiltration, but do not ameliorate the renal response to UUO. We speculate that the persistent stimulus for inflammation triggered by UUO cannot be reversed by agents that suppress inflammatory cell activation alone.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Apoptosis; Cell Proliferation; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Fibrosis; Inflammation; Kidney Diseases; Mice; Mice, Inbred C57BL; Phosphodiesterase Inhibitors; Purines; Receptors, Adenosine A2; Rolipram; Ureteral Obstruction

Reperfusion injury continues to significantly affect patients undergoing lung transplantation. Isolated lung models have demonstrated that adenosine A 2A receptor activation preserves function while decreasing inflammation. We hypothesized that adenosine A 2A receptor activation by ATL-146e during the initial reperfusion period preserves pulmonary function and attenuates inflammation in a porcine model of lung transplantation.. Mature pig lungs preserved with Viaspan (Barr Laboratories, Pomona, NY) underwent 6 hours of cold ischemia before transplantation and 4 hours of reperfusion. Animals were treated with (ATL group, n = 7) and without (IR group, n = 7) ATL-146e (0.05 microg kg -1 . min -1 ATL-146e administered intravenously for 3 hours). With occlusion of the opposite pulmonary artery, the animal was maintained for the final 30 minutes on the allograft alone. Recipient lung physiology was monitored before tissue evaluation of pulmonary edema (wet-to-dry weight ratio), myeloperoxidase assay, and tissue tumor necrosis factor alpha by means of enzyme-linked immunosorbent assay.. When the ATL group was compared with the IR group, the ATL group had better partial pressure of carbon dioxide (43.8 +/- 4.1 vs 68.9 +/- 6.3 mm Hg, P < .01) and partial pressure of oxygen (272.3 +/- 132.7 vs 100.1 +/- 21.4 mm Hg, P < .01). ATL-146e-treated animals exhibited lower pulmonary artery pressures (33.6 +/- 2.1 vs 47.9 +/- 3.5 mm Hg, P < .01) and mean airway pressures (16.25 +/- 0.08 vs 16.64 +/- 0.15 mm Hg, P = .04). ATL-146e-treated lungs had lower wet-to-dry ratios (5.9 +/- 0.39 vs 7.3 +/- 0.38, P < .02), lower myeloperoxidase levels (2.9 x 10 -5 +/- 1.2 x 10 -5 vs 1.3 x 10 -4 +/- 4.0 x 10 -5 DeltaOD mg -1 . min -1 , P = .03), and a trend toward decreased lung tumor necrosis factor alpha levels (57 +/- 12 vs 96 +/- 15 pg/mL, P = .06). The ATL group demonstrated significantly less inflammation on histology.. Adenosine A 2A activation during early reperfusion attenuated lung inflammation and preserved pulmonary function in this model of lung transplantation. ATL-146e and similar compounds could play a significant role in improving outcomes of pulmonary transplantation.

Topics: Adenosine A2 Receptor Agonists; Animals; Blood Gas Analysis; Carbon Dioxide; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Female; Inflammation; Lung; Lung Transplantation; Male; Neutrophil Activation; Organ Size; Oxygen; Peroxidase; Pulmonary Edema; Purines; Random Allocation; Receptor, Adenosine A2A; Reperfusion Injury; Respiratory Function Tests; Severity of Illness Index; Swine; Time Factors; Tumor Necrosis Factor-alpha