Serum Tumor Necrosis Factor-α Concentrations Research Articles

Different Regulatory Effects of Heated Products and Maillard Reaction Products of Half-Fin Anchovy Hydrolysates on Intestinal Antioxidant Defense in Healthy Animals.

The oxidative state of intestinal tracts of healthy animals were investigated after short-term intake of half-fin anchovy hydrolysates (HAHp) and their thermal or Maillard reaction products (MRPs). After one month of continuous oral gavage of HAHp, HAHp-heated products (HAHp-H), the MRPs of HAHp with 3% of glucose (HAHp-3%G MRPs), and the MRPs of HAHp with 3% of fructose (HAHp-3%F MRPs) at a dose of 1.0 g/kg of body weight per day into healthy ICR male mice, the concentrations of serum low-density and high-density lipoprotein cholesterol did not significantly change compared to the control group (CK, gavage with saline). Similar results were found for the interleukin-6 concentrations of all groups. By comparison, HAHp-H, HAHp-3%G MRPs, and HAHp-3%F MRPs administration decreased serum tumor necrosis factor-α concentration as compared to the CK group (p < 0.05). No histological damage was observed in the jejunum, ileum, and colonic tissues of all groups. However, HAHp-H treatment induced higher upregulation of Kelch-like ECH-associated protein 1, transcription factors Nrf-2, associated protective phase-II enzymes of NAD(P)H: quinine oxidoreductase-1, and hemoxygenase-1 in colon tissue, as well as higher upregulation of endogenous antioxidant enzymes, including copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase 2 than other groups (p < 0.05). Additionally, increases in Nε-carboxymethyllysine expression in the colonic tissues of all groups were consistent with their increased oligopeptide transporter 1 expressions. Our results suggest that the thermal products of HAHp might have a broad application prospect in improving antioxidant defense in vivo in healthy animals.

Alleviation of Neuronal Cell Death and Memory Deficit with Chungkookjang Made with Bacillus amyloliquefaciens and Bacillus subtilis Potentially through Promoting Gut-Brain Axis in Artery-Occluded Gerbils.

Short-term fermented soybeans (chungkookjang) with specific Bacillus (B.) spp. have anti-obesity, antidiabetic, and anti-stroke functions. We examined the hypothesis that the long-term consumption of B. amyloliquefaciens SCGB 1 fermented (CKJ1) and B. subtilis SCDB 291 (CKJ291) chungkookjang can alleviate clinical symptoms and hyperglycemia after ischemic stroke by promoting the gut microbiota–brain axis. We examined this hypothesis in Mongolian male gerbils with stroke symptoms induced by carotid artery occlusion. The artery-occluded gerbils were divided into five groups: no supplementation (Control, Normal-control), 4% cooked soybeans (CSB), CKJ1, or CKJ291 in a high-fat diet for 3 weeks. The carotid arteries of gerbils in the Control, CSB, CKJ1, and CKJ291 groups were occluded for 8 min and they then continued on their assigned diets for an additional 3 weeks. Normal-control gerbils had no artery occlusion. The diets in all groups contained an identical macronutrient composition using starch, casein, soybean oil, and dietary fiber. The CSB, CKJ1, and CKJ291 groups exhibited less neuronal cell death than the Control group, while the CKJ1 group produced the most significant reduction among all groups, as much as 85% of the Normal-control group. CKJ1 and CKJ291 increased the blood flow and removal of blood clots, as determined by Doppler, more than the Control. They also showed more improvement in neurological disorders from ischemic stroke. Their improvement showed a similar tendency as neuronal cell death. CKJ1 treatment improved memory impairment, measured with Y maze and passive avoidance tests, similar to the Normal-control. The gerbils in the Control group had post-stroke hyperglycemia due to decreased insulin sensitivity and β-cell function and mass; the CKJ291, CSB, and CKJ1 treatments protected against glucose disturbance after artery occlusion and were similar to the Normal-control. CKJ1 and CKJ291 also reduced serum tumor necrosis factor-α concentrations and hippocampal interleukin-1β expression levels, compared to the Control. CKJ1 and CKJ291 increased the contents of Lactobacillus, Bacillus, and Akkermansia in the cecum feces, similar to the Normal-control. Picrust2 analysis showed that CKJ1 and CKJ291 increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced the lipopolysaccharide biosynthesis and fatty acid metabolism compared to the Control. In conclusion, daily CKJ1 and CKJ291 intake prevented neuronal cell death and memory dysfunction from the artery occlusion by increasing blood flow and β-cell survival and reducing post-stroke-hyperglycemia through modulating the gut microbiome composition and metabolites to influence the host metabolism, especially inflammation and insulin resistance, protecting against neuronal cell death and brain dysfunction. CKJ1 had better effects than CKJ291.

Effects of benzoic acid, Bacillus coagulans and oregano oil combined supplementation on growth performance, immune status and intestinal barrier integrity of weaned piglets.

This experiment was conducted to investigate the effects of benzoic acid, Bacillus coagulans and oregano oil combined supplementation on growth performance, immune status and intestinal barrier integrity of piglets. In a 26-d experiment, 25 piglets were randomly assigned to 5 treatments: 1) a basal diet, negative control (NC), 2) NC added with antibiotics, positive control (PC); 3) NC added with benzoic acid at 3,000 g/t and Bacillus coagulans at 400 g/t (AB); 4) NC added with benzoic acid at 3,000 g/t and oregano oil at 400 g/t (AO); 5) NC added with 3,000 g/t benzoic acid and Bacillus coagulans at 400 g/t and oregano oil at 400 g/t (ABO). On d 27, all piglets were euthanized to obtain jejunal mucosa to measure immune status and intestinal barrier integrity. Results showed that pigs fed AB diet increased the final body weight and average daily body weight gain and decreased the ratio of feed to gain compared with NC group (P < 0.05). Compared with NC group, AB, AO and ABO decreased serum tumor necrosis factor-α concentration and ABO decreased interleukin-1β concentration in serum and jejunal mucosa (P < 0.05). Compared with NC group, AB up-regulated mRNA expressions of sodium-glucose cotransporte1, claudin-1, occludin and mucin2 in jejunal mucosa and the populations of Bifidobacterium and Bacillus in cecal digesta (P < 0.05). Compared with NC group, ABO increased jejunal mucosal occludin mRNA abundance and Bifidobacterium population in cecal digesta, and decreased Escherichia coli population in cecal digesta (P < 0.05). Furthermore, AB and ABO increased Bacillus population in cecal digesta compared with PC group (P < 0.05). These results indicated that dietary AB supplementation could improve growth performance and intestinal barrier integrity of piglets when fed antibiotic-free diets, which was possibly associated with the improvement of immune status and intestinal microflora. Dietary ABO supplementation is also beneficial to improve immune status and intestinal barrier integrity and microflora of piglets.

Effect of anti-inflammatory compounds or antibiotic administration on receiving performance and physiological responses of transported heifers.

The objectives of this experiment was to evaluate the effects of products with anti-inflammatory properties (yeast product [YEA; 20 g/heifer daily] or astragalus polysaccharide [APS; 20 g/heifer daily]) or an antibiotic (TUL, tulathromycin; 0.025 mL/kg body weight [BW]) on receiving performance and stress responses of transported heifers. Angus heifers (n = 80) were ranked by BW (315 ± 6 kg) and assigned to one of four treatments (five pens per treatment, four heifers per pen) 7 d before shipping 1,400 km (day -7): 1) fed a basal diet of ad libitum hay and concentrate supplement (CON) from day -7 to day 29; 2) YEA in supplemental concentrate from day -7 to day 7 (YEA); 3) APS in supplemental concentrate from day -7 to day 7 (APS); 4) administration of TUL at loading for shipping (day 0; TUL). Upon arrival at the receiving facility (day 1), heifers within each treatment were ranked by BW and assigned to 20 feedlot pens in the same manner as pre-transport. Daily dry matter intake (DMI) was recorded from day 1 to day 28. Full BW was recorded on days -7, -1, 0, 1, 28, and 29. Blood samples were collected on days -7, -1, 1, 4, 7, 14, and 28. Over the receiving period, average daily gain (ADG) and gain: feed did not differ (P ≥ 0.19) for YEA, APS, and TUL, which were greater (P ≤ 0.01) than CON. Average daily gain was also lower (P < 0.01) for CON vs. YEA, APS, and TUL from day -7 to day 28. During the first week of receiving, hay, concentrate, and total DMI were lower (P < 0.01) in CON than the YEA, APS, and TUL, but did not differ (P ≥ 0.13) among these three groups. Hay and total DMI were still lower (P < 0.01) in CON vs. TUL in the second week. Total DMI was greater (P = 0.01) for TUL vs. YEA, and greater (P < 0.01) for YEA vs. CON. Serum nonesterified fatty acid concentrations were greater (P ≤ 0.05) for CON and TUL vs. YEA and APS on day 1. Plasma cortisol concentrations were greater (P ≤ 0.05) for YEA and CON vs. APS and TUL on day 1. Serum tumor necrosis factor-α concentrations were lower (P ≤ 0.05) for APS vs. CON, YEA, and TUL on days 1 and 4. Plasma haptoglobin concentrations were greater (P ≤ 0.05) for CON vs. YEA, APS, and TUL on days 1 and 4, greater (P ≤ 0.05) for YEA, APS vs. TUL on day 1, and greater (P = 0.03) for YEA vs. TUL on day 4. Plasma ceruloplasmin concentrations were greater (P ≤ 0.05) for CON vs. YEA, APS and TUL vs. APS on days 1, 4, and 7. In conclusion, YEA, APS, and TUL modulated the physiological stress responses and alleviated the performance losses caused by long-distance transportation.

Pre-weaning plane of nutrition and Mannheimia haemolytica dose influence inflammatory responses to a bovine herpesvirus-1 and Mannheimia haemolytica challenge in post-weaning Holstein calves

The objectives of this study were to determine whether plane of nutrition (PON) of milk replacer previously provided to calves, and dosage level of Mannheimia haemolytica (MH), influenced inflammatory responses to a combined viral-bacterial respiratory challenge. Holstein calves (1 d of age; n = 30) were assigned to treatments in a 2 × 3 factorial with pre-weaning PON and MH dose as main effects (n = 5 per treatment). Calves were fed either a low (LPN; n = 15) or a high PON (HPN; n = 15) from birth through weaning. Calves fed LPN were fed 436 g of dry matter (DM) per day of milk replacer until weaning, and HPN calves were fed 797 g of DM per day of milk replacer from d 1 to 10 and 1,080 g of DM per day from d 11 until weaning. Calf starter and water were offered ad libitum. Calves were step-down weaned beginning at d 54 and moved into an enclosed barn at d 70. Indwelling rectal temperature (RT) recording devices and jugular catheters were inserted at d 80. Calves were challenged with 1.5 × 108 plaque-forming units (pfu) per mL of bovine herpesvirus-1 (BHV-1) in each nostril at d 81 and with either 106, 107, or 108 cfu of MH at d 84. Blood samples were collected at varying intervals relative to BHV-1 and MH challenges. Four LPN calves either died or were euthanized soon after the 144-h observation period, whereas all HPN calves survived the entire observation period. As dosage of MH administered increased, acute and systemic inflammatory responses increased. Higher doses of MH resulted in increased leukocyte, neutrophil, and haptoglobin concentrations in infected calves. Data from the current study suggest that the highest dose, 108 cfu, triggered weaned calves' acute disease response, whereas the lower doses, 106 and 107 cfu, caused more moderate inflammation and disease. The effects of PON on inflammation responses to the disease challenge indicated that calves previously fed the LPN diet had more severe pathophysiological responses. Calves fed LPN showed higher peripheral neutrophil and leukocyte counts and serum haptoglobin concentrations following the BHV-1 challenge. Additionally, following the MH challenge, LPN calves had higher peripheral neutrophil counts, neutrophil-to-lymphocyte ratios, and serum tumor necrosis factor-α concentrations. These data demonstrate that higher doses of MH increase the acute inflammatory response and prolong inflammation, and that calves previously fed LPN responded more severely to the combined viral-bacterial respiratory challenge.

Effects of pomegranate aril juice and its punicalagin on some key regulators of insulin resistance and oxidative liver injury in streptozotocin-nicotinamide type 2 diabetic rats.

Nowadays, medicinal plants have been widely used everywhere to provide essential care for many disorders including diabetes. Recent reports assumed that the antidiabetic activities of pomegranate aril juice (PAJ) may be ascribed to its punicalagin (PCG). Therefore, the present study evaluated and compared the antidiabetic activities of PAJ and its PCG, and monitored some mechanisms of their actions in streptozotocin-nicotinamide (STZ-NA) type 2 diabetic rats. STZ-NA diabetic rats were given, orally/daily, PAJ (100 or 300mg/kg body weight, containing 2.6 and 7.8mg of PCG/kg body weight, respectively), pure PCG (2.6 or 7.8mg/kg body weight), or distilled water (vehicle) for 6weeks. PAJ (especially at the high dose) alleviated significantly (P < 0.05-0.001) most signs of type 2 diabetes including body-weight loss, insulin resistance (IR) and hyperglycemia through decreasing serum tumor necrosis factor-α concentration and the expression of hepatic c-Jun N-terminal kinase, and increasing the skeletal muscle weight and the expression of hepatic insulin receptor substrate-1 in STZ-NA diabetic rats. Also, it decreased significantly (P < 0.001) the oxidative liver injury in STZ-NA diabetic rats through decreasing the hepatic lipid peroxidation and nitric oxide production, and improving the hepatic antioxidant defense system. Although the low dose of PCG induced some modulation in STZ-NA diabetic rats, the high dose of PCG did not show any valuable antidiabetic activity, but induced many side effects. In conclusion, PAJ was safer and more effective than pure PCG in alleviating IR and oxidative liver injury in STZ-NA diabetic rats.

Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elaboration in myelodysplastic syndromes

Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes. A key myeloid-related inflammatory protein, S100A9, serves as a Toll-like receptor ligand regulating tumor necrosis factor-α and interleukin-1β production. The role of myelodysplastic syndrome-related inflammatory proteins in endogenous erythropoietin regulation and response to erythroid-stimulating agents or lenalidomide has not been investigated. The HepG2 hepatoma cell line was used to investigate in vitro erythropoietin elaboration. Serum samples collected from 311 patients with myelodysplastic syndrome were investigated (125 prior to treatment with erythroid-stimulating agents and 186 prior to lenalidomide therapy). Serum concentrations of S100A9, S100A8, tumor necrosis factor-α, interleukin-1β and erythropoietin were analyzed by enzyme-linked immunosorbent assay. Using erythropoietin-producing HepG2 cells, we show that S100A9, tumor necrosis factor-α and interleukin-1β suppress transcription and cellular elaboration of erythropoietin. Pre-incubation with lenalidomide significantly diminished suppression of erythropoietin production by S100A9 or tumor necrosis factor-α. Moreover, in peripheral blood mononuclear cells from patients with myelodysplastic syndromes, lenalidomide significantly reduced steady-state S100A9 generation (P=0.01) and lipopolysaccharide-induced tumor necrosis factor-α elaboration (P=0.002). Enzyme-linked immunosorbent assays of serum from 316 patients with non-del(5q) myelodysplastic syndromes demonstrated a significant inverse correlation between tumor necrosis factor-α and erythropoietin concentrations (P=0.006), and between S100A9 and erythropoietin (P=0.01). Moreover, baseline serum tumor necrosis factor-α concentration was significantly higher in responders to erythroid-stimulating agents (P=0.03), whereas lenalidomide responders had significantly lower tumor necrosis factor-α and higher S100A9 serum concentrations (P=0.03). These findings suggest that S100A9 and its nuclear factor-κB transcriptional target, tumor necrosis factor-α, directly suppress erythropoietin elaboration in myelodysplastic syndromes. These cytokines may serve as rational biomarkers of response to lenalidomide and erythroid-stimulating agent treatments. Therapeutic strategies that either neutralize or suppress S100A9 may improve erythropoiesis in patients with myelodysplastic syndromes.

Effects of clopidogrel on horses with experimentally induced endotoxemia.

To evaluate the effects of clopidogrel on clinical and clinicopathologic variables in healthy horses with experimentally induced endotoxemia. 12 adult mares. Procedures-Horses were assigned with a randomization procedure to receive clopidogrel (4 mg/kg, once, then 2 mg/kg, q 24 h; n = 6) or a placebo (6) through a nasogastric tube. After 72 hours of treatment, horses received lipopolysaccharide (LPS; 30 ng/kg, IV). Heart rate, respiratory rate, rectal temperature, CBC variables, plasma fibrinogen concentration, serum tumor necrosis factor-α concentration, plasma von Willebrand factor concentration, and measures of platelet activation (including ADP- and collagen-induced platelet aggregation and closure times, thrombelastography variables, and results of flow cytometric detection of platelet membrane P-selectin, phosphatidylserine, and microparticles) were determined at various times before and after LPS administration by investigators unaware of the treatment groups. Statistical analyses were performed with repeated-measures ANOVA. 4 of 6 clopidogrel-treated horses had significant decreases in ADP-induced platelet aggregation before and after LPS administration. Heart rate increased significantly after LPS administration only for the placebo group. No significant differences were detected between groups for CBC variables, closure time, and plasma concentration of fibrinogen or serum concentration of tumor necrosis factor-α, and no clinically relevant differences were detected for other hemostatic variables. In this study, administration of LPS did not induce platelet hyperreactivity in horses on the basis of measures of platelet adhesion, aggregation, degranulation, and procoagulant activity. Administration of clopidogrel was associated with variable platelet antiaggregatory activity and attenuated some clinical signs of endotoxemia.

Effects of intravenous administration of polymyxin B in neonatal foals with experimental endotoxemia

To evaluate the effect of IV administration of polymyxin B on clinical and serum biochemical variables in foals with experimental endotoxemia. Prospective experimental study. 14 healthy neonatal foals. Foals were randomly assigned to a treatment or control group and were administered a single dose of lipopolysaccharide (0.5 μg/kg [0.23 μg/lb]) IV over 30 minutes. The treatment group received polymyxin B (6,000 U/kg [2,727 U/lb], IV) immediately after completion of lipopolysaccharide infusion; the control group was administered an equal volume of saline (0.9% NaCl) solution. Subsequent doses of polymyxin B or saline solution were administered IV at 8 and 16 hours. Blood was collected at various time points, and outcome variables, including heart rate, respiratory rate, rectal temperature, attitude score, WBC count, neutrophil count, lymphocyte count, monocyte count, platelet count, Hct, blood lactate concentration, blood glucose concentration, serum tumor necrosis factor-α concentration, and plasma thromboxane B2 concentration, were measured. Urine was collected prior to and after experimentation to determine whether nephrotoxicosis was associated with treatment. The treatment group had significantly lower blood lactate concentration and serum tumor necrosis factor-α and plasma thromboxane B2 concentrations and had higher blood glucose concentrations and better attitude scores, compared with the control group, at various time points during the study. No other significant differences and no evidence of overt nephrotoxicosis were detected. Administration of polymyxin B IV in healthy neonatal foals challenged with lipopolysaccharide attenuated some clinical and serum biochemical derangements associated with endotoxemia.

Melatonin improves metabolic syndrome induced by high fructose intake in rats

In this study, we examined whether melatonin improves metabolic syndrome induced by high fructose intake in male Wistar rats. Feeding of a diet containing 60% fructose (HFD) for 4 or 6 wk caused increased serum insulin, triglyceride, total cholesterol, free fatty acids, uric acid, leptin, and lipid peroxide concentrations as well as hepatic triglyceride and cholesterol concentrations, and relative intra-abdominal fat and liver weights. The 4- or 6-wk HFD feeding reduced serum high-density lipoprotein cholesterol and adiponectin concentrations. The 6-wk HFD feeding increased serum tumor necrosis factor-α concentration and hepatic lipid peroxide concentration and lowered hepatic reduced glutathione concentration. Daily intraperitoneal administration of melatonin (1 or 10mg/kg body weight), starting at 4-wk HFD feeding, attenuated these changes at 6-wk HFD feeding more effectively at its higher dose than at its lower dose. In an oral glucose tolerance test, rats with 4- or 6-wk HFD feeding showed higher serum insulin response curve and normal serum glucose response curve when compared with the corresponding animals that received the control diet. The 4- or 6-wk HFD feeding caused insulin resistance, judging from the scores of HOMR-IR and QUICKI, which are indices of insulin resistance. The daily administered melatonin (1 or 10mg/kg body weight) ameliorated the higher serum insulin response curve in the oral glucose tolerance test and insulin resistance at 6-wk HFD feeding more effectively at its higher dose than at its lower dose. These results indicate that melatonin improves metabolic syndrome induced by high fructose intake in rats.

EFFECTS OF CONJUGATED LINOLEIC ACID ISOMERS ON SERUM TUMOR NECROSIS FACTOR-A CONCENTRATION IN MICE

In previously studies, we showed that tumor necrosis factor-α (TNF-a), a cytokine involved in a variety of biologically important events, is partially involved in the effects of conjugated linoleic acid (CLA). In this report, we further tested the effects of individual CLA isomers on serum TNF-a concentration along with other biological markers in mice. The animals were fed experimental diets (control, 0.5% CLA-mixed isomer, 0.25% cis-9, trans-11 CLA or 0.25% trans-10, cis-12 CLA) for 5 days and were then challenged with endotoxin. Both cis-9, trans-11 and trans-10, cis-12 CLA isomers reduced serum TNF-a levels compared to control. CLA had no effect on the other biological markers examined. These results suggest possible early involvement of CLA in immune and/or inflammatory responses, followed by reduction of body fat. Its effect on TNF-a helps explain in part how CLA modulates other biological functions such as immune response, insulin responses, atherosclerosis and cancer.

A potential role of hyperbaric oxygen exposure through intestinal nuclear factor-kappaB.

Recent studies have demonstrated the therapeutic effectiveness and pharmacologic mechanisms of hyperbaric oxygen therapy (HBOT) in the treatment of a systemic shock state. To elucidate the in vivo role of HBOT during sepsis, we evaluated the effects of HBOT on intestinal mucosal injury and bacterial translocation after lipopolysaccharide challenge. Experimental study. First Department of Surgery and Division of Emergency Care, Kagoshima University School of Medicine, Kagoshima, Japan. : Male rats were treated with lipopolysaccharide by an intraperitoneal route or with lipopolysaccharide and HBOT. The survival rate, small intestinal tissue damage, and bacterial translocation in the HBOT-treated group were compared with those in the untreated group. Moreover, plasma tumor necrosis factor-alpha and nitrite/nitrate concentrations, inducible nitric oxide synthase and myeloperoxidase activities, and nuclear factor-kappaB in ileal mucosa were investigated. HBOT was initiated 3 hrs after lipopolysaccharide challenge and administered as 100% oxygen, at 2.53 x 10 kPa (2.5 atm absolute), for 60 mins. When a sublethal dose of lipopolysaccharide (24 mg/kg) was given, the survival rate was much better in the HBOT-treated group (75%) than in the untreated group (33%). HBOT given 3 hrs after lipopolysaccharide injection (10 mg/kg) also lessened the histologic tissue damage of the terminal ileum and the incidence and magnitude of bacterial translocation to mesenteric lymph nodes at 24 hrs after the lipopolysaccharide injection. Moreover, HBOT was able to reduce mucosal inducible nitric oxide synthase and myeloperoxidase activities and plasma nitrite/nitrate concentrations but not serum tumor necrosis factor-alpha concentrations. Immunohistochemical examination revealed that HBOT specifically modified the mucosal nuclear factor-kappaB activation within 4-6 hrs after the injection. HBOT performed 3 hrs after lipopolysaccharide challenge alleviates intestinal barrier dysfunction and improves survival rates. Herein, we propose one possible mechanism for these beneficial effects: HBOT can modify the nuclear factor-kappaB activation in the intestinal mucosa and attenuate the sequential nitric oxide overproduction and myeloperoxidase activation. Consequently, bacterial translocation could be potentially decreased. We believe that the present study should lead to an improved understanding of HBOT's potential role in sepsis.

Activated protein C prevents multiple organ injury following extensive hepatectomy in cirrhotic rats

Background/Aims: Extended hepatectomy for cirrhotic liver in patients with hepatocellular carcinoma often triggers posthepatectomy liver failure. It has been shown that the microcirculatory disturbance caused by microthrombus formation and sinusoidal endothelial cellular injury is one of the causes of posthepatectomy liver dysfunction. We therefore investigated the effect of activated protein C (APC), a potent antithrombotic serine protease with anti-in-flammatory effects, on posthepatectomy liver dysfunction and multiple organ injury in cirrhotic rats. Methods/Results: Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received lipopolysaccharide (200 μg/kg) 48 h later to prepare a lethal posthepatectomy acute liver failure model. APC (1500 U/kg), given intravenously 15 min before and 1 h after endotoxin challenge, attenuated liver dysfunction and decreased serum tumor necrosis factor-α concentration. APC significantly improved the survival rate of rats at 12 h after endotoxin challenge. Histological examination revealed that APC treatment inhibited not only intrasinusoidal fibrin deposition and massive hepatocellular necrosis but also pulmonary injury and glomerular fibrin deposition. Immunohistochemically, expression of intercellular adhesion molecule-1 on sinusoidal cells and renal glomeruli was decreased in the APC-treated animals. Conclusions: APC administration prevented acute liver dysfunction and attenuated multiple organ injury following extended hepatectomy in cirrhotic rats, possibly via anticoagulant and anti-inflammatory effects.

Partial liquid ventilation decreases serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model.

To examine the hypothesis that partial liquid ventilation (PLV) with perfluorocarbon would decrease serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model. Prospective, controlled animal study. Research laboratory in a university setting. Male Sprague-Dawley rats. Treatment with intratracheal perflubron or control mechanical ventilation beginning 30 mins after acid aspiration. PLV with perfluorocarbon compared with control ventilation resulted in significantly greater mean arterial blood pressures at 3 and 4 hrs and greater arterial Po2 at all times. Serum tumor necrosis factor-alpha at 2, 3, and 4 hrs was significantly less than that observed in the control group (4-hr values: 80+/-64 pg/mL vs. 658+/-688 pg/mL; p<.05), although no significant difference in tracheal fluid tumor necrosis factor-alpha concentrations (1425+/-1347 pg/mL vs. 2219+/-1933 pg/mL) was found. We conclude that the effects of PLV with perfluorocarbon can extend beyond improvements in pulmonary physiology and that PLV may be beneficial in reducing systemic sequelae of acute lung injury and inflammation.

Proinflammatory cytokines in early assessment of the prognosis of acute pancreatitis

Objective: Proinflammatory cytokines are involved in the pathogenesis of acute pancreatitis. The value of serum levels of tumor necrosis factor-α, interleukin-1-β, interleukin-6, and interleukin-8 in predicting the outcome of acute pancreatitis was evaluated. Methods: In 50 patients with acute pancreatitis, the serum concentrations of tumor necrosis factor-α, interleukin-1-β, interleukin-6, interleukin-8, and C-reactive protein were determined on days 1, 2, 3, 4, and 7 after admission. Acute Physiology and Chronic Health Evaluation (APACHE II) scores were recorded on days 1, 2, and 3. Results: Serum concentrations of interleukin-1-β, interleukin-6, interleukin-8, and C-reactive protein on days 1–7 were significantly higher in patients with severe pancreatitis than in patients with mild pancreatitis. Patients with severe attacks had significantly elevated serum tumor necrosis factor-α concentrations on days 1–3 compared with those with mild attacks, but not on days 4 and 7. The median peak value of tumor necrosis factor-α, interleukin-1-β, interleukin-6, and interleukin-8 was reached on day 1, in contrast to the median peak of C-reactive protein, which was reached on day 2. Using cutoff levels of 12 pg/ml for tumor necrosis factor-α, 1 pg/ml for interleukin-1-β, 400 pg/ml for interleukin-6, 100 pg/ml for interleukin-8, 12 mg/dl for C-reactive protein, and 10 for the Acute Physiology and Chronic Health Evaluation (APACHE II) score, the accuracy rates for detecting severe pancreatitis were 72%, 82%, 88%, 74%, 80%, and 72%, respectively, on day 1 and 78%, 74%, 80%, 76%, 80%, and 78%, respectively, on day 2. Conclusion: Among the proinflammatory cytokines, interleukin-6 is the most useful parameter for early prediction of the prognosis of acute pancreatitis.

The role of tumor necrosis factor-α in acute endotoxin-induced hepatotoxicity in ethanol-fed rats

An in vivo model of ethanol ingestion in rats was used to examine tumor necrosis factor-α production after intravenous injection with lipopolysaccharide or saline solution. Four groups of 125-gm male Sprague-Dawley rats were given one of the following four diets: liquid ethanol diet (ethanol, 36% of calories), liquid control diet, chow ad libitum or control liquid diet pair-fed to match calories consumed by ethanol-fed rats. After 6 wk of diet, all rats were injected with 1 mg/kg lipopolysaccharide or 0.9% saline. AST concentrations in the ethanol-lipopolysaccharide group (388 ± 54 U/ml) were significantly increased compared with those in control-saline, ethanol-saline and control-lipopolysaccharide groups (166 ± 23, 166 ± 18, 219 ± 47; p<0.01). Serum tumor necrosis factor-α concentrations for the ethanol-LPS group (3,990 ± 624 pg/ml) were increased compared with those in control-saline (87 ± 18), ethanol-saline (68 ± 24) and control-LPS (695 ± 165) groups (p<0.001). A strong correlation was seen between serum tumor necrosis factor-α and AST concentrations (r=0.91, p<0.001). Treatment with lipopolysaccharide also increased transcriptional levels of tumor necrosis factor-α-specific mRNA from hepatic Kupffer cells isolated from rats fed the long-term ethanol diet by a factor of 3 compared with control rats. From these data, we conclude that long-term ethanol administration sensitized hepatic Kupffer cells to secrete high levels of tumor necrosis factor-α after lipopolysaccharide injection. Increased serum tumor necrosis factor-α concentrations correlated directly with increased levels of serum transaminase, which may have reflected hepatic injury. (Hepatology 1994;20:461–474.)