Ghrelin Pre-treatment Attenuates Local Oxidative Stress and End Organ Damage During Cardiopulmonary Bypass in Anesthetized Rats (original) (raw)
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PLOS ONE, 2013
Background: Ghrelin has been reported to protect the cardiovascular system; however, the cardioprotective effect of ghrelin against cardiopulmonary bypass (CPB) induced myocardial injury are unclear. In this study, the protective effect of ghrelin on CPB induced myocardial injury and the underlying mechanisms were investigated. Methods and Results: Adult male rats were subjected to CPB and randomly to receive vehicle (n = 8), ghrelin (n = 8), ghrelin plus [D-Lys3]-GHRP-6, a GHSR-1a inhibitor (n = 8), or ghrelin plus wortmannin, a phosphoinositide 39-kinase (PI3K) inhibitor (n = 8). In vitro study was performed on cultured cardiomyocytes subjected to simulated cardiopulmonary bypass (SCPB). Ghrelin attenuated the inammatory response, as evidenced by reduced induction of TNF-a, IL-6 and myocardial myeloperoxidase activity and concurrent reduction in apoptosis, oxidative stress, and levels of myocardial injury markers following CPB. Moreover, ghrelin significantly increased cardiac function after CPB. In cultured cardiomyocytes subjected to simulated CPB, ghrelin increased cell viability and decreased the percentage of apoptotic myocytes. Inhibition of ghrelin downstream signaling blocked the cardioprotective effects both in vivo and vitro. Conclusions: Ghrelin could provide an effective approach to the attenuation of CPB induced myocardial injury. The cardioprotective effects elicited by ghrelin may contribute to the inhibition of inflammatory response through the Aktactivated pathway.
American Journal of BioMedicine, 2013
Ghrelin is a small endogenous peptide principally produced and secreted by the gastric mucosa, with a major role in appetite and metabolism regulation. We hypothesized that anti-inflammatory therapy, as produced by exogenous administration of ghrelin, would decrease the myocardial inflammatory response to global hypothermia I/R, thereby affording myocardial protection. Heterotopic cervical heart transplantation that allows to subject donor hearts to global hypothermic ischemia and blood reperfusion, which very closely stimulates I/R conditions associated with cardiac surgical operations. Ghrelin administration prior to blood reperfusion significantly decreased serum concentrations of cTn-I versus animals subjected I/R alone, with a significantly attenuated VCAM-1 expression in I/R animals pre-treated with ghrelin. The tissue concentrations of pro-inflammatory cytokines (IL-6, IL-1β, and MCP-1) were ameliorated by the administration of ghrelin prior to reperfusion versus the concentr...
Background and aim of the study: Oxygen free radicals and cytokines are important components involved in the pathophysiological tissue alterations observed during ischemia/ reperfusion (I/R). Based on the anti-oxidant and anti-inflammatory effects of ghrelin, this research was designed to investigate the supposed protective role of ghrelin against I/R-induced oxidative remote organ injury. Materials and methods: This study was performed on 30 male albino rats divided into three groups (10 rats each). Group I (sham group) were subjected to sham operation and the other two groups were prepared to perform renal ischemia/reperfusion by bilateral renal artery clamping for 45 min and reperfusion for 24 h. Normal saline and ghrelin (100 µg/kg) 10 ng/kg body was injected subcutaneously six times before and three times after ischemia every 8 h for group II & III respectively. At the end of the reperfusion period, blood samples were collected and hepatic tissue were removed for biochemical analyses and histopathological examination. Results: By checking the results of the renal I/R group we noticed significant increase in the malondialdehyde level and the myeloperoxidase activity and a decrease in activity of superoxide dismutase and catalase as compared to the sham operated control group. Furthermore, serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels, and tissue cytokines were elevated. In the vehicle group (RIR +saline) areas of hepatic necrosis, leucocytic infiltration, expansion of sinusoids and congestion were detected. On the other hand, ghrelin treatment succeeded to modulate these observed abnormalities resulting from I/R in group III and the average of its results come near or close to the control one. Conclusion: As shown from the results of the current search we can claim that ghrelin administration has a protective effect against oxidative organ damage induced by I/R and can be used as a chemoprophylactic measure in patients of intensive care and organ transplantation units.
International Journal of Obesity, 2019
Background/objectives Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB). Subjects/methods Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed. Results Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68 +-and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78. Conclusions Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.
Ghrelin Attenuates Sepsis-induced Acute Lung Injury and Mortality in Rats
American Journal of Respiratory and Critical Care Medicine, 2007
Our study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and that ghrelin administration improves organ blood flow via a nuclear factor (NF)-kB-dependent pathway. However, it remains unknown whether ghrelin has any protective effects on severe sepsis-induced acute lung injury (ALI) and, if so, whether inhibition of NF-kB plays any role in it. Objectives: To test the hypothesis that ghrelin reduces severe sepsisinduced ALI and mortality through inhibition of NF-kB. Methods: Sepsis was induced in rats by cecal ligation and puncture (CLP). Five hours after CLP, a bolus intravenous injection of 2 nmol of ghrelin was followed by continuous infusion of 12 nmol of ghrelin via a minipump for 15 hours. Samples were harvested 20 hours post-CLP (i.e., severe sepsis). Pulmonary levels of ghrelin and proinflammatory cytokines were measured by ELISA. NF-kB p65 and IkBa expression and NF-kB activity were measured by Western blot analysis and ELISA, respectively. Pulmonary blood flow was measured with radioactive microspheres. In additional animals, the necrotic cecum was excised 20 hours post-CLP and 10-day survival was recorded. Measurements and Main Results: Pulmonary levels of ghrelin decreased significantly 20 hours post-CLP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-kB activation, and improved survival in sepsis. Administration of a specific ghrelin receptor antagonist worsened the survival rate after CLP and cecal excision. Conclusions: Ghrelin can be developed as a novel treatment for severe sepsis-induced ALI. The protective effect of ghrelin is mediated through inhibition of NF-kB.
Journal of Gastroenterology and Hepatology, 2007
Background and Aim: Gherlin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells. It regulates food intake, gastric secretion and motility. However, its role as a protective agent in gastric ischemia/reperfusion (I/R) injury has not yet been investigated. Therefore, the objectives of the present study were to: (i) test the in vivo effect of peripherally administered ghrelin on gastric I/R-induced lesions in rats; and (ii) investigate in vitro the effect of ghrelin on reactive oxygen species (ROS) production by human polymorphoneuclear (PMN) cells.Methods: The present study was carried out on three groups of rats (six per group): control (sham–operated), I/R (clamping of celiac artery for 30 min and reperfusion for 1 h), and I/R + ghrelin (200 ng/kg i.v., 15 min before ischemia and before reperfusion, respectively). Histological assessment of hematoxylin and eosin stained sections was performed and immunostaining with inducible nitric oxide (iNOS) antibody were performed on a gastric paraffin embedded section. Oxidative stress markers thiobarbituric acid reactive substance (TBARS) and glutathione (GSH) were measured in gastric tissue homogenates. Serum lactic acid dehydrogenase (LDH) was determined. Tumor necrosis factor-alpha (TNF-α) was assayed in gastric tissue homogenate. Gastric permeability was assessed calorimetrically using Evans blue dye. In vitro studies were carried out on isolated human PMN cells incubated with ghrelin and tested for ROS generation as measured by chemiluminecence (CL).Results: Peripheral administration of ghrelin attenuated gastric injury by reducing ulceration, tissue congestion, cellular infiltration and vascular permeability. Serum level of LDH and tissue content of TNF-α were markedly reduced. A decrement in TBARS and an increment in GSH were observed. Ghrelin treatment attenuated iNOS protein expression which was upregulated by gastric ischemic injury. In vitro studies showed for the first time that ghrelin inhibited ROS generation by human PMN in a dose-dependent manner.Conclusions: These results provide evidence that peripherally administered ghrelin protects against gastric I/R injury. We also demonstrated that this protection is possibly accomplished through the antioxidant activity of ghrelin observed in vivo and in vitro.
PLoS ONE, 2008
Background: Gut ischemia/reperfusion (I/R) injury is a serious condition in intensive care patients. Activation of immune cells adjacent to the huge endothelial cell surface area of the intestinal microvasculature produces initially local and then systemic inflammatory responses. Stimulation of the vagus nerve can rapidly attenuate systemic inflammatory responses through inhibiting the activation of macrophages and endothelial cells. Ghrelin, a novel orexigenic hormone, is produced predominately in the gastrointestinal system. Ghrelin receptors are expressed at a high density in the dorsal vagal complex of the brain stem. In this study, we investigated the regulation of the cholinergic anti-inflammatory pathway by the novel gastrointestinal hormone, ghrelin, after gut I/R. Methods and Findings: Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery for 90 min in male adult rats. Our results showed that ghrelin levels were significantly reduced after gut I/R and that ghrelin administration inhibited pro-inflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated organ injury, and improved survival after gut I/R. Administration of a specific ghrelin receptor antagonist worsened gut I/R-induced organ injury and mortality. To determine whether ghrelin's beneficial effects after gut I/R require the intact vagus nerve, vagotomy was performed in sham and gut I/R animals immediately prior to the induction of gut ischemia. Our result showed that vagotomy completely eliminated ghrelin's beneficial effect after gut I/R. To further confirm that ghrelin's beneficial effects after gut I/R are mediated through the central nervous system, intracerebroventricular administration of ghrelin was performed at the beginning of reperfusion after 90-min gut ischemia. Our result showed that intracerebroventricular injection of ghrelin also protected the rats from gut I/R injury.
Ghrelin and toxicity: recent findings and future challenges
Journal of Applied Toxicology, 2013
Ghrelin is a novel brain-gut peptide that plays various roles in mammals, including control of food intake and growth hormone release, as well as gastric motility and acid secretion in the gastrointestinal tract. It is mainly secreted by the gastric mucosa, but is also expressed in various other tissues. Different studies confirm the multiple biological roles of and possible protective effects of ghrelin. Multiple in vitro and in vivo studies support the powerful protective action of ghrelin against heart, gastric and liver injury. Moreover, ghrelin has been reported to be beneficial in renal tissue injury and excretory function after ischemia-reperfusion and to exert neuroprotective effects in cerebral ischemic regions. The aim of this review is to summarize and evaluate all the currently available in vivo and in vitro studies regarding the effects of ghrelin on tissue injury induced in different organs and tissues.