[show abstract][hide abstract] ABSTRACT: A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo. Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106-125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.
[show abstract][hide abstract] ABSTRACT: Sepsis is an acute inflammatory condition that can result in multiple organ failure and acute lung injury (ALI). Growth arrest-specific protein 6 (Gas6) is a broad regulator of the innate immune response involved with the NF-κB signaling pathway. We hypothesized that Gas6 could have a protective role in attenuating the severity of ALI and sepsis. Male mice were subjected to sepsis by cecal ligation and puncture (CLP) after which recombinant murine Gas6 (rmGas6; 5 μg/mouse) or normal saline (vehicle) was administered intravenously. Blood and lung tissues were collected at 20 h after CLP for various measurements. Treatment with rmGas6 significantly reduced serum levels of the injury markers AST, ALT and LDH as well as proinflammatory cytokines IL-6 and IL-17, compared to the vehicle group (P<0.05). The parenchyma of the lungs damaged by CLP was attenuated by rmGas6 treatment. Lung mRNA levels of TNF-α, IL-1β, IL-6, IL-17 and MIP-2 were decreased by 60%, 86%, 82%, 93% and 82%, respectively, with rmGas6 treatment as determined by real time RT-PCR (P<0.05). The degradation of IκB-α induced by CLP in the lungs was inhibited by rmGas6 treatment. The number of neutrophils and myeloperoxidase activity in the lungs were significantly reduced in the rmGas6 group. Moreover, rmGas6 reduced the in-vitro migration of differentiated human promyelocytic HL60 cells by 64%. Finally, the 10-day survival rate of mice subjected to CLP was increased from 31% in the vehicle group to 67% in the rmGas6 group (P<0.05). Thus, Gas6 has potential to be developed as a novel therapeutic agent to treat patients with sepsis and acute lung injury.
[show abstract][hide abstract] ABSTRACT: The Wnt/β-catenin signaling pathway is well characterized in stem cell biology and plays a critical role in liver development, regeneration, and homeostasis. We hypothesized that pharmacological activation of Wnt signaling protects against hepatic ischemia/reperfusion (I/R) injury through its known proliferative and anti-apoptotic properties. Sprague-Dawley rats underwent 70% hepatic ischemia by microvascular clamping of the hilum of the left and median lobes of the liver for 90 min, followed by reperfusion. Wnt agonist (2-amino-4-[3,4-(methylenedioxy) benzylamino]-6-(3-methoxyphenyl) pyrimidine, 5 mg/kg BW) or vehicle (20% DMSO in saline) in 0.5 ml was injected intraperitoneally (i.p.) 1 h prior to ischemia or infused intravenously over 30 min right after ischemia. Blood and tissue samples from the pre-treated groups were collected 24 h after reperfusion, and a survival study was performed. Hepatic expression of β-catenin and its downstream target gene Axin2 were decreased after I/R while Wnt agonist restored their expression to sham levels. Wnt agonist blunted I/R-induced elevations of AST, ALT, and LDH and significantly improved the microarchitecture of the liver. The cell proliferation determined by Ki67 immunostaining significantly increased with Wnt agonist treatment and inflammatory cascades were dampened in Wnt agonist-treated animals, as demonstrated by attenuations in IL-6, myeloperoxdase, iNOS and nitrotyrosine. Wnt agonist also significantly decreased the amount of apoptosis, as evidenced by decreases in both TUNEL staining as well as caspase-3 activity levels. Finally, the 10-day survival rate was increased from 27% in the vehicle group to 73% in the pre-treated Wnt agonist group and 55% in the Wnt agonist post-ischemia treatment group. Thus, we propose that direct Wnt/β-catenin stimulation may represent a novel therapeutic approach in the treatment of hepatic I/R.
[show abstract][hide abstract] ABSTRACT: An ectopic pancreas is defined as pancreatic tissue lacking vascular or anatomic communication with the normal body of the pancreas. It is rarely symptomatic as it is found incidentally at laparotomy most of the time. Despite advances in diagnostic modalities, it still remains a challenge to the clinician to differentiate it from a neoplasm. It is prudent to differentiate it from neoplastic etiologies, as simple surgical excision can potentially be curative. We discuss the presentation, diagnosis, and treatment of an interesting case of ectopic pancreas presenting as a gastric antral tumor.
International Journal of Angiology 09/2012; 21(3):177-80.
[show abstract][hide abstract] ABSTRACT: Renal injury as a result of ischemia/reperfusion (I/R) is a major clinical problem with a high mortality rate and a lack of therapeutic treatment. During I/R, cellular homeostasis is disrupted owing to energy depletion, leading to cell death. Fatty acid β-oxidation is the major metabolic pathway for generating adenosine triphosphate (ATP) in the kidneys, which is governed by carnitine palmitoyltransferase 1 (CPT1). C75 is a synthetic compound that up-regulates CPT1 activity. Thus, we hypothesized that C75 treatment could increase energy production and alleviate renal I/R injury.
We subjected male adult rats to renal I/R by bilateral renal pedicle clamping with microvascular clips for 60 min, followed by administration of 8% dimethyl sulfoxide (vehicle) or C75 (3 mg/kg body weight), with 5 animals/group. We collected blood and renal tissues 24 h after reperfusion and subjected them to various measurements and histological examination.
C75 treatment restored the loss of CPT1 activity and intracellular ATP levels in the kidneys after I/R. Administration of C75 significantly lowered serum creatinine, blood urea nitrogen, aspartate aminotransferase, and lactate dehydrogenase levels elevated by I/R. C75 treatment preserved morphological features of the kidneys with a significant improvement in the damage score. In addition, C75 treatment inhibited the increase of TNF-α levels in serum and kidneys, and lowered myeloperoxidase activity in the kidneys after I/R.
Stimulation of CPT1 activity by C75 recovered ATP depletion, improved renal function, attenuated tissue injury, and inhibited proinflammatory cytokine production and neutrophil infiltration after renal I/R injury. Therefore, enhancing the metabolism pathways for energy production may provide a novel modality to treat renal I/R injury.
Journal of Surgical Research 06/2012; 177(1):157-64. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Insufficient clearance of apoptotic cells leads to increased inflammation and exaggerated organ injury. The opsonizing protein, milk fat globule epidermal growth factor-factor 8 (MFG-E8), upregulates apoptotic cell clearance. The purpose of this study was to determine the degree of apoptotic cell clearance, and whether inflammation, organ injury, and survival are improved after treatment with recombinant human MFG-E8 (rhMFG-E8) after hemorrhagic shock.
Male mice underwent a pressure-controlled (25 mm Hg ± 5 mm Hg) model of hemorrhagic shock for 90 minutes. They were resuscitated with normal saline with or without recombinant human MFG-E8 (rhMFG-E8) over 30 minutes. At 3.5-hour postresuscitation, blood and tissue were collected. MFG-E8 levels in the plasma, lungs, and spleen were measured. Apoptotic cell clearance was measured by cleaved caspase-3 levels and TUNEL staining. Neutrophil infiltration was assessed using myeloperoxidase activity in the lungs and spleen. Plasma and tissue levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured by ELISA. Finally, a seven-day survival study was also conducted.
MFG-E8 levels in the plasma, lungs, and spleen significantly decreased by 33%, 44%, and 55%, respectively, at 3.5 hour after hemorrhage and resuscitation with rhMFG-E8. Treatment with rhMFG-E8 significantly improved apoptosis, by reducing TUNEL+ cells after treatment and restoring cleaved caspase-3 expression back to baseline. Neutrophil infiltration was blunted by 29% and 41% in the lungs and spleen, respectively. Cytokine expression was also reduced significantly, by 64% to 73% in plasma, 24% to 58% in the lungs, and 49% to 76% in the spleen. Finally, animals demonstrated a superior survival rate over 7 days after treatment with rhMFG-E8.
The administration of rhMFG-E8 is a potent treatment in animals after hemorrhagic shock.
The journal of trauma and acute care surgery. 04/2012; 72(4):861-9.
[show abstract][hide abstract] ABSTRACT: Cardiovascular dysfunction, characterized by reduced cardiac contractility and depressed endothelium-dependent vascular relaxation, is common in severe sepsis. Although it is known that ghrelin produces beneficial effects following various adverse circulatory conditions, it remains unknown whether ghrelin increases cardiac contractility and improves vascular responsiveness to vasoactive agents in severe sepsis.
Male adult rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed mini-pump over 15 h. At 20 h after CLP (i.e., severe sepsis), the maximal rates of ventricular pressure increase (+dP/dt(max)) and decrease (-dP/dt(max)) were determined in vivo. In additional groups of animals, the thoracic aortae were isolated at 20 h after CLP. The aortae were cut into rings, and placed in organ chambers. Norepinephrine (NE) was used to induce vascular contraction. Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerine (NTG) were carried out.
+dP/dt(max) and -dP/dt(max) decreased significantly at 20 h after CLP. Treatment with ghrelin significantly increased +dP/dt(max) and -dP/dt(max) by 36% (P < 0.05) and 35% (P < 0.05), respectively. Moreover, NE-induced vascular contraction and endothelium-dependent (ACh-induced) vascular relaxation decreased significantly at 20 h after CLP. Administration of ghrelin, however, increased NE-induced vascular contraction and ACh-induced vascular relaxation. In contrast, no significant reduction in NTG-induced vascular relaxation was seen in rats with severe sepsis irrespective of ghrelin treatment.
Ghrelin may be further developed as a useful agent for maintaining cardiovascular stability in severe sepsis.
Journal of Surgical Research 03/2012; 178(1):370-7. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: The gastrointestinal (GI) syndrome component of acute radiation syndrome (ARS) results from depletion of immature parenchymal stem cells after high dose irradiation and contributes significantly to early mortality. It is associated with severe, irreparable damage in the GI tract and extremely low survival. There is a need for the development of viable mitigators of whole body irradiation (WBI) due to the possibility of unexpected high level radiation exposure from nuclear accidents or attacks. We therefore examined the effect of recombinant human milk fat globule-EGF factor 8 (rhMFG-E8) in mitigating damage after WBI. Male Sprague-Dawley rats were exposed to 10 Gy WBI using Cesium-137 as the radiation source. The animals in the treatment group received rhMFG-E8 (166 µg/kg BW) subcutaneously once a day with the first dose given 6 h after WBI. Blood and tissue samples from the ileum were collected after 3 days of treatment. A separate cohort of animals was treated for 7 days and the 21 day mortality rate was determined. Treatment with rhMFG-E8 significantly improved the survival from 31% to 75% over 21 days. Furthermore, rhMFG-E8 treatment resulted in a 36% reduction in the radiation injury intestinal mucosal damage score, corresponding to visible histological changes. MFG-E8 gene expression was significantly decreased in WBI-induced animals as compared to sham controls. Treatment with rhMFG-E8 increased p53 and p21 expression by 207% and 84% compared to untreated controls. This was accompanied by an 80% increase in the expression of anti-apoptotic cell regulator Bcl-2. p53 and p21 levels correlate with improved survival after radiation injury. These cell regulators arrest the cell after DNA damage and enable DNA repair as well as optimize cell survival. Taken together, these results indicate that rhMFG-E8 ameliorates the GI syndrome and improves survival after WBI by minimizing intestinal cell damage and optimizing recovery.
PLoS ONE 01/2012; 7(10):e46540. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Traumatic brain injury (TBI) and hemorrhagic shock often occur concomitantly due to multiple injuries. Gastrointestinal dysfunction occurs frequently in patients with TBI. However, whether alterations in the gastrointestinal system are involved in modulating neuronal damage and recovery after TBI is largely neglected. Ghrelin is a "gut-brain" hormone with multiple functions including antiinflammation and antiapoptosis. The purpose of this study was to determine whether ghrelin attenuates brain injury in a rat model of TBI and uncontrolled hemorrhage (UH). To study this, brain injury was induced by dropping a 450-g weight from 1.5 m onto a steel helmet attached to the skull of male adult rats. Immediately after TBI, a midline laparotomy was performed and both lumbar veins were isolated and severed at the junction with the vena cava. At 45 min after TBI/UH, ghrelin (4, 8 or 16 nmol/rat) or 1 mL normal saline (vehicle) was intravenously administered. Brain levels of TNF-α and IL-6, and cleaved PARP-1 levels in the cortex were measured at 4 h after TBI/UH. Beam balance test, forelimb placing test and hindlimb placing test were used to assess sensorimotor and reflex function. In additional groups of animals, ghrelin (16 nmol/rat) or vehicle was subcutaneously (s.c.) administered daily for 10 d after TBI/UH. The animals were monitored for 28 d to record body weight changes, neurological severity scale and survival. Our results showed that ghrelin downregulated brain levels of TNF-α and IL-6, reduced cortical levels of cleaved PARP-1, improved sensorimotor and reflex functions, and decreased mortality after TBI/UH. Thus, ghrelin has a great potential to be further developed as an effective resuscitation approach for the trauma victims with brain injury and severe blood loss.
Molecular Medicine 12/2011; 18(1):186-93. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vascular complications after a renal transplant are rare and critical. Duplex Doppler evaluation constitutes the primary imaging modality in renal transplant. Early diagnosis and appropriate intervention to address potential complications are crucial in graft survival. This report describes a 25-year-old woman who underwent a live-donor renal transplant. During a routine study 4 hours after surgery, she was found to have high peak flow velocities suggestive of stenosis. An angiogram obtained as a result of this finding showed no abnormalities. A repeat duplex Doppler sonogram performed 12 hours later revealed normal waveforms and velocities. Postrenal transplant vascular complications are rare but may represent a significant morbidity factor for patients and grafts. Peak wave forms, elevated velocities, and a tardus-parvus configuration are suggestive of vascular disorders that require aggressive evaluation. In our patient, the Doppler ultrasound, angiogram, and lack of clinical signs were compatible with a renal artery vasospasm. This entity, despite its reversibility in the majority of instances, may cause severe graft injury if it does not regress promptly.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 12/2011; 9(6):421-4.
[show abstract][hide abstract] ABSTRACT: Excessive inflammation and apoptosis contribute to the pathogenesis of ischemic stroke. MFG-E8 is a 66-kDa glycoprotein that has shown tissue protection in various models of organ injury. However, the potential role of MFG-E8 in cerebral ischemia has not been investigated. We found that levels of MFG-E8 protein in the brain were reduced at 24 h after cerebral ischemia. To assess the potential role of MFG-E8 in cerebral ischemia, adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). At 1 h post-stroke onset, an intravenous administration of 1 ml saline as vehicle or 160 μg/kg BW recombinant human MFG-E8 (rhMFG-E8) as treatment was given. The optimal dose of rhMFG-E8 was obtained from previous dose-response organ protection in rat sepsis studies. Neurological scores were determined at 24 h and 48 h post-MCAO. Rats were sacrificed thereafter and brains rapidly removed and analyzed for infarct size, histopathology, and markers of inflammation and apoptosis. Compared with saline vehicle, rhMFG-E8 treatment led to significant decreases in sensorimotor and vestibulomotor deficits, and infarct size at 24 h and 48 h post-MCAO. Measures associated with improved outcome included reduced microglial inflammatory cytokine secretion, adhesion molecules and neutrophil influx, cleaved caspase-3, and upregulation of peroxisome proliferator activated receptor-γ (PPAR-γ), and Bcl-2/Bax ratio leading to decreased apoptosis. Thus, rhMFG-E8 treatment is neuroprotective against cerebral ischemia through suppression of inflammation and apoptosis. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
[show abstract][hide abstract] ABSTRACT: Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans.
Rats were subjected to sepsis by cecal ligation and puncture (CLP), and at 5 h post-CLP, they were given different doses of rhMFG-E8 (20, 40, 80, 160 μg/kg BW) in normal saline. At 20 h post-CLP, samples were collected for further analysis. A 10-day survival study was also performed.
At 20 h after CLP, organ injury indicators, serum IL-6 and TNF-α, and plasma HMGB-1 levels were significantly increased as compared to sham-operated animals. Treatment with 20 μg/kg rhMFG-E8 significantly reduced these levels. With higher doses, further reductions in AST and ALT (59-62%), creatinine (65-68%), and lactate (46-57%), and serum IL-6 and TNF-α were obtained. The 160 μg/kg dose produced the greatest reduction in serum TNF-α. With treatment with 20 μg/kg rhMFG-E8, HMGB-1 levels decreased by 80%, returning back to sham values. In a 10-day survival study, vehicle-treated animals produced a 36% survival rate, while rhMFG-E8 significantly improved the survival rate to 68-72%. Treatment with increasing doses of rhMFG-E8 significantly reduced the number of apoptotic cells detected and markedly attenuated the tissue damages observed in the lungs.
These data suggest that recombinant human MFG-E8 is beneficial in ameliorating sepsis in an animal model of sepsis.
European Journal of Intensive Care Medicine 09/2011; 38(1):128-36. · 5.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Surgery 09/2011; 151(1):37-47. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Renal ischemia/reperfusion (I/R) injury is a major clinical problem where main metabolic pathways are compromised and cellular homeostasis crashes after ATP depletion. Fatty acids are major energy source in the kidneys. Carnitine palmitoyltransferase I (CPT1), a mitochondrial membrane enzyme, utilizes carnitine to transport fatty acids to mitochondria for the process of β-oxidation and ATP generation. In addition, CPT1 activity is indirectly regulated by adenosine monophosphate-activated protein kinase, which can be activated by 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). We hypothesized that administration of carnitine and AICAR could reestablish the energetic balance after reperfusion and ameliorate renal I/R injury. Male adult rats were subjected to renal I/R by bilateral renal pedicle clamping for 60 min, followed by administration of saline (vehicle), carnitine (250 mg/kg BW), AICAR (30 mg/kg BW), or combination of both drugs. Blood and renal tissues were collected 24 h after reperfusion for various measurements. Renal carnitine levels decreased 53% after I/R. The combined treatment significantly increased CPT1 activity and ATP levels and lowered renal malondialdehyde and serum TNF-α levels against the vehicle group. It led to improvement in renal morphology and histological damage score associated with diminution in serum creatinine, blood urea nitrogen, and aspartate aminotransferase levels. Moreover, the combined treatment significantly improved the survival rate in comparison to the vehicle group. In contrast, administration of either drug alone did not show a significant improvement in most of the measurements. In conclusion, enhancing energy metabolism by combination of carnitine and AICAR provides a novel modality to treat renal I/R injury.
[show abstract][hide abstract] ABSTRACT: Alcohol-induced liver disease is associated with unacceptable morbidity and mortality. When activated, Kupffer cells (KCs), the resident macrophages in the liver, release proinflammatory cytokine TNF-α, a key mediator of hepatic damage. Although chronic alcohol causes increase in norepinephrine (NE) release leading to hepatic dysfunction, the mechanism of NE-induced hepatic injury in chronic alcohol exposure has not been elucidated. This study was conducted to determine whether chronic alcohol exposure increases NE and upregulates KC α(2A)-adrenoceptors (α(2A)-AR) to cause TNF-α release. We also examined the role of mitogen activated protein kinase (MAPK) phosphatase-1 (MKP-1) in this process. Male adult rats were fed the Lieber-DeCarli liquid diet containing alcohol as 36% of total calories. The animals were sacrificed after 6 weeks and blood and liver samples were harvested for further analysis. KCs from healthy male rats were cultured with alcohol for 7 days, and cells then harvested for RNA and protein analyses. Chronic alcohol exposure resulted in hepatic damage. Alcohol caused a 276% increase in circulating NE and 86% increase in TNF-α in the liver. There was a 75% and 62% decrease in MKP-1 mRNA and protein levels, respectively in the liver. In-vitro experiments revealed 121% and 98% increase in TNF-α and α(2A)-AR mRNA levels with alcohol exposure, respectively, and a 32% decrease in MKP-1 mRNA compared to controls. In summary, chronic alcohol exposure elevates NE and upregulates KC α(2A)-AR to release TNF-α. Alcohol induced downregulation of MKP-1 leads to further release of TNF-α and hepatic injury.
Biochemical and Biophysical Research Communications 06/2011; 409(3):406-11. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alcoholic liver disease accounts for 12,000 deaths per year in the United States and is the second leading indication for liver transplantation. It covers a spectrum of disease conditions ranging from steatosis and cirrhosis to hepatic malignancies. Epidemiological data clearly show a strong correlation between alcohol consumption and liver diseases. A large body of evidence has accumulated over the years in determining the molecular mediators of alcohol-induced liver injury. In this review, we provide an overview of such mediators, which include alcohol metabolites and reactive oxygen/nitrogen species, endotoxin via bacterial translocation from the gut and TNF-α, and highlight the role of the sympathetic nervous stimuli, norepinephrine and the α2A-adrenergic receptors in contributing to the deleterious effect observed in alcohol-induced hepatic dysfunction.
Molecular Medicine Reports 04/2011; 4(4):597-602. · 1.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Stroke is a devastating neurovascular disease with limited therapeutic options. The pathogenesis of stroke involves complex interrelated molecular mechanisms including excitotoxicity, oxidative and nitrosative stress, cortical spreading depolarizations, inflammation, necrosis, and apoptosis. Successful development of stroke therapeutics depends on understanding these molecular mechanisms and how to counteract them to limit tissue damage during stroke. Activation of the parasympathetic nervous system (PNS) has been shown to antagonize a multiplicity of pathologic mechanisms. Elements of parasympathetic activation such as vagus nerve stimulation have already been used successfully in treating brain disorders such as epilepsy and depression. This review discusses the anatomical basis and molecular mechanisms involved in activation of the PNS, and assesses the strength of available evidence for the further development of this modality into a stroke therapy.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2011; 31(5):1187-95. · 5.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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%.
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.
The Journal of trauma 11/2010; 69(6):1415-21; discussion 1421-2. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sepsis and ischemia-reperfusion (I/R) injury are among the leading causes of death in critically ill patients at the surgical intensive care unit setting. Both conditions are marked by the excessive inflammatory response which leads to a lethal disease complex such as acute lung injury, systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Despite the advances in the understanding of the pathophysiology of those conditions, very little progress has been made toward therapeutic interventions. One of the key aspects of these conditions is the accumulation of apoptotic cells that have the potential to release toxic and proinflammatory contents due to secondary necrosis without appropriate clearance by phagocytes. Along with the prevention of apoptosis, that is reported to be beneficial in sepsis and I/R injury, thwarting the development of secondary necrosis through the active removal of apoptotic cells via phagocytosis may offer a novel therapy. Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.
Molecular Medicine 09/2010; 17(1-2):126-33. · 4.47 Impact Factor