Expression of hypothalamic neuropeptides and the desensitization of pituitary-adrenal axis and hypophagia in the endotoxin tolerance

Repeated exposure to lipopolysaccharide (LPS) induces desensitization of hypothalamus-pituitary-adrenal axis (HPA) responses and hypophagia. We investigated the interplay between the neural circuitries involved in the control of food intake and HPA axis activity following single or repeated LPS injections. Male Wistar rats received a single or repeated i.p. injection of LPS (100 microg/kg) for 6 days and were subdivided into four groups: 6 saline, 5 saline+1 LPS, 5 LPS+1 saline and 6 LPS. Animals with a single exposure to LPS showed increased plasma levels of ACTH, CORT, PRL, TNF-alpha and also CRF mRNA in the paraventricular nucleus of the hypothalamus. These animals exhibited a reduced food intake and body weight associated with an increase of CART expression in the arcuate nucleus (ARC). Leptin plasma levels were not altered. On the other hand, repeated LPS administration did not alter ACTH, CORT, PRL and TNF-alpha, but it reduced leptin level, compared to single LPS or saline treatment. Furthermore, repeated LPS administration did not increase CRF or CART mRNA expression. Food intake and weight gain after repeated LPS injections were not different from saline-treated animals. There was no change in NPY and POMC mRNA expression in the ARC after single or repeated injections of LPS. In conclusion, desensitization induced by repeated exposure to LPS involves the blockade of HPA axis activation and anorexigenic response, which are both associated with an unresponsiveness of TNF-alpha production and CRF and CART expression in the hypothalamus.     

Saccharated colloidal iron enhances lipopolysaccharide-induced nitric oxide production in vivo

We investigated the effects of iron on the production of nitric oxide (NO), inducible NO synthase (iNOS), and plasma cytokines induced by lipopolysaccharide (LPS) in vivo. Male Wistar rats were preloaded with a single intravenous injection of saccharated colloidal iron (Fesin, 70 mg iron/kg body weight) or normal saline as a control, and then given an intraperitoneal injection of LPS (5.0 mg/kg body weight). Rats, preloaded with iron, had evidence of both iron deposition and strong iNOS induction in liver Kupffer cells upon injection of LPS; phagocytic cells in the spleen and lung had similar findings. LPS-induced NO production in iron-preloaded rats was significantly higher than control rats as accessed by NO-hemoglobin levels measured by ESR (electron spin resonance) and NOx (nitrate plus nitrite) levels. Western blot analysis showed that iron preloading significantly enhanced LPS-induced iNOS induction in the liver, but not in the spleen or lung. LPS-induced plasma levels of IL-6, IL-1beta, and TNF-alpha were also significantly higher in iron-preloaded rats as shown by ELISA, but IFN-gamma levels were unchanged. We conclude that colloidal-iron phagocytosed by liver Kupffer cells enhanced LPS-induced NO production in vivo, iNOS induction in the liver, and release of IL-6, IL-1beta, and TNF-alpha.     

Mineralocorticoids act centrally to regulate blood-borne tumor necrosis factor-alpha in normal rats

Excessive mineralocorticoid receptor (MR) stimulation induces neurohumoral excitation and cardiac and vascular fibrosis. In heart failure (HF) rats, with excessive neurohumoral drive, central infusion of the MR antagonist spironolactone (SL) decreases blood-borne TNF-alpha. This study aimed to determine whether DOCA, a precursor of aldosterone, acts centrally to stimulate TNF-alpha production in normal rats. DOCA (5 mg sc daily for 8 days) induced a progressive increase in TNF-alpha beginning on day 3 and increased tissue TNF-alpha in hypothalamus, pituitary, and heart but not in other brain and peripheral tissues harvested on day 9. A continuous intracerebroventricular infusion of SL (100 ng/h) blocked the plasma TNF-alpha response. Oral SL (1 mg/kg) blocked the plasma and tissue TNF-alpha responses. Thus DOCA increases TNF-alpha in brain, heart, and blood in normal rats. Activation of brain MR appears to account for the increase in plasma TNF-alpha. These findings have important implications for the understanding of pathophysiological states (e.g., HF, hypertension) characterized by high circulating levels of aldosterone.     

Inhibition of prostaglandins does not reduce the cardiovascular changes during endotoxemia in rats

Vasodilatory prostanoids, such as prostacyclin and PGE2, and pro-inflammatory cytokines are known to play a central role in the pathogenesis of endotoxemia. This study was undertaken to elucidate whether indomethacin (INDO), a non-selective COX inhibitor, has protective effects against the cardiovascular alterations that occur during endotoxemia. Sprague-Dawley rats were injected intraperitoneally with 15 mg/kg lipopolysaccharide (LPS). LPS injection led to a prominent decrease in cardiac left ventricular end diastolic area (LVEDA) and increased LV fractional shortening (FS), as measured by echocardigraphy. LPS also led to a significant increase in plasma and myocardial TNF-alpha and IL-1beta levels, and elevated plasma and hypothalamic levels of PGE2. Neither the decrease in LVEDA and the increase in FS, nor the elevation in plasma and myocardial cytokine levels were altered by INDO (10 mg/kg). On the other hand, pretreatment with INDO significantly reduced the elevation in PGE2 and the hypothermia induced by LPS. Taken together, this study demonstrates that solely inhibiting the production of PGE2 is not sufficient to reduce the cardiovascular alteration seen in endotoxemia.     

Influence of rat prenatal and postnatal exposure to a non-steroidal anti-inflammatory agent (flunoxaprofen) on cardiovascular function in the progeny

The present experiments evaluated in rats the effects of prenatal and postnatal exposure to a non-steroidal antiinflammatory agent, flunoxaprofen (5-10 and 20 mg/kg/day by the oral route), on cardiovascular function in the pups. In both conscious and anaesthetized rats pre- and postnatal flunoxaprofen exposure at the 30th and 60th day of age, significantly (P less than .05) induced a decrease of pressor response to carotid-sinus baroreceptor stimulation and to L-noradrenaline (0.1-1 and 5 micrograms/kg iv), and an increase of the hypotensive responses to L-isoprenaline (0.01-0.1 and 1 microgram/kg iv) and acetylcholine (0.01-0.1 and 1 microgram/kg iv). These effects were not observed in rats on the 90th day of age. Moreover, pre- and postnatal flunoxaprofen exposure did not modify systolic arterial blood pressure of plasma levels of catecholamines and acetylcholinesterases. Our results also show that in normotensive rats flunoxaprofen exposure during pregnancy did not affect the body weight, systolic or diastolic blood pressure or heart rate of pregnant rats. It did not affect the length of gestation, number of pups per litter or pup body weight. No macroscopic teratogenic effects were observed.     

高密度脂蛋白减轻小鼠内毒素性急性肺损伤

高密度脂蛋白(high density lipoprotein, HDL)是一种血浆含量丰富的脂蛋白,通常认为它可在体内发挥抗炎作用,能够与内毒素结合而抑制其生物活性.为探讨人HDL对内毒素性急性肺损伤的影响,将昆明小鼠分为假手术对照组、脂多糖(lipopolysaccharide, LPS)组、HDL组和LPS HDL组,腹腔注射LPS(10mg/kg体重)复制内毒素性急性肺损伤模型,于腹腔注射LPS 30min后经尾静脉给予人血浆HDL(70mg/kg体重),6h后结束实验.处死动物前抽取动脉血测定血气变化(PaO2, pH, PaCO2).处死后行支气管肺泡灌洗,计数灌洗液中白细胞(white blood cell, WBC)数量,测定蛋白含量和乳酸脱氢酶(lactate dehydrogenase, LDH)活性,并取肺组织进行病理学观察,测定肺组织湿/干重比值、丙二醛(malondialdehyde, MDA)含量、髓过氧化酶(myeloperoxidase, MPO)活性和肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)含量.结果显示:(1)HDL改善小鼠肺换气功能,显著降低LPS所致的PaO2、pH的降低和PaCO2的增高(P<0.01);(2)HDL显著抑制LPS所致的肺泡灌洗液中WBC数量、总蛋白浓度和LDH活性的增高(P<0.01),降低肺组织湿/干重比值、MPO活性、MDA和TNF-α含量(P<0.05, P<0.01);(3)病理形态学分析及评分显示,HDL治疗组小鼠在出血、肺水肿及肺组织内中性粒细胞浸润的程度均低于LPS所致肺损伤组(P<0.01).结果提示,HDL可减轻小鼠内毒素性急性肺损伤.     

Hypothalamic neuronal histamine modulates febrile response but not anorexia induced by lipopolysaccharide

This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats.To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.     

Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor-alpha production through inhibition of Egr-1 expression

Although urinary trypsin inhibitor (UTI) has been shown to inhibit tumor necrosis factor (TNF)-alpha- production, the detailed mechanism(s) remains unclear. This study was undertaken to elucidate the molecular mechanism(s) underlying this inhibitory effect in monocytes in vitro and in rats given lipopolysaccharide (LPS). TNF-alpha production by monocytes stimulated with LPS (100 ng/ml) was inhibited by UTI at concentrations higher than 100 U/ml. Expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated protein kinases 1/2 in monocytes stimulated with LPS were inhibited by UTI. UTI (50,000 U/kg i.v.) inhibited LPS (5 mg/kg i.v.)-induced increases in lung tissue levels of Egr-1, TNF-alpha mRNA, and TNF-alpha in rats. UTI inhibited LPS-induced hypotension by inhibiting pulmonary induction of inducible nitric oxide synthase (iNOS). We previously demonstrated that anti-TNF-alpha antibody and aminoguanidine, a selective inhibitor of iNOS, reduced LPS-induced hypotension in this animal model. Furthermore, we also reported that reduction of LPS-induced coagulation abnormalities in rats did not affect inflammatory responses and hypotension in this animal model. Taken together, these observations strongly suggested that UTI inhibited LPS-induced production of TNF-alpha by inhibiting activation of the extracellular signal-regulated protein kinases 1/2-Egr-1 pathway in monocytes, which might at least partly contribute to reduction of hypotension through inhibition of iNOS induction in rats given LPS.     

Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans

Type 2 diabetes is associated with biochemical evidence of low-grade inflammation, and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans, we administered 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp (n = 6) or an infusion of sterile saline (n = 8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin, and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations, and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-alpha production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.     

Comparison between effects of dantrolene and nifedipine on lipopolysaccharide-induced endotoxemia in the anesthetized rats

Intracellular calcium is an important mediator for regulating the cellular response in endotoxemia. In this study, we investigated the effects of dantrolene and nifedipine, two agents of reducing intracellular calcium levels, on bacterial endotoxin (lipopolysaccharide, LPS; 10 mg/kg i.v.)-induced production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) as well as hemodynamic changes in the anesthetized rat. Injection of LPS (i) induced biphasic changes of blood glucose and rectal temperature: an initial increased phase (<180 min after injection of LPS) followed by a decreased phase (at 240 or 360 min), (ii) caused a significant fall in mean arterial blood pressure from 119+/-3 mmHg (at time 0) to 73+/-67 mmHg (at 360 min) with a concomitant increase of heart rate, (iii) resulted in a substantial hyporeactivity to norepinephrine (NE) (1 microg/kg i.v.), (iv) increased plasma nitrate (an indicator of NO formation) in a time-dependent manner, and (v) induced bell-shape changes in plasma TNF-alpha levels which reached a peak at 60 min. Pretreatment of animals with dantrolene (1 mg/kg i.v. at 20 min prior to LPS) or nifedipine (20 microg/kg i.v. infusion for 20 min at 20 min prior to LPS) not only attenuated the delayed circulatory failure (e.g. delayed hypotension and vascular hyporeactivity to NE), but also prevented the overproduction of NO caused by LPS in the rat. However, the prevention of NO overproduction by dantrolene, but not by nifedipine, was associated with an inhibition of TNF-alpha production elicited by LPS. Thus, both dantrolene and nifedipine have beneficial hemodynamic effects, although through different mechanisms, in animals with endotoxic shock.     

Silicon Deprivation Does Not Significantly Modify the Acute White Blood Cell Response but Does Modify Tissue Mineral Distribution Response to an Endotoxin Challenge

An experiment with rats was conducted to determine whether silicon deprivation affects the acute-phase immune response to an endotoxin challenge. Weanling female rats were assigned to two weight-matched groups of 24; one group was fed a basal diet containing about 1.9 µg Si/kg; the other group was fed the basal diet supplemented with 35 µg Si/kg as arginine silicate inositol complex. After being fed their respective diets for 8 weeks, 12 rats in each group were injected subcutaneously with 1 mg lipopolysaccharide (LPS)/kg body weight; the other 12 rats in each group were injected with deionized water. Two hours after injection, the rats were anesthetized with ether for collection of blood (for plasma), liver and femurs, and then euthanized by decapitation. LPS injection decreased total white blood cell, lymphocyte, monocyte, eosinophil, and basophil counts by 80–90%, but did not affect neutrophil counts. LPS injection also increased plasma tumor necrosis factor-α and osteopontin and decreased plasma hyaluronic acid. Silicon deprivation did not significantly affect any of these responses to LPS. Silicon in liver and silicon, iron, and zinc in femur were increased by LPS injection only in silicon-deprived rats. Silicon deprivation also increased monocyte counts and osteopontin and decreased femur zinc in rats not injected with LPS. The findings indicate that silicon deprivation does not affect the acute-immune phase decrease in inflammatory cell numbers and increase in inflammatory cytokines in response to an endotoxin challenge. Silicon deprivation, however, apparently causes slight chronic inflammation and might influence inflammatory cell proliferation in the chronic-phase inflammatory response.     

Neonatal endotoxin exposure changes neuroendocrine, cardiovascular function and mortality during polymicrobial sepsis in adult rats

Our aim was to investigate whether neonatal LPS challenge may improve hormonal, cardiovascular response and mortality, this being a beneficial adaptation when adult rats are submitted to polymicrobial sepsis by cecal ligation and puncture (CLP). Fourteen days after birth, pups received an intraperitoneal injection of lipopolysaccharide (LPS; 100μg/kg) or saline. After 8-12 weeks, they were submitted to CLP, decapitated 4, 6 or 24h after surgery and blood was collected for vasopressin (AVP), corticosterone and nitrate measurement, while AVP contents were measured in neurohypophysis, supra-optic (SON) and paraventricular (PVN) nuclei. Moreover, rats had their mean arterial pressure (MAP) and heart rate (HR) evaluated, and mortality and bacteremia were determined at 24h. Septic animals with neonatal LPS exposure had higher plasma AVP and corticosterone levels, and higher c-Fos expression in SON and PVN at 24h after surgery when compared to saline treated rats. The LPS pretreated group showed increased AVP content in SON and PVN at 6h, while we did not observe any change in neurohypophyseal AVP content. The nitrate levels were significantly reduced in plasma at 6 and 24h after surgery, and in both hypothalamic nuclei only at 6h. Septic animals with neonatal LPS exposure showed increase in MAP during the initial phase of sepsis, but HR was not different from the neonatal saline group. Furthermore, neonatally LPS exposed rats showed a significant decrease in mortality rate as well as in bacteremia. These data suggest that neonatal LPS challenge is able to promote beneficial effects on neuroendocrine and cardiovascular responses to polymicrobial sepsis in adulthood.     

Inhibition of TNF-alpha production contributes to the attenuation of LPS-induced hypophagia by pentoxifylline

Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are assumed to mediate anorexia during bacterial infections. To improve our understanding of the role that these two cytokines serve in mediating infection during anorexia, we investigated the ability of pentoxifylline (PTX), a potent inhibitor of TNF-alpha production, to block the anorectic effects of the bacterial products lipopolysaccharide (LPS) and muramyl dipeptide (MDP) in rats. Intraperitoneally injected PTX (100 mg/kg body wt) completely eliminated the anorectic effect of intraperitoneally injected LPS (100 microg/kg body wt) and attenuated the anorectic effect of a higher dose of intraperitoneally injected LPS (250 microg/kg body wt). Concurrently, PTX pretreatment suppressed low-dose LPS-induced TNF-alpha production by more than 95% and IL-1beta production 39%, as measured by ELISA. Similarly, high-dose LPS-induced TNF-alpha production was reduced by approximately 90%. PTX administration also attenuated the tolerance that is normally observed with a second injection of LPS. In addition, PTX pretreatment attenuated the hypophagic effect of intraperitoneally injected MDP (2 mg/kg body wt) but had no effect on the anorectic response to intraperitoneally injected recombinant human TNF-alpha (150 ug/kg body wt). The results suggest that suppression of TNF-alpha production is sufficient to attenuate LPS- and MDP-induced anorexia. This is consistent with the hypothesis that TNF-alpha plays a major role in the anorexia associated with bacterial infection.     

Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats

N-acetylcysteine (NAC) is an antioxidant and cytoprotective agent with scavenging action against reactive oxygen species and inhibitory effects on pro-inflammatory cytokines. In a previous study, we found that pretreatment with NAC attenuated organ dysfunction and damage, reduced the production of free radicals, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) following endotoxemia elicited by administration of lipopolysaccharide (LPS). In the present study, we tested the effects of post-treatment with NAC on the sepsis-induced change. Post-treatment imitates clinical therapeutic regimen with administration of drug after endotoxemia. Endotoxin shock was induced by intravenous injection of Klebsiella pneumoniae LPS (10 mg/kg) in conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 48 h after LPS administration. NAC was given 20 min after LPS. Measurements of biochemical substances were taken to reflect organ functions. Biochemical factors included blood urea nitrogen (BUN), creatinine (Cre), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate transferase (GOT), alanine transferase (GPT), TNF-alpha, interleukin-6 (IL-6), and interleukin-10 (IL-10). LPS significantly increased blood BUN, Cre, LDH, CPK, GOT, GPT, TNF-alpha, IL-6, IL-10 levels and HR, and decreased MAP. Post-treatment with NAC diminished the decrease in MAP, increased the HR, and decreased the markers of organ injury (BUN, Cre, LDH, CPK, GOT, GPT) and inflammatory biomarkers (TNF-alpha, IL-6, IL-10) after LPS. We conclude that post-treatment with NAC suppresses the release of plasma TNF-alpha, IL-6, and IL-10 in endotoxin shock, and decreases the markers of organ injury. These beneficial effects protect against LPS-induced kidney, heart and liver damage in conscious rats. The beneficial effects may suggest a potential chemopreventive effect of this compound after sepsis.     

Effect of heat stress on LPS-induced febrile response in D-galactosamine-sensitized rats

We have previously reported that heat conditioning augments lipopolysaccharide (LPS)-induced fever in rats, which is accompanied by an accumulation of heat shock protein (HSP) in the liver and the reduction of the plasma level of tumor necrosis factor (TNF-alpha) (Kluger MJ, Rudolph K, Soszynski D, Conn CA, Leon LR, Kozak W, Wallen ES, and Moseley PL. Am J Physiol Regulatory Integrative Comp Physiol 273: R858-R863, 1997). In the present study we have tested whether inhibition of protein synthesis in the liver can reduce the effect of this heat conditioning on the LPS-induced febrile response in the rat. D-galactosamine (D-gal) was used to selectively inhibit liver protein synthesis. D-gal (500 mg/kg) or PBS as control was administered intraperitoneally 1 h before heat stress. LPS (50 microg/kg ip) was injected 24 h post-heat exposure. Treatment with D-gal blunted the febrile response to LPS. Moreover, heat-conditioned rats treated first with D-gal and subsequently with LPS demonstrated a profound fall in core temperature 10--18 h post-LPS. A significant increase of serum TNF-alpha accompanied this effect of D-gal on fever. Heat-conditioned animals receiving D-gal showed an inhibition in inducible HSP-70 in the liver. These data support the role of hepatic function in modulating the febrile response to LPS.     

Halothane potentiates the alcohol-adduct induced TNF-alpha release in heart endothelial cells

BACKGROUND: The possibility exists for major complications to occur when individuals are intoxicated with alcohol prior to anesthetization. Halothane is an anesthetic that can be metabolized by the liver into a highly reactive product, trifluoroacetyl chloride, which reacts with endogenous proteins to form a trifluoroacetyl-adduct (TFA-adduct). The MAA-adduct which is formed by acetaldehyde (AA) and malondialdehyde reacting with endogenous proteins, has been found in both patients and animals chronically consuming alcohol. These TFA and MAA-adducts have been shown to cause the release of inflammatory products by various cell types. If both adducts share a similar mechanism of cell activation, receiving halothane anesthesia while intoxicated with alcohol could exacerbate the inflammatory response and lead to cardiovascular injury. METHODS: We have recently demonstrated that the MAA-adduct induces tumor necrosis factor-alpha (TNF-alpha) release by heart endothelial cells (HECs). In this study, pair and alcohol-fed rats were randomized to receive halothane pretreatments intra peritoneal. Following the pretreatments, the intact heart was removed, HECs were isolated and stimulated with unmodified bovine serum albumin (Alb), MAA-modified Alb (MAA-Alb), Hexyl-MAA, or lipopolysaccharide (LPS), and supernatant concentrations of TNF-alpha were measured by ELISA. RESULTS: Halothane pre-treated rat HECs released significantly greater TNF-alpha concentration following MAA-adduct and LPS stimulation than the non-halothane pre-treated in both pair and alcohol-fed rats, but was significantly greater in the alcohol-fed rats. CONCLUSION: These results demonstrate that halothane and MAA-adduct pre-treatment increases the inflammatory response (TNF-alpha release). Also, these results suggest that halothane exposure may increase the risk of alcohol-induced heart injury, since halothane pre-treatment potentiates the HEC TNF-alpha release measured following both MAA-Alb and LPS stimulation.     

Lipids and lipoprotein profile in doxorubicin treated rats: influence of alpha-tocopherol administration

The effect of doxorubicin (DXR) on the levels of heart, liver and plasma lipids and plasma lipoproteins were studied in rats. Rats were treated with DXR (2.5 mg/kg body weight weekly for 8 weeks, iv) with or without alpha-tocopherol (alpha-TPL) (400 mg/kg body wt daily for 60 days) co-administration. DXR treated rats showed increase in plasma total cholesterol, triglycerides and phospholipids. The activities of lecithin cholesterol-acyl transferase and hepatic and extrahepatic lipoprotein lipase were lowered significantly with concomitant increase in liver and heart lipid peroxide levels in DXR treatment. HDL cholesterol level was found to be decreased significantly in DXR treated rats as a result of which there was an increase of LDLc/HDLc ratio. alpha-TPL coadministration brought back the enzyme activity to near normal and reduced the level of lipid peroxides. The lipid changes were minimum in rats treated with both alpha-TPL and DXR. This study suggests that the toxicity of DXR is reflected in lipids and lipoprotein profile.     

硫化氢与内毒素血症大鼠心肌损伤的关系

为探讨硫化氢（hydrogen sulfide,H2S）与内毒素血症大鼠心肌损伤的关系,采用静脉注射脂多糖（lipopolysaccharide,LPS）的方法制备内毒素血症大鼠模型,将雄性Wistar大鼠随机分为正常对照组、LPS组、LPS＋炔丙基甘氨酸（propargylglycine,PPG,H2S代谢酶抑制剂）组、LPS＋NaHS（H2S供体）组。观察给药后4h内大鼠平均动脉压（mean arterial pressure,MAP）的变化,测定血浆肿瘤坏死因子-α（tumor necrosis factor-α,TNF-α）和H2S含量,光学显微镜观察心肌组织形态学变化并测定心肌组织中TNF-α、H2S含量及乳酸脱氢酶（lactate dehydrogenase,LDH）和髓过氧化物酶（myeloperoxidase,MPO）的活性。结果如下：（1）与正常对照组相比,LPS组大鼠血压迅速下降,血浆TNF-α、H2S含量显著增高,且血浆中H2S含量与血压呈显著负相关,LPS注射后1、2、4h时相关系数分别为-0．936、-0．913和-0．908（均P〈0．05）;心肌组织TNF-α、H2S含量及LDH、MPO活性也明显升高,并出现组织损伤;（2）给予PPG能显著抑制血浆TNF-α、H2S含量的增高,并可显著减轻LPS所致的血压下降（均P〈0．05）和心肌组织损伤,降低心肌组织中TNF-α、H2S含量及LDH、MPO活性;（3）给予NaHS后,与LPS组相比,大鼠血浆TNF-α、H2S含量增高,血压明显下降（均P〈0．05）,心肌组织损伤加重,心肌组织中TNF-α、H2S含量及LDH、MPO活性增高。结果提示,内毒素血症大鼠低血压和心肌损伤的部分原因是由于H2S生成增多。     

Gender-specific orexigenic and anorexigenic mechanisms in rats

Feeding dysregulation may manifest as either under-nourishment (e.g., anorexia) or excessive eating leading to obesity. Recent studies have suggested a gender-related variance in weight maintenance in response to chronic disease or obesity-related dietary regimens. However it is unclear whether these gender differences in weight management are secondary to appetite-mediated food intake or alternative mechanisms (e.g., exercise, metabolism). In this study, we explored gender-dependent feeding and hormonal responses to dietary restriction (12-h fast) or to an inflammatory stimulus (LPS, 100 microg/kg b.w.; i.p.) in rats. In response to a 12 h fast, female rats increased (p<0.05) total daily food intake above that of male rats by primarily increasing nighttime feeding by 40%, as compared to 10% in males. Consistent with the increased food intake, fasting induced a greater percent increase in female as compared to male plasma ghrelin (141 vs. 65%, p<0.001). In response to LPS, both male and female rats showed similar reductions in total daily food consumption. However LPS (6 h) induced a greater percent increase in plasma leptin in female than male rats (230 vs. 33%, p<0.01), whereas ghrelin was similarly decreased in both females and males (66 vs. 44%). These findings demonstrate sexual dimorphic responses in feeding and appetite-associated hormonal responses to fasting or LPS treatment. Our findings suggest that therapeutic interventions with ghrelin or leptin must be modified according to gender in order to optimally achieve either weight loss for obesity or weight gain/maintenance for chronic illness-associated anorexia.