neuropeptide-y and Endotoxemia

Endotoxin is a major stimulus for triggering the host response in septicaemia. The pathophysiology of sepsis involves activation of the vascular endothelium and leukocytes, resulting in the release of various mediators, e.g. cytokines, nitric oxide (NO), endothelin (ET-1) and complement factors. We evaluated the blood levels of complement activation, ET-1 and neuropeptide Y (NPY) in parallel with the haemodynamic and oxygen transport response during human experimental endotoxemia.. Eleven healthy men had venous, arterial and pulmonary arterial catheters placed for continuous haemodynamic measuring. After 30 min rest endotoxin (E. Coli 4 ng kg(-1), Lot G1) was intravenously administered. Blood samples from pulmonary and arterial catheters were collected hourly over 4 h.. Body temperature augmented significantly from baseline values (36.7 +/- 0.7 degrees C, mean +/- SEM) with a maximum after 3.5 h (39.1 +/- 0.3 degrees C, P < 0.001). Cardiac output increased by 100%, systemic vascular resistance decreased by 50%, the oxygen consumption and the tissue oxygen transport increased. Activation of the complement system was indicated by an increase in SC5b-9. Endothelin-1-like immunoreactivity (ET-1-LI) increased over time in arterial blood. NPY-like immunoreactivity (NPY-LI) did not change over time.. A dose of endotoxin associated with reproducible systemic vasodilation and fever in healthy subjects causes complement activation and increased systemic levels of ET-1-LI, illustrating that the model is a useful tool for inducing moderate systemic inflammation where several mediator systems are activated.

Topics: Adult; Body Temperature; Complement Activation; Endothelin-1; Endotoxemia; Endotoxins; Hemodynamics; Humans; Inflammation; Male; Neuropeptide Y; Oxygen Consumption; Pulmonary Alveoli; Pulmonary Gas Exchange

Dexmedetomidine is generally used for sedaton in critically ill, it could shorten duration of mechanical ventilation, ICU stay and lower basic metabolism. However, the exact mechanism of these positive effects remains unkown. Here we investigated the hypothesis that dexmedetomidine could ameliorate muscle wasting in endotoxemic rats and whether it was related to hypothalamic neuropeptides alteration and inflammation. Fourty-eight adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by 50 μg/kg dexmedetomidine or saline administration via the femoral vein catheter (infusion at 5 μg·kg-1·hr-1). Twenty-four hours after injection, hypothalamus tissues and skeletal muscle were obtained. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF-1) as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also detected in all four groups. Results showed that LPS administration led to significant increase in hypothalamic inflammation together with muscle wasting. Increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were also observed. Meanwhile dexmedetomidine administration ameliorated muscle wasting, hypothalamic inflammation and modulated the alteration of neuropeptides, POMC, CART and AgRP, in endotoxemic rats. In conclusion, dexmedetomidine could alleviate muscle wasting in endotoxemic rats, and it could also attenuate the alteration of hypothalamic neuropeptides and reduce hypothalamic inflammation.

Topics: Agouti-Related Protein; Animals; Dexmedetomidine; Endotoxemia; Hypothalamus; Inflammation; Interleukin-1; Male; Methylhistidines; Muscle, Skeletal; Muscular Atrophy; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Septic patients always develop muscle wasting, which delays the rehabilitation and contributes to the increased complications and mortality. Previous studies have implied the crucial role of central inflammation and neuropeptides in the energy balance and muscle metabolism. Insulin has been confirmed to attenuate muscle degradation and inhibit inflammation. We tested the hypothesis whether insulin ameliorating muscle wasting was associated with modulating hypothalamic inflammation and neuropeptides.. Thirty-two adult male Sprague-Dawley rats were in intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by subcutaneous injection of insulin (5 IU/kg) or saline. Twenty-four hours after injection, skeletal muscle and hypothalamus tissues were harvested. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also measured in four groups.. LPS injection led to significant increase in hypothalamic inflammation as well as muscle wasting. Also, increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were observed. Insulin treatment ameliorated endotoxaemia-induced muscle wasting and hypothalamic inflammation, and attenuated the alteration of neuropeptides, POMC, CART and AgRP.. Hypothalamic inflammation and neuropeptides are involved in the endotoxaemia-induced muscle wasting. Insulin treatment can reduce muscle wasting, which is associated with reduced hypothalamic inflammation and alteration of hypothalamic neuropeptides.

Topics: Agouti-Related Protein; Animals; Cytokines; Disease Models, Animal; Endotoxemia; Gene Expression Regulation; Hypothalamus; Inflammation; Insulin; Lipopolysaccharides; Male; Muscles; Neuropeptide Y; Neuropeptides; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Sepsis; Wasting Syndrome

Even now, sepsis remains a major problem in modern clinical medicine, leading to systemic inflammatory response including altered leukocyte subset distribution and increased cytokine release. As immune cells are known to express NPY receptors, we investigated the effects of a specific NPY Y(2) receptor agonist (NPY(13-36)) and/or the corresponding Y(2) receptor antagonist BIIE0246 treatment on blood (by FACS analyses) and tissue (by immunohistochemistry) leukocyte subsets as well as on levels of IL-4, IL-6, IL-10, TNF-α, INF-γ (by Cytometric Bead Array) in healthy and acutely endotoxemic rats. Results show a significant decrease in blood monocytes after LPS challenge in endotoxemic control animals (by 93%), in endotoxemic NPY(13-36) treated animals (by 83%) and in endotoxemic BIIE0246 treated animals (by 88%) as compared to the corresponding healthy controls. Endotoxemic control animals showed a significant increase of TNF-α (by 98%) as compared to the healthy control group. A treatment with NPY(13-36) significantly stabilized TNF-α level in endotoxemic animals. This study indicates distinct subset- and cytokine-specific in vivo effects induced by an NPY Y(2) receptor specific treatment after a short-term LPS challenge.

Topics: Animals; Arginine; Benzazepines; Cells, Cultured; Cytokines; Endotoxemia; Leukocytes; Male; Neuropeptide Y; Peptide Fragments; Rats; Rats, Inbred Lew; Receptors, Neuropeptide Y

Neuropeptide Y (NPY) increases survival in experimental septic shock, which might be mediated by cardiovascular and/or immunological effects. To study the latter hypothesis, we monitored blood leukocyte subsets over 96 h after intravenous (i.v.) application of LPS in chronically i.v.-cannulated rats. LPS induced a dramatic leukopenia at 4 h after challenge, which was blunted in NPY-treated animals by stabilizing granulocyte and T-lymphocyte numbers. In addition, NPY treatment prevented tissue immigration of monocytes at early time points and consecutively mobilized activated monocytes from the third day after challenge. RT-PCR and in vitro adhesion studies provided evidence for a NPY Y2 receptor-mediated effect on monocytes. Thus, NPY treatment has profound receptor-specific effects on the migration and adhesion of leukocytes under endotoxemic conditions.

Topics: Animals; Apoptosis; Cell Adhesion; Cells, Cultured; Chemotaxis, Leukocyte; Down-Regulation; Endotoxemia; Flow Cytometry; Free Radicals; Injections, Intravenous; Leukopenia; Lipopolysaccharides; Male; Monocytes; Neuropeptide Y; Rats; Rats, Inbred Lew; Receptors, Neuropeptide Y; RNA, Messenger; T-Lymphocytes; Tumor Necrosis Factor-alpha

The on-going high mortality from sepsis motivates continuous research for novel therapeutic strategies. Neuropeptide Y (NPY), a sympathetic neurotransmitter, has been shown to increase survival in experimental septic shock in rats. This protective effect might be due to immunological, cardiovascular or thermoregulatory effects. The aim of this study was to examine the in vivo effect of peripherally administered NPY on body temperature, blood pressure and heart rate in endotoxaemic animals. In order to obtain clinically relevant data, various physiological parameters were monitored in parallel via radio-telemetry in chronically intravenously cannulated, freely behaving rats. Rats received a sublethal bolus of lipopolysaccharide (LPS, 100 microg kg(-1) I.V.) and the three parameters were continuously recorded for 72 h. Endotoxaemic rats showed a long-lasting hypotension, an initial hypothermia (-0.5 degrees C), followed by a prolonged febrile phase (+1.6 degrees C 6 h after endotoxin challenge) associated with a decrease of the circadian rhythm amplitude of temperature. Pretreatment with NPY (160 pmol kg(-1) I.V. over 75 min) prevented hypotension and significantly stabilized body temperature immediately following the application. The febrile phase was effectively reduced for at least 72 h. These telemetrically obtained findings clearly demonstrate that pretreatment with NPY positively influences two life-threatening symptoms in endotoxaemia and might be a future option for a successful clinical treatment regimen.

Topics: Animals; Blood Pressure; Body Temperature; Body Temperature Regulation; Endotoxemia; Heart Rate; Hypotension; Lipopolysaccharides; Male; Neuropeptide Y; Rats; Rats, Inbred Lew; Telemetry

The objective of this study was to determine whether neuropeptide Y (NPY) and recombinant human interleukin-1 receptor antagonist (IL-1ra) would: first, increase food intake; secondly, decrease concentrations of GH; thirdly, reduce GHRH-induced release of GH; and fourthly, reduce changes to concentrations of IGF-I in plasma during experimental endotoxemia in sheep. Six treatments were given to six castrated male sheep in a 6x6 Latin square treatment order. Osmotic mini-pumps were implanted at 0 h and a jugular vein was cannulated. Each sheep was continuously infused with saline (0.9%) or lipopolysaccharide (LPS) (20 micrograms/kg per 24 h, s.c.) at 10 microliters/h for 72 h via the osmotic mini-pumps. Blood samples (3 ml) were collected at 15-min intervals from 24 to 33 h. At 26 h, one of three treatments (artificial cerebrospinal fluid, NPY or IL-1ra) was injected i.c.v. within 30 s (0.3 microgram/kg), then infused i.c.v. from 26 to 33 h (600 microliters/h) at 0.3 microgram/kg per h. GHRH was injected i.v. (0.075 microgram/kg) at 32 h after which blood samples were collected at 5, 10, 15, 30, 45 and 60 min. Feed intake was reduced up to 50% for 48 h in LPS-treated compared with non-LPS-treated sheep. NPY restored feed intake in LPS-treated sheep and induced hyperphagia in non-LPS-treated sheep from 24 to 48 h. In contrast, IL-1ra did not affect appetite. Injection of NPY increased concentrations of GH from 26 to 27 h, while IL-1ra had no effect. Infusion of NPY suppressed GHRH-induced release of GH. However, no treatment altered pulse secretion parameters of GH. Concentrations of IGF-I were 20% higher at 72 h in LPS-treated sheep given NPY than in sheep treated with LPS alone, and this may reflect increased appetite from 24 to 48 h. We concluded that reduced appetite during endotoxemia is due to down-regulation of an NPY-mediated mechanism. Furthermore, NPY stimulates release of GH in healthy sheep, does not reduce pulse secretion parameters of GH, but does suppress GHRH-induced release of GH in endotoxic sheep. Therefore, NPY may be an important neurotransmitter linking appetite with regulation of GH during endotoxemic and healthy states in sheep.

Topics: Animals; Appetite; Appetite Stimulants; Body Temperature; Eating; Endotoxemia; Growth Hormone; Humans; Insulin-Like Growth Factor I; Lipopolysaccharides; Male; Neuropeptide Y; Receptors, Interleukin-1; Recombinant Proteins; Sheep