Abstract 12850: The Early Relaxin-Induced Protection of Rat Lungs From Ischemia/Reperfusion Injury is Nitric Oxide-Dependent
Early allograft dysfunction following lung transplantation is mainly caused by ischemia/reperfusion (IR) injury which is characterised by endothelial damage, neutrophil extravasation into tissue, peroxidation of cell membrane lipids, pulmonary cell alterations, pulmonary hypertension, and edema. We have recently shown that human relaxin-2 exerts a protective effect in IR-induced lung injury, attributable to ET-1 reduction, decreased leukocyte recruitment and hindrance of free radical-mediated tissue injury. Here, we summarize our investigations into the signal transduction of this relaxin effect: In general, relaxin-2 has been found to signal via cAMP/protein kinase A (PKA), iNOS/NO, endothelin-1 type-B (ETB) receptor upregulation, or via glucocorticoid receptor (GR). Isolated male Wistar rat lungs were perfused in recirculatory mode in the presence of vehicle or 5 nM human relaxin-2 (RLX) (n = 6–10 each). Thereafter, experiments were also conducted in the presence of RLX plus vehicle, the protein kinase A inhibitors H-89 and KT-5720, the NO synthase inhibitor L-NAME, the ETB antagonist A-192621, or the GR antagonist RU−486. After 45 min ischemia and 60 min reperfusion we determined wet-to-dry (W/D) weight ratio and vascular release of ET-1, neutrophil elastase (NE), myeloperoxidase (MPO), and malondialdehyd (MDA). IR lungs displayed significantly elevated W/D ratios (270 % of control), mean arterial pressure (300 %), as well as release of ET-1 (320 %), NE (840 %), MDA (270 %), and MPO (600 %) compared with control lungs. In the presence of RLX, these parameters were markedly improved, to 150 % of baseline (W/D), 200 % (vascular pressure), 180 % (ET-1), 410 % (NE), 150 % (MDA), and 290 % (MPO). This protective effect of relaxin-2 was completely abolished by inhibition of NO synthase whereas PKA inhibition or ETB and GR antagonism had no effect. These results indicate that in this short-time experimental setting, human RLX exerts its protective effect in IR-induced lung injury via NO, very likely attributable to immediate iNOS upregulation. Alternative pathways, particularly ETB upregulation and GR agonism, may come into play after longer relaxin exposure, which has to be investigated in further studies.
- © 2010 by American Heart Association, Inc.