As a dangerous disease with rapid progression, endotoxemia is easy to induce the damage to multiple organs. However, its specific and efficient treatment methods are still lacking at present. Both Qingkailing Injection(QKLI) and Shengmai Injection(SMI) have been proved effective in anti-inflammation, anti-endotoxin and organ protection. In this study, carrageenan and endotoxin were injected successively into rats to establish an endotoxemia model. Different doses of QKLI and SMI were administered to the endotoxemia rats by intraperitoneal injection separately or in combination. Then the count of white blood cells, the number of platelets, the content of cytokines, biochemical indexes, organ coefficient and pathological changes of main organs in the rats were detected. The results showed that the rats in the model group had obvious symptoms of endotoxemia, i.e., leucopenia, thrombocytopenia, increase in cytokines(IL-6 and TNF-α) and biochemical indexes of liver and kidney function as well as pathological damage to liver, kidney and lung. QKLI alone can alleviate the above symptoms of endotoxemia and the organ injury. SMI alone is less effective in improving disseminated intravascular coagulation(DIC) and cytokine secretion complicated with endotoxemia, but capable of reducing the inflammation degree of the lung, liver and kidney. The combination of QKLI and SMI remarkably increased the number of platelets in the peripheral blood, improved the liver and kidney function and reduced inflammatory factors, with lung, liver, kidney and other organ structures protected well. Moreover, the improvement effect of the combination of QKLI and SMI was stronger than those of the two injections alone at fixed doses, indicative of a synergistic effect.
Animals ; Drug Combinations ; Drugs, Chinese Herbal ; Endotoxemia/drug therapy* ; Rats

BACKGROUNDAcute lung injury/acute respiratory distress syndrome presents with not only local inflammation, but also pulmonary coagulopathy which is characterized by an alveolar procoagulant response, anticoagulant inhibition, fibrinolytic supression and fibrin deposition. We thus had hypothesized that if aerosolized unfractionated heparin was inhaled into alveolar spaces, it could block the procoagulant tendency, lessen depletion of coagulation factors, and even influence the inflammatory response. We also assessed the effects of different administration regimens of heparin.

METHODSMale Wistar rats were given inhaled heparin starting 30 minutes before (prophylactic heparin) or 2 hours after (therapeutic heparin) intravenous lipopolysaccharide (LPS) was administered at 6-hour intervals; control groups received inhaled normal saline with or without being exposed to LPS. Thrombin-antithrombin complexes, activated protein C, tissue type and urokinase type plasminogen activators (t-PA/u-PA), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α, interleukin-6 in bronchoalveolar lavage, and lung tissue myeloperoxidase activity, and histology score were measured at three time-points. PAI-1/(t-PA + u-PA) was calculated based on the before-mentioned parameters. Statistical analysis was made using one-way analysis of variance (ANOVA) with post hoc test or Student's t test in the case of heterogeneity of variance.

RESULTSAn alveolar procoagulant reaction, depressed fibrinolysis, and inflammatory response occurred in endotoxemia-induced lung injury. Local prophylactic application of heparin attenuated coagulation and early inflammation, promoted fibrinolysis, and reduced the histology score. Therapeutic application of heparin had similar, but weaker effects.

CONCLUSIONSIntrapulmonary application of unfractionated heparin by inhalation might inhibit alveolar procoagulant reaction and the early inflammatory response, promote fibrinolysis, and alleviate pulmonary pathology in endotoxemia-induced lung injury rats. Administration of heparin before LPS challenge was more efficacious.

Acute Lung Injury ; blood ; drug therapy ; Administration, Inhalation ; Animals ; Blood Coagulation ; drug effects ; Endotoxemia ; complications ; Fibrinolysis ; drug effects ; Heparin ; administration & dosage ; Inflammation ; drug therapy ; Lung ; pathology ; Male ; Rats ; Rats, Wistar

The aim of the present study was to investigate the effects of sodium butyrate (SB) on systemic inflammation, lung injury and survival rate of mice with endotoxemia. Balb/c mice were pre-treated with SB or vehicle, and then endotoxemia was induced by lethal dose of lipopolysaccharide (LPS, 20 mg/kg, i.p.) and the survival rate of mice was monitored. A separated set of animals were sacrificed at 18 h after LPS challenge, and blood samples were harvested for measuring TNF-α and IL-6 levels. Lung tissues were also harvested to determine the ratio of wet weight to dry weight of lung tissue and myeloperoxidase (MPO) activity in lung tissue. In addition, the formalin-fixed lung specimens were stained with HE routinely for morphologic evaluation. The results showed that pre-treatment with SB alleviated LPS-induced morphological damage in lung tissue. This was accompanied by reduced ratio of wet weight to dry weight of lung tissue and MPO activity in lung homogenates. Additionally, the up-regulation of pro-inflammatory cytokines TNF-α and IL-6 was also suppressed by SB, while the survival rate of mice with lethal endotoxemia was significantly increased by SB pre-treatment. The results suggest that SB effectively attenuates intrapulmonary inflammatory response and improves the survival of endotoxemic mice.
Animals ; Butyric Acid ; pharmacology ; Endotoxemia ; drug therapy ; Inflammation ; drug therapy ; Interleukin-6 ; metabolism ; Lipopolysaccharides ; Lung ; drug effects ; pathology ; Lung Injury ; drug therapy ; Male ; Mice ; Mice, Inbred BALB C ; Peroxidase ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo study the effects of intestinal trefoil factor (ITF) on Toll-like receptors (TLR) 2 and 4 expression in intestinal tissue and on intestinal injury in young rats with endotoxemia.

METHODSA total of 24 10-day-old Wistar rat pups were equally randomly divided into three groups: a control group, intraperitoneally injected with normal saline 1 mL/kg; an endotoxemia group, intraperitoneally injected with lipopolysaccharide (LPS) 5 mg/kg and an ITF group,intraperitoneally injected with rITF 0.1 mL/each plus LPS 5 mg/kg. Rats were sacrificed 3 h after injection. A segment of distal ileum was dissected for pathologic examinations under an optical microscope (hematoxylin-eosin staning). The mRNA expressions of TLR2 and TLR4 were detected by reverse transcriptase polymerase chain reaction (RT-PCR).

RESULTSThe structure of the small intestine remained normal in the control group. Edema of interstitial substance and epithelium were observed in both LPS and ITF groups, whereas such changes were significantly lower in the ITF group than in the LPS group. The ITF group had significantly higher TLR2 mRNA expression than the NS and LPS groups (P<0.01), whereas the mRNA expression of TLR4 in the ITF group was significantly lower than in the NS and LPS groups (both P<0.01).

CONCLUSIONSITF can alleviate intestinal injury in young rats with endotoxemia, which may be related to the down-regulation of TLR4 mRNA expression.

Animals ; Endotoxemia ; drug therapy ; metabolism ; Female ; Gene Expression Regulation ; drug effects ; Intestines ; metabolism ; pathology ; Male ; Peptides ; therapeutic use ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Toll-Like Receptor 2 ; genetics ; Toll-Like Receptor 4 ; genetics ; Trefoil Factor-2

BACKGROUNDTreatment with melatonin significantly reduces lung injury induced by bleomycin, paraquat and ischemia reperfusion. In the present study, we investigated the possible protective roles of melatonin in pulmonary inflammation and lung injury during acute endotoxemia.

METHODSThirty-two male Sprague-Dawley rats were randomly assigned to four groups: vehicle + saline group, melatonin + saline group, vehicle + lipopolysaccharide group, melatonin + lipopolysaccharide group. The rats were treated with melatonin (10 mg/kg, intraperitoneal injection (i.p.)) or vehicle (1% ethanol saline), 30 minutes prior to lipopolysaccharide administration (6 mg/kg, intravenous injection). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Blood gas analysis was carried out. Optical microscopy was performed to examine pathological changes in lungs and lung injury score was assessed. Wet/dry ratios (W/D), myeloperoxidase activity, malondialdehyde concentrations and tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels in lungs were measured. The pulmonary expression of nuclear factor-kappa B (NF-kappaB) p65 was evaluated by Western blotting.

RESULTSPaO(2) in the vehicle + lipopolysaccharide group decreased compared with that in the vehicle + saline group. This decrease was significantly reduced in the melatonin + lipopolysaccharide group. The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the melatonin + lipopolysaccharide group. The W/D ratio increased significantly in the vehicle + lipopolysaccharide group (6.1 +/- 0.18) as compared with that in the vehicle + saline group (3.61 +/- 0.3) (P < 0.01), which was significantly reduced in the melatonin + lipopolysaccharide group (4.8 +/- 0.25) (P < 0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the vehicle + lipopolysaccharide group compared with that in the vehicle + saline group, which was reduced in the melatonin + lipopolysaccharide group. The TNF-alpha level of pulmonary tissue increased significantly in the vehicle + lipopolysaccharide group ((8.7 +/- 0.91) pg/mg protein) compared with that in the vehicle + saline group ((4.3 +/- 0.62) pg/mg protein, P < 0.01). However, the increase of TNF-alpha level of pulmonary tissue was significantly reduced in the melatonin + lipopolysaccharide group ((5.9 +/- 0.56) pg/mg protein, P < 0.01). Pulmonary IL-10 levels were elevated markedly in the vehicle + lipopolysaccharide group in contrast to that in the vehicle + saline group, whereas the elevation was augmented in the melatonin + lipopolysaccharide group. The nuclear localization of p65 increased markedly in the vehicle + lipopolysaccharide group and this enhancement of nuclear p65 expression was much less in the melatonin + lipopolysaccharide group.

CONCLUSIONMelatonin reduces acute lung injury in endotoxemic rats by attenuating pulmonary inflammation and inhibiting NF-kappaB activation.

Acute Lung Injury ; drug therapy ; pathology ; Animals ; Blotting, Western ; Endotoxemia ; drug therapy ; physiopathology ; Interleukin-10 ; metabolism ; Lipopolysaccharides ; toxicity ; Lung ; drug effects ; metabolism ; Male ; Melatonin ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo investigate the changes in the plasma levels of endotoxin in severe burn patients during administration of antibiotics.

METHODSFifty severe burn patients with burn area larger than 30% TBSA were enrolled in the study, and they were respectively treated with Netilmicin (A group), Cefoperazone (B group), Ceftazidime (C group) and Imipenem/Cilastatin (D group). Venous blood samples were harvested for determination of endotoxins levels before treatment and 1, 2, 3, 5, 7 post-treatment day (PTD).

RESULTSThe plasma levels of endotoxin were elevated in different degrees in A, B and C groups. The plasma levels of endotoxin in B group were higher on 1, 2 PTD than on 3, 5, 7 PTD, and they were also higher than that in D group (P < 0.05). The plasma levels of endotoxin in C group reached the peak on 5 PTD [(0.398 +/- 0.172) EU/mL], which were higher than that before treatment [(0.251 +/- 0.142) EU/mL, P < 0.05] and other groups (P < 0.05). The plasma levels of endotoxin in D group were lower on 1, 2 PTD than that before treatment (P < 0.05).

CONCLUSIONDifferent amounts of endotoxins can be released after treatment with antibiotics in severe burn patients. Attention should be paid to the effect of antibiotics on the levels of endotoxin in practice.

Adolescent ; Adult ; Anti-Bacterial Agents ; therapeutic use ; Burns ; blood ; drug therapy ; Endotoxemia ; etiology ; Endotoxins ; blood ; Female ; Humans ; Male ; Middle Aged ; Plasma ; Young Adult

OBJECTIVETo investigate the liver injury in model rats with endotoxemia and to observe the protective effect of Compound 912 Liquid on it.

METHODSRats were randomly divided into three groups, the endotoxemia model group (EMG, injected by lipoplysaccharides (LPS) peritoneally), the intervention group (IG, treated with Compound 912 Liquid via gastrogavage 1 h before model establishing) and the normal control group (NCG). Blood samples of rats were taken at the time points of the 2nd, 4th, 8th, 12th, 48th, 72nd hour and the 7th day after modeling for measuring liver function, levels of plasmatic endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-10 (IL-10). The pathological change of liver was observed using light microscope and electro-transmission microscope.

RESULTSThe peak concentration of endotoxin detected at 2 hour after modeling in the IG was significantly lower than that in the EMG (0.358 +/- 0.056 vs 0.685 +/- 0.030), but insignificant difference (P > 0.05) was shown between them in TNF-alpha level. The level of IL-10 continuously rose in IG after treatment, it was still higher than normal level until day 7 (49.096 +/- 4.076 vs 43.454 +/- 5.928, P < 0.05).

CONCLUSIONLPS can induce the increase of serum inflammatory cytokines and anti-inflammatory cytokines in rats to injure liver. Therefore, the inflammatory reaction indicated by LPS may be one of the mechanisms for liver injury. Preventive medication with Compound 912 Liquid showed a significant liver protective effect.

Animals ; Drugs, Chinese Herbal ; therapeutic use ; Endotoxemia ; blood ; chemically induced ; drug therapy ; Female ; Interleukin-10 ; blood ; Lipopolysaccharides ; Liver Diseases ; prevention & control ; Male ; Multiple Organ Failure ; prevention & control ; Phytotherapy ; Random Allocation ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effects of Radix Salviae Miltiorrhiae, Radix Aconiti Lateralis Preparata and Rhizoma Anemarrhena on nitric oxide (NO) system of heart, liver, intestine, lung, kidney and serum in mice with endotoxemia, and to explore the potential molecular mechanism of the three kinds of traditional Chinese drugs.

METHODSModel mice of endotoxemia were established by intraperitoneally injected with E. coli. endotoxin at the dose of 6 mg/kg. The levels of NO, nitric oxide synthase ( NOS) and superoxide dismutase ( SOD) in heart, liver, intestine, lung, kidney and serum of mice were measured at the points after injection for 4 hours, 8 hours and 24 hours, respectively.

RESULTS(1) Radix Salviae Miltiorrhiae could significantly increase the contents of constitutive nitric oxide synthase (cNOS) and SOD in the above tissues and serum, while decrease the content of inducible nitric oxide synthase (iNOS). (2) As compared with the model group, Radix Aconiti Lateralis could significantly decrease the contents of iNOS and NO, increase content of SOD in heart, lung and kidney tissues. (3) N.-Nitro-L-arginine (L-NNA) significantly decreased the content of iNOS, NO and SOD in all above tissues and serum, and also decreased the content of cNOS in lung and kidney tissues and serum. (4) Rhizoma Anemarrhenae could significantly increase the concentrations of iNOS and NO and decrease content of SOD in liver, lung and kidney tissues than those in the model group.

CONCLUSIONRadix Salviae Miltiorrhiae and Radix Aconiti Lateralis have a protective effect on the endotoxemia mice by suppressing the content of iNOS to reduce the production of NO induced by iNOS. At the same time, Radix Salviae Miltiorrhiae can improve the mice symptoms by increasing the beneficial NO through the increasing production of cNOS. Rhizoma Anemarrhenae can aggravate the injury of endotoxemia mice by increasing the production of NO due to producing large numbers of iNOS. L-NNA, non-selective inhibitor of NOS, aggravates damage of tissues and increases mortality, though it can reduce the increase of iNOS and NO induced by lipopolysaccharide.

Aconitum ; Anemarrhena ; Animals ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Endotoxemia ; drug therapy ; enzymology ; metabolism ; Intestines ; metabolism ; Kidney ; metabolism ; Liver ; metabolism ; Mice ; Myocardium ; metabolism ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; antagonists & inhibitors ; metabolism ; Phytotherapy ; Salvia miltiorrhiza

OBJECTIVETo observe the effect of Gingerol on endotoxemia mouse induced by heatstroke.

METHODSForty mice were randomly divided into five groups, the endotoxemia model group (A), the normal temperature group (B), the Gingerol treated group (C), the solvent control group (D), and the saline control group (E), 8 mice in each group. Group B to E was administered with saline, Gingerol, solvent and saline respectively. Mice in group B were placed at room temperature 25 +/- 0.5 degrees C , relative humidity 43 +/- 5 % for 2 hrs, while mice in the other groups were exposed under 35 +/- 0.5 degrees C and relative humidity 65 +/- 5 % for 2 hrs in an artificial hot-climate mimic cabin to establish heatstroke endotoxemia model. The energy metabolic level of celiomacrophage was detected with MTT; the phagocytic ability was examined with neutral red chromometry; the hepatocyte ultrastructure was observed with transmission electron microscopy, as well as the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) in plasma was tested.

RESULTSAs compared with Group A, D and E, in Group C, energy metabolic levels of macrophage, phagocytic ability, and activity of SOD were significantly higher (P < 0.01), and the level of MDA was significantly lower respectively (P < 0.01), with the levels of SOD and MDA approaching to those in Group B (P >0.05). The pathologic changes of hepatocyte ultrastructure in group C were less than those in the other three endotoxemia groups.

CONCLUSIONGingerol could raise the energy metabolic level of celio-macrophage to enhance its phagocytic ability, increase the activity of SOD and reduce the production of MDA in mouse with heatstroke endotoxemia, so as to alleviate the liver damage.

Animals ; Catechols ; Endotoxemia ; drug therapy ; etiology ; Fatty Alcohols ; isolation & purification ; pharmacology ; therapeutic use ; Female ; Ginger ; chemistry ; Heat Stroke ; complications ; Macrophages ; immunology ; Male ; Mice ; Phagocytosis ; drug effects ; Phytotherapy ; Random Allocation

OBJECTIVETo observe the antifebrile effect of Naoreqing (NRQ) oral liquid on secretive function of vaso-endothelial cells in rabbits with endotoxic fever.

METHODSEndotoxic fever rabbit model was duplicated to observe the effects of NRQ on body temperature, blood levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and endothelin (ET) using radioimmunoassay, as well as activity of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in plasma by chromophoric substrate assay.

RESULTSComparisons of various indexes between the two groups showed significantly difference, i.e. the maximal increment of body temperature: 0.69 +/- 0.07 degrees C vs 1.31 +/- 0.13 degrees C (the NRQ treated group vs the untreated model group, the same hereafter); 2h thermal response index TRI2 4.85 +/- 0.57 vs 8.44 +/- 0.98; plasma ET content 197.96 +/- 39.11 ng/L vs 250.80 +/- 40.99 ng/L; TXB2 content 177.35 +/- 77.30 ng/L vs 279.64 +/- 83.74 ng/L; activity of PAI 0.84 +/- 0.01AU/ml vs 0.86 +/- 0.01 AU/ml; plasma 6-keto-PGF1alpha content 986.70 +/- 327.36 ng/L vs 507.81 +/- 170.01 ng/L; activity of t-PA 0.25 +/- 0.02 IU/ml vs 0.21 +/- 0.02 IU/ml (P < 0.05, P < 0.01).

CONCLUSIONNRQ may improve secretive function of vaso-endothelial cells to dilate blood vessel and quicken heat dissipation through body surface, so as to play an integral antipyretic effect in rabbits with endotoxic fever.

Animals ; Drugs, Chinese Herbal ; therapeutic use ; Endothelium, Vascular ; drug effects ; secretion ; Endotoxemia ; complications ; Fever ; drug therapy ; etiology ; Male ; Phytotherapy ; Rabbits ; Random Allocation