Human ghrelin protects animals from renal ischemia-reperfusion injury through the vagus nerve.

BACKGROUND: Acute kidney injury secondary to renal ischemia and reperfusion injury is widely prevalent. Ghrelin, which is a stomach-derived peptide, has been shown to be anti-inflammatory. The purpose of this study was to examine whether human ghrelin has any beneficial effects after renal ischemia and reperfusion injury, and if so, whether ghrelin's action in renal ischemia and reperfusion injury is mediated by the vagus nerve. METHODS: Male adult rats were subjected to renal ischemia and reperfusion by bilateral renal pedicle clamping for 60 min, treated intravenously with human ghrelin (4 nmol/rat) or normal saline (vehicle) immediately after reperfusion. After 24 h, the animals were killed and samples were harvested. In separate groups, subdiaphragmatic vagotomy prior to renal ischemia and reperfusion was performed, treated with human ghrelin or vehicle, and at 24 h, blood and organs were harvested. RESULTS: Renal ischemia and reperfusion injury caused significant increases in the serum levels of tissue injury markers compared with the sham operation. Human ghrelin treatment attenuated serum creatinine and blood urea nitrogen significantly by 55% and 53%, and liver enzymes (aminotransferase [AST] and alanine aminotransferase [ALT]) by 20% and 24%, respectively, compared with the vehicle-treated groups. Tissue water contents, plasma and kidney interleukin-6, and kidney myeloperoxidase activity were decreased. Bcl-2/Bax ratio was increased, and histology of the kidneys was improved. More importantly, prior vagotomy abolished ghrelin's protective effect in tissue injury markers and tissue water contents in renal ischemia and reperfusion injured animals. CONCLUSION: Human ghrelin treatment in renal ischemia and reperfusion injured rats attenuated systemic and kidney-specific inflammatory responses. The protection of human ghrelin in renal ischemia and reperfusion injury was mediated by the vagus nerve. These data suggest that ghrelin can be developed as a novel treatment for patients with acute kidney injury induced by renal ischemia and reperfusion injury.

Deep venous thrombosis in lap band surgery: a single center study.

Bariatric surgery has been demonstrated to be an effective treatment for morbid obesity. The purpose of this study is to investigate the incidence of pre- and post-operative deep venous thrombosis (DVT) in Lap-Band surgical patients. This study group comprised 56 consecutive patients who underwent Lap-Band surgery. Mean age and body mass index were 38 years (range: 18-64 years) and 50.9 kg/m(2) (range: 53-74 kg/m(2)), respectively. All the patients were screened with duplex ultrasonography pre- and post-operatively. There were no iliac, femoral, or popliteal vein thromboses detected at any given point of time. No patient had any clinical signs or symptoms of DVT post-operatively. There were no observable differences attributable to DVT prophylaxis. This data suggest that in the setting of chemical and mechanical prophylaxis, the incidence of DVT in patients undergoing Lap-Band surgery at an established bariatric centre is minimal.

Resuscitation of uncontrolled traumatic hemorrhage induced by severe liver injury: the use of human adrenomedullin and adrenomedullin binding protein-1.

BACKGROUND: The liver is a major organ that is susceptible to injury after blunt or penetrating trauma to the abdomen. No specific nonoperative treatment exists for traumatic hepatic injury (THI). Adrenomedullin (AM), a vasoactive peptide, combined with its binding protein, AM protein (AMBP-1), is beneficial in various disease conditions. In this study, we propose to analyze whether human AM combined with human AMBP-1 provides benefit in a model of THI in the rat. METHODS: Male adult rats were subjected to trauma hemorrhage by resection of ∼50% of total liver tissues and allowed bleeding for 15 minutes. Immediately thereafter, human AM (48 µg/kg birth weight) plus human AMBP-1 (160 µg/kg birth weight) were given intravenously over 30 minutes in 1-mL normal saline. After 4 hours, the rats were killed, blood was collected, and tissue injury indicators were assessed. A 10-day survival study was also conducted. RESULTS: At 4 hours after THI, plasma AMBP-1 levels were markedly decreased. Plasma levels of liver injury indicators (i.e., aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) were significantly increased after THI. Similarly, lactate, creatinine, and tumor necrosis factor-α levels were significantly increased after THI. Administration of human AM/AMBP-1 after THI produced significant decreases of 64%, 23%, and 19% of plasma aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels, respectively. Similarly, plasma levels of lactate, creatinine, and tumor necrosis factor-α were also decreased by 42%, 28%, and 46% after human AM/AMBP-1 treatment, respectively. In a 10-day survival study, although vehicle treatment produced 41% survival, human AM/AMBP-1 treatment improved the survival rate to 81%. CONCLUSIONS: Administration of human AM/AMBP-1 significantly attenuated tissue injury and inflammation and improved survival after THI. Thus, human AM/AMBP-1 can be developed as a novel treatment for victims with uncontrolled traumatic hemorrhage.

Attenuation of renal ischemia and reperfusion injury by human adrenomedullin and its binding protein.

BACKGROUND: Acute renal failure secondary to ischemia and reperfusion (I/R) injury poses a significant burden on both surgeons and patients. It carries a high morbidity and mortality rate and no specific treatment currently exists. Major causes of renal I/R injury include trauma, sepsis, hypoperfusion, and various surgical procedures. We have demonstrated that adrenomedullin (AM), a novel vasoactive peptide, combined with AM binding protein-1 (AMBP-1), which augments the activity of AM, is beneficial in various disease conditions. However, it remains unknown whether human AM/AMBP-1 provides any beneficial effects in renal I/R injury. The objective of our study therefore was to determine whether administration of human AM/AMBP-1 can prevent and/or minimize damage in a rat model of renal I/R injury. METHODS: Male adult rats were subjected to renal I/R injury by bilateral renal pedicle clamping with microvascular clips for 60 min followed by reperfusion. Human AM (12 microg/kg BW) and human AMBP-1 (40 microg/kg BW) or vehicle (52 microg/kg BW human albumin) were given intravenously over 30 min immediately following the clip removal (i.e., reperfusion). Rats were allowed to recover for 24 h post-treatment, and blood and renal tissue samples were collected. Plasma levels of AM were measured using a radioimmunoassay specific for rat AM. Plasma AMBP-1 was measured by Western analysis. Renal water content and serum levels of systemic markers of tissue injury were measured. Serum and renal TNF-alpha levels were also assessed. RESULTS: At 24 h after renal I/R injury, plasma levels of AM were significantly increased while plasma AMBP-1 was markedly decreased. Renal water content and systemic markers of tissue injury (e.g., creatinine, BUN, AST, and ALT) were significantly increased following renal I/R injury. Serum and renal TNF-alpha levels were also increased post injury. Administration of human AM/AMBP-1 decreased renal water content, and plasma levels of creatinine, BUN, AST, and ALT. Serum and renal TNF-alpha levels were also significantly decreased after AM/AMBP-1 treatment. CONCLUSION: Treatment with human AM/AMBP-1 in renal I/R injury significantly attenuated organ injury and the inflammatory response. Thus, human AM combined with human AMBP-1 may be developed as a novel treatment for patients with acute renal I/R injury.

The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1.

Hepatocellular dysfunction occurs early in sepsis and this appears to be caused by Kupffer cell-derived TNF-alpha production from the liver as a result of the increased release of the sympathetic neurotransmitter, norepinephrine, from the gut. Ghrelin, a novel stomach-derived peptide, is down-regulated in sepsis and administration of ghrelin into rodents decrease pro-inflammatory cytokines, attenuates hepatic and other organ injuries and improves survival. Ghrelin's beneficial effect in sepsis is mediated by the inhibition of the sympathetic nervous system (SNS), as evidenced by the reduced gut-derived norepineprine (NE) release in sepsis after ghrelin treatment. Recent data suggest that MKP-1, the MAPK phosphatase-1, is involved in the innate immune responses. To determine that the beneficial effect of ghrelin in sepsis is mediated by MKP-1, rats were subjected to sepsis by cecal ligation and puncture (CLP) alone, or treated with ghrelin, beginning at 5-h post-CLP and liver tissues were harvested and examined for MKP-1 mRNA and protein expression. CLP alone produced a significant decrease in MKP-1 gene expression in liver tissues at 20 h after CLP (P<0.05). MKP-1 mRNA was decreased by 30-40% at 2 and 5 h after CLP, but not statistically significant. MKP-1 protein expression was significantly decreased as early as 2 h after CLP and remained low at 5-20 h after CLP. While septic rats treated with vehicle produced significant decreases from sham rats, ghrelin treatment improved both mRNA and protein from vehicle group (0.58+/-0.069 vs. 0.91+/-0.16, P<0.05; 0.14+/-0.027 vs. 0.22+/-0.017, P=0.013), respectively. Since ghrelin's inhibitory effect is mediated by the SNS, we hypothesized that NE treatment in Kupffer cells may downregulate MKP-1. Kupffer cells were treated with NE and examined for MKP-1. Treatment with NE for 60 min showed an average of 46.9% decrease in MKP-1 mRNA expression compared to untreated cells (P<0.001). Likewise, NE treatment in RAW264.7 cells produced significantly lower MKP-1 mRNA than that of control cells. To further confirm the effect of NE on MKP-1, normal rats were infused with NE for 2 h through the portal vein and MKP-1 mRNA from the liver was examined. Infusion with NE produced a significant 73.7% decrease in MKP-1 mRNA. Therefore, ghrelin's inhibitory effect on gut-derived NE release in sepsis leading to the downregulation of pro-inflammatory cytokines is mediated by MKP-1.