Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A severe acute pancreatitis was produced by intraperitoneal injection of lipopolysaccharide (LPS) in rats with preexisting hemorrhagic and necrotizing pancreatitis induced by retrograde injection of a 5% taurocholate plus 1% trypsin solution into the pancreatic duct. Mortality and time-course changes in pancreatic, hepatic, renal and pulmonary functions, and organ myeloperoxidase (MPO) levels were examined in this model. LPS at an intraperitoneal dose of 30 mg/kg, which scarcely caused death and had no marked effect on serum parameters and organ MPO levels in rats without pancreatitis, increased the mortality in rats with taurocholate plus trypsin-induced pancreatitis. Pancreatic weight and ascitic volume increased in rats with taurocholate plus trypsin-induced pancreatitis regardless of the presence or absence of LPS. Serum amylase and lipase levels were also significantly increased in rats with induced pancreatitis, but was higher in the group given LPS. Serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN) and creatinine levels were significantly elevated in LPS-treated rats with induced pancreatitis, whereas levels in rats with induced pancreatitis not given LPS were only slightly elevated. Renal weight was also significantly increased in rats with induced pancreatitis despite the presence or absence of LPS. In LPS-treated rats with induced pancreatitis, the arterial oxygen pressure, pulmonary weight and pulmonary MPO level were significantly elevated. However, the MPO level in the kidney in these rats was not different from that in control rats, indicating that the renal dysfunction was not produced by the infiltration of neutrophils into the kidney. Increase in the pancreatic MPO level was observed in rats with induced pancreatitis, but combination treatment with LPS did not raise it. Protective effects of prophylactic treatment of 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, and trifluoroacetyl-L-lysyl-L-alaninanilide hydrochloride (compound 2), a pancreatic elastase inhibitor, on mortality were also examined in this model. Results were compared with that of the combined treatment of compound 1 and compound 2. In LPS-treated rats with taurocholate plus trypsin-induced pancreatitis, the combined treatment of compound 1 (2 mg/kg/h) and compound 2 (30 mg/kg/h) significantly reduced mortality, whereas single treatment of compound 1 or compound 2 did not show the beneficial effect. These results suggest that marked hepatic and renal dysfunction accompanies pancreatitis in this pancreatitis model rats, which may be good models for acute pancreatitis in humans. It is also suggested that neutrophil and pancreatic elastases may be synergistically involved in the pathogenesis of acute pancreatitis in this model.
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PMID:Protective effect of the combined treatment of pancreatic and neutrophil elastase inhibitors on acute pancreatitis elicited by lipopolysaccharide in rats given intraductal injection of taurocholate plus trypsin. 965 Aug 10

The inhibitory effects of YM264, a selective platelet activating factor (PAF) receptor antagonist, and 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, on mortality, and pancreatic, hepatic, renal and pulmonary dysfunction were evaluated in a rat model of multiple organ failure (MOF) accompanying acute pancreatitis. MOF was produced by intraperitoneal injection of lipopolysaccharide (LPS, 30 mg/kg) in rats with cerulein-induced pancreatitis. LPS dose-dependently increased the mortality in rats with or without pancreatitis. The threshold dose which produced death in rats without pancreatitis was 30 mg/kg. This same dose evoked death in more than 40% of rats with pancreatitis. Time-course changes in serum enzyme and organ myeloperoxidase (MPO) levels were first examined in rats with induced MOF, and the results were compared with those in rats treated with only LPS or cerulein. Pancreatic weight, and serum amylase and lipase levels significantly increased in rats with cerulein-induced pancreatitis despite the presence or absence of LPS, but recovery of these pancreatic dysfunctions was slower in the group given LPS. However, serum GOT, GPT, BUN and creatinine levels were significantly elevated only in MOF rats. In the MOF rats, the MPO level in the lung was significantly elevated and arterial oxygen pressure was decreased, indicating that infiltration of neutrophils into the lung might be involved in pulmonary dysfunction. However, the MPO levels in the pancreas and kidney in the MOF rats were not remarkably different from those in normal rats. The inhibitory effects of YM264 and compound 1 on mortality and organ dysfunction were examined in this MOF model. The 24-h survival rate for rats prophylactically and therapeutically treated with an intravenous infusion of YM264 at 0.1 mg/kg h was significantly higher than that of controls. The 24-h survival rate for rats treated prophylactically by intravenous infusion of 2 mg/kg h of compound 1 was significantly higher than that of control, whereas a beneficial dose of compound 1 was 5 mg/kg h in therapeutically treated rats. Prophylactic treatment with YM264 (0.1 mg/kg h) and compound 1 (2 mg/kg h) ameliorated organ dysfunction in rats with MOF. In conclusion, pancreatic, hepatic, renal and pulmonary dysfunctions are observed in this rat MOF model. The PAF receptor antagonist and neutrophil elastase inhibitor reduce the mortality rate in rats with MOF due to their inhibitory effects on organ dysfunction, indicating that PAF and neutrophil elastase may play important roles in the development of MOF. These results in the present model are largely consistent with those in patients with MOF, indicating that this model is suited for MOF in humans and may be used as a model to test new therapeutic approaches.
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PMID:Protective effects of a PAF receptor antagonist and a neutrophil elastase inhibitor on multiple organ failure induced by cerulein plus lipopolysaccharide in rats. 975 12

To investigate the possible role of lipopolysaccharide (LPS, endotoxin) in the pathogenesis of Kawasaki disease, neutrophils from 15 patients with the disease and 7 with sepsis (4 infected with gram-negative bacteria and 3 with gram-positive bacteria) were analyzed by flow cytometry using anti-LPS and anti-CD14 monoclonal antibodies. The number of LPS- and CD14-positive neutrophils was dramatically higher early after the onset of Kawasaki disease and gram-negative sepsis but not with gram-positive sepsis. An immunoprecipitation analysis revealed LPS was bound to CD14 in vivo on neutrophils from Kawasaki disease patients. The mean plasma level of neutrophil elastase was significantly higher in the acute phase of Kawasaki disease than in the acute phase of sepsis. These findings suggest that exposure to LPS occurs at the onset of Kawasaki disease when LPS-bound neutrophils secrete excess protease (implicated in neutrophil-mediated endothelial injury) into the circulation.
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PMID:The role of bacterial lipopolysaccharide-bound neutrophils in the pathogenesis of Kawasaki disease. 987 40

1. TEI-8362, 4-(N-(3-((3-carboxypropyl)amino)-8-methyl-1-oxo-4-azaisochromen-6- yl)carbamoyl)-4-((phenylmethoxy)carbonylamino)butanoic acid (C26H28N4O9) is a novel inhibitor of human neutrophil elastase (HNE). We evaluated its pharmacological profile in vitro and in vivo. 2. TEI-8362 demonstrated potent inhibition of HNE with a Ki value of 1.38 x 10(-9) M. Its selectivity for HNE among a variety of proteases ranged from 163 fold to 68,000 fold in favour of HNE. 3. The pulmonary haemorrhage that occurred after i.t. instillation of HNE to hamsters was inhibited by either i.t., i.v., or inhalant administration of TEI-8362. 4. Intratracheal administration of lipopolysaccharide induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the additional treatment with formyl-methionyl-leucyl-phenylalanine resulted in a specific neutrophil-dependent acute lung injury. In this model, lung injury was significantly attenuated by i.t., i.v., or inhalant administration of TEI-8362. 5. These pharmacological actions of TEI-8362 suggest that this drug has therapeutic value in the treatment of destructive lung diseases due to neutrophils.
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PMID:Pharmacological activities of TEI-8362, a novel inhibitor of human neutrophil elastase. 1020 2

Two important cytokines mediating inflammation are tumor necrosis factor alpha (TNFalpha) and IL-1beta, both of which require conversion to soluble forms by converting enzymes. The importance of TNFalpha-converting enzyme and IL-1beta-converting enzyme in the production of circulating TNFalpha and IL-1beta in response to systemic challenges has been demonstrated by the use of specific converting enzyme inhibitors. Many inflammatory responses, however, are not systemic but instead are localized. In these situations release and/or activation of cytokines may be different from that seen in response to a systemic stimulus, particularly because associations of various cell populations in these foci allows for the exposure of procytokines to the proteolytic enzymes produced by activated neutrophils, neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (Cat G). To investigate the possibility of alternative processing of TNFalpha and/or IL-1beta by neutrophil-derived proteinases, immunoreactive TNFalpha and IL-1beta release from lipopolysaccharide-stimulated THP-1 cells was measured in the presence of activated human neutrophils. Under these conditions, TNFalpha and IL-1beta release was augmented 2- to 5-fold. In the presence of a specific inhibitor of NE and PR3, enhanced release of both cytokines was largely abolished; however, in the presence of a NE and Cat G selective inhibitor, secretory leucocyte proteinase inhibitor, reduction of the enhanced release was minimal. This finding suggested that the augmented release was attributable to PR3 but not NE nor Cat G. Use of purified enzymes confirmed this conclusion. These results indicate that there may be alternative pathways for the production of these two proinflammatory cytokines, particularly in the context of local inflammatory processes.
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PMID:Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. 1033 75

Neutrophil elastase degrades extracellular matrix components and is involved in tissue destruction in several inflammatory states. We examined the inhibition of the elastase activity derived from activated neutrophils in vitro and in vivo by FR134043, disodium-(Z,1S,15S,18S,24S,27R,29S,34S,37R)-29-b enzyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31, 37-dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,2 8,31,33-octaazatetracyclo[16.13.6.1(24,28).0(3,8)]octatriconta+ ++-3,5,7-trien-5,6-diyl disulfate, an elastase inhibitor with broad specificity, and elucidated the role of neutrophil elastase in pathogenesis of acute inflammation. In a culture of human neutrophils, phorbol myristate acetate (PMA) and calcium ionophore increased elastase activity in the supernatants, which was amplified by co-existing mononuclear leukocytes. Formyl-Met-Leu-Phe stimulated elastase release in the presence of, not without, mononuclear leukocytes. Intratracheal injection of lipopolysaccharide elevated the elastase activity in bronchoalveolar lavage fluid of rats. These elastase activities were significantly inhibited by FR134043. Intratracheal treatment with FR134043 in rats also inhibited the enzyme induced by lipopolysaccharide, though the maximum inhibition was 52%. Ear edema elicited by topical application of PMA in mice was significantly suppressed by pretreatment with FR134043 (38% inhibition at 1 mg/ear). In carrageenan-induced joint injury in rats, plasma extravasation into the synovial cavity was partially and significantly inhibited by FR134043 at 1 mg/knee, while an elastase-specific inhibitor showed no effect. These results suggest that neutrophil elastase is partially involved in tissue damage in acute inflammation provoked by irritants, but not in carrageenan-induced hyperpermeability.
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PMID:Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043. 1042 48

Cepharanthine, a biscoclaurine alkaloid, has been shown to inhibit leukocyte activation in vitro. To determine whether cepharanthine may be of use in the treatment of acute respiratory distress syndrome (ARDS), we investigated its effect on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats, in which activated leukocytes have been implicated. Intravenous administration of LPS (5 mg/kg) induced pulmonary vascular injury, as indicated by increases in both the pulmonary vascular permeability and the lung wet/dry weight ratio. LPS-induced pulmonary vascular injury was significantly less in animals given cepharanthine (10 mg/kg) intraperitoneally. Cepharanthine significantly inhibited the LPS-induced increases in plasma tumor necrosis factor-alpha (TNF-alpha) concentrations in vivo and significantly inhibited the production of TNF-alpha by LPS-stimulated monocytes in vitro. Cepharanthine also inhibited the functions of activated neutrophils in vitro such as neutrophil elastase release, oxygen radical generation, and neutrophil aggregation, probably by inhibiting a rise in the intracellular free calcium concentration. These findings suggest that cepharanthine prevents LPS-induced pulmonary vascular injury by inhibiting leukocyte activation.
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PMID:The prevention of lipopolysaccharide-induced pulmonary vascular injury by pretreatment with cepharanthine in rats. 1061 98

The role of anti-neutrophil cytoplasmic autoantibodies against bactericidal/permeability-increasing protein (BPI-ANCA) in chronic airway infections was investigated. The serum BPI-ANCA titer was correlated with the severity of clinical symptoms in patients with chronic airway infections (P < 0.01), and the serum BPI-ANCA titer decreased with the improvement of the clinical picture, compared with its deterioration (P < 0.05). The serum BPI-ANCA titer was significantly higher in patients with far-advanced lesions on chest X-rays than in patients with milder lesions (P < 0.01) and in patients with reduced respiratory function (P < 0.05). Also, the serum BPI-ANCA titer was significantly higher in patients with prolonged colonization of gram-negative bacteria than in those without prolonged gram-negative bacterial colonization (P < 0.05). When neutrophils from healthy volunteers were incubated with BPI-ANCA before stimulation with lipopolysaccharide (LPS), neutrophil elastase levels decreased in a dose-dependent manner (P < 0.01). The phagocytic activity of neutrophils was significantly inhibited by BPI-ANCA in a dose-dependent manner (P < 0.01). The above findings suggest that BPI-ANCA, an autoimmune factor, appears during the course of chronic airway infections, and that this autoimmune factor may make chronic airway infections more intractable, by inhibiting the phagocytic activity of neutrophils for gram-negative bacteria.
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PMID:Analysis of intractable factors in chronic airway infections: role of the autoimmunity induced by BPI-ANCA. 1181 May 89

We investigated the role of polymorphonuclear neutrophil (PMN) proteinases, elastase, and gelatinase B in rat models of acute lung injury. Three groups of rats were studied 6 hours after unilateral instillation of hydrochloric acid (HCl; 0.1 N), lipopolysaccharide (LPS) (4 microg), or saline. The results demonstrated that HCl-induced lung injury, as compared with LPS-induced lung injury, was associated with an increase in permeability (wet/dry weight ratio and proteins in bronchoalveolar lavage fluid). In contrast, there was similar PMN recruitment (in bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenates) and similar proteinase exocytosis (residual alveolar PMN content of elastase and gelatinase B) in both types of lung injury. In situ zymography, evaluating interstitial protease/inhibitor balance, demonstrated a decrease in gelatinolytic activity in both HCl- and LPS-injured lungs compared with normal lung. The increase in interleukin 6 concentration in lung homogenates, which is observed after both injuries compared with saline-instilled animals, could be involved in up-regulation of tissue inhibitor of matrix metalloproteinase-1, shown by immunocytochemistry to participate in antiproteinase excess. Neither inhibition of alveolar neutrophil influx using a leukocyte elastase inhibitor (EPI-hNE-4) nor inhibition of gelatinase activities by recombinant adenovirus for the human tissue inhibitor of matrix metalloproteinase 1 gene transfer decreased lung edema in HCl-induced injury. These data suggest that PMN proteinases do not contribute to HCl-induced acute lung injury in rats.
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PMID:Neutrophil proteinases in hydrochloric acid- and endotoxin-induced acute lung injury: evaluation of interstitial protease activity by in situ zymography. 1185 May 27

Low-molecular-mass neutrophil elastase inhibitors have been shown to be important in the control of lung inflammation. In addition to inhibiting the enzyme neutrophil elastase, these low-molecular-mass compounds (10 kDa) have been shown to have other activities. For example, secretory leucocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor/SKALP (skin-derived antileucoproteinase)/elafin have also been shown to have "defensin"-like antimicrobial activities. Indeed, these inhibitors have antimicrobial properties in vitro against bacteria, fungi and, potentially, HIV. In addition, we have shown, using an adenovirus-mediated gene transfer overexpression strategy, that elafin is also active against Pseudomonas aeruginosa infection in mice in vivo. The mechanism of action is currently under investigation. In addition to these direct or indirect effects on microbes, it has been shown that lipopolysaccharide is able to up-regulate SPLI production in macrophages in vitro, and that the addition of recombinant SLPI to human monocytes or the transfection of macrophages with SPLI can down-regulate pro-inflammatory mediators such as tumour necrosis factor, presumably to limit self-damaging excessive inflammation. Using viral gene transfer vectors, we are currently investigating the potential of these inhibitors in various models of inflammation in vivo.
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PMID:Antimicrobial activity of antiproteinases. 1202 36


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