Ghrelin Pre-treatment Attenuates Local Oxidative Stress and End Organ Damage During Cardiopulmonary Bypass in Anesthetized Rats

Abstract

Cardiopulmonary bypass (CPB) induced systemic inflammation significantly contributes to the development of postoperative complications, including respiratory failure, myocardial, renal and neurological dysfunction and ultimately can lead to failure of multiple organs. Ghrelin is a small endogenous peptide with wide ranging physiological effects on metabolism and cardiovascular regulation. Herein, we investigated the protective effects of ghrelin against CPB-induced inflammatory reactions, oxidative stress and acute organ damage. Adult male Sprague Dawley rats randomly received vehicle (n = 5) or a bolus of ghrelin (150 μg/kg, sc, n = 5) and were subjected to CPB for 4 h (protocol 1). In separate rats, ghrelin pre-treatment (protocol 2) was compared to two doses of ghrelin (protocol 3) before and after CPB for 2 h followed by recovery for 2 h. Blood samples were taken prior to CPB, and following CPB at 2 h and 4 h. Organ nitrosative stress (3-nitrotyrosine) was measured by Western blotting. CPB induced leukocytosis with increased plasma levels of tumor necrosis factor-α and interleukin-6 indicating a potent inflammatory response. Ghrelin treatment significantly reduced plasma organ damage markers (lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase) and protein levels of 3-nitrotyrosine, particularly in the brain, lung and liver, but only partly suppressed inflammatory cell invasion and did not reduce proinflammatory cytokine production. Ghrelin partially attenuated the CPB-induced elevation of epinephrine and to a lesser extent norepinephrine when compared to the CPB saline group, while dopamine levels were completely suppressed. Ghrelin treatment sustained plasma levels of reduced glutathione and decreased glutathione disulphide when compared to CPB saline rats. These results suggest that even though ghrelin only partially inhibited the large CPB induced increase in catecholamines and organ macrophage infiltration, it reduced oxidative stress and subsequent cell damage. Pre-treatment with ghrelin might provide an effective adjunct therapy for preventing widespread CPB induced organ injury.

Ghrelin and vascular protection

“…Ischemia, septic shock and cardiopulmonary bypass-induced injury all involve pronounced cytokine mediated vascular inflammation and oxidative stress, which have been shown to be ameliorated by AG treatment ( 21 , 22 , 23 , 24 , 25 , 26 ). AG suppresses interleukin-6 and tumor necrosis factor-α generation by lymphocytes and monocytes in part through vagal efferent release of acetylcholine, which turns off production ( 23 , 27 ), and in part by central inhibition of sympathetic potentiation of cytokine release ( 28 ) and has been shown to suppress immune cell recruitment to vascular injury sites following endothelial activation ( 26 ). Indeed, T lymphocytes and monocytes express both AG and GHS-R1a, which function as negative regulators of these key cytokines ( 5 ).…”

Relationships between Ghrelin and Obestatin with MDA, Proinflammatory Cytokines, GSH/GSSG Ratio, Catalase Activity, and Semen Parameters in Infertile Patients with Leukocytospermia and Varicocele

“…However, growing evidences suggest that obestatin could be considered a sort of “protective” peptide as it may support cell survival and proliferation and could play a healing role in different organs [4]. Recently, much attention has been dedicated to the ability of ghrelin to reduce the inflammation processes by promoting a strong inhibition of inflammatory cytokine expression [5] and attenuating the oxidative stress in different organs [6–8]. Ghrelin exerts its antioxidant and anti-inflammatory effects by preventing the peroxidation and enhancing the activity of antioxidant enzymes [9].…”

Unacylated Ghrelin Improves Vascular Dysfunction and Attenuates Atherosclerosis during High-Fat Diet Consumption in Rodents

“…In addition, we found that sustained UnGhr overexpression was associated with lower oxidative stress in the aorta. Indeed, many studies in animal models have shown an effect of unacylated ghrelin on the redox state [29,30], indicating that in normal conditions the peptide protects vessels from oxidative stress, both by inducing the expression of endogenous antioxidants [22] and by quenching the activity of NADPH oxidase [19]. Similar results have been obtained in patients in the setting of hypertension and diabetes [8,23].…”