Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0519030 (Klebsiella)
 21,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bactericidal/permeability-increasing protein (BPI) of neutrophils and BPI fragments neutralize the effects of isolated Gram-negative bacterial lipopolysaccharides both in vitro and in vivo. Since endotoxin most commonly enters the host as constituents of invading Gram-negative bacteria, we raised the question: Can BPI and its bioactive fragments also protect against whole bacteria? To determine whether the bactericidal and endotoxin-neutralizing activities of BPI/fragments are expressed when Gram-negative bacteria are introduced to the complex environment of whole blood we examined the effects of added BPI and proteolytically prepared and recombinant NH2-terminal fragments on: (a) the fate of serum-resistant encapsulated Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa that survive the antibacterial actions of whole blood and (b) the ability of these bacteria to trigger cytokine release. Added BPI in nanomolar concentrations killed each of three encapsulated strains of E. coli and in closely parallel fashion inhibited tumor necrosis factor (TNF) release. Holo-BPI and its NH2-terminal fragment were equipotent toward a rough LPS chemotype K1-encapsulated strain, but the fragment was substantially more potent than holo-BPI toward two encapsulated smooth LPS chemotype strains. TNF release induced by K. pneumoniae and P. aeruginosa was also inhibited by both holo-BPI and fragment but, at the protein concentrations tested, P. aeruginosa was killed only by the fragment and K. pneumoniae was not killed by either protein. The bactericidal action of BPI/fragment toward E. coli is inhibited by C7-depleted serum, but accelerated by normal serum, indicating that BPI, acting in synergy with late complement components, enhances extracellular killing of serum-resistant bacteria. Thus, BPI and an even more potent NH2-terminal fragment may protect against Gram-negative bacteria in the host by blocking bacterial proliferation as well as endotoxin-mediated effects, not only as components of the intracellular antibacterial arsenal of the neutrophil, but also as potentially therapeutic extracellular agents.
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PMID:Human bactericidal/permeability-increasing protein and a recombinant NH2-terminal fragment cause killing of serum-resistant gram-negative bacteria in whole blood and inhibit tumor necrosis factor release induced by the bacteria. 152 21

Several antitumor substances that effectively inhibited the growth of ascites and solid tumor cells transplanted in mice were isolated from pine cone NaOH extract by acid- and ethanol-precipitation. These antitumor substances were also potent antiviral agents against human immunodeficiency virus, herpes simplex virus and influenza virus; they induced antimicrobial activity against Staphylococcal aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Candida albicans, and induced antiparasite activity against Hymenolepis nana in mice. Chemical analysis of these substances by IR, UV, NMR, ESR and partition chromatography on cellulose-TLC plate disclosed that they had lignin-related structures complexed with sugars or polysaccharides. Chlorinated decomposition of the lignin portion significantly reduced their antiviral activity. In agreement with this, the antiviral activity of synthesized lignins prepared by polymerization of phenylpropanoid precursors was comparable to that of the undecomposed counterparts of the pine cone extract. Acid hydrolysis of the polysaccharide portion significantly reduced the ability of the substances to induce antitumor and antimicrobial activities in mice. With an appropriate eliciting agent, intravenous administration of natural lignified substances transiently induced endogenous production of a cytotoxic factor (possibly tumor necrosis factor) in normal mice. Their priming activity was significantly higher than that of their component units or degradation products. These data suggest the importance of conjugating lignins with polysaccharides for in vivo expression of various kinds of immunopotentiating activity. As possible explanations for their induction of a variety of immunopotentiating activities, these natural and synthetic lignins stimulated macrophage NBT-reducing activity, polymorphonuclear cell (PMN) iodination and splenocyte DNA synthesis and inhibited poly (ADP-ribose) glycohydrolase, RNA-dependent DNA polymerase (reverse transcriptase) and RNA-dependent RNA polymerase activities.
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PMID:Antitumor, antiviral and immunopotentiating activities of pine cone extracts: potential medicinal efficacy of natural and synthetic lignin-related materials (review). 164 35

A monoclonal antibody to recombinant murine tumor necrosis factor-alpha (TNF alpha), TN3-19.12, was used to explore pathogenetic mechanisms and therapeutic strategies in gram-negative shock. In mice receiving an LD90 dose of Escherichia coli O111, TN3-19.12 prevented death if given 1.5 h before or 30 min after challenge. Less protection was conferred if the antibody was given 2.5 h after challenge. In control mice receiving an irrelevant antibody, L2-3D9, TNF alpha levels rose (less than or equal to 185.1 +/- 26.1 ng/ml) by 90 min and had returned to baseline by 5 h. Mice receiving TN3-19.12 did not have this response. TN3-19.12 was of limited benefit in mice receiving Pseudomonas aeruginosa but had no protective effect in cyclophosphamide-treated mice receiving Klebsiella pneumoniae. In L2-3D9-treated mice, TNF alpha levels were elevated to 61.8 +/- 27.9 and 49.7 +/- 5.1 ng/ml by 90 min in the two models, respectively. TNF alpha levels in TN3-19.12-treated mice in these two models were very low (3.9-5.5 ng/ml). TNF alpha is a mediator in gram-negative shock; antibody to TNF alpha can be of value in prophylaxis and treatment, but its clinical use remains to be established.
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PMID:Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative shock. 237 72

Intradermal palpable MBT-2 tumor responded with bacterial lipopolysaccharide to hemorrhagic necrosis (LPS) in C3H/HeN (endotoxin sensitive) mice. We have tested LPS fractions isolated from E. coli, Klebsiella pneumoniae, Salmonella minnesota, Pseudomonas aeruginosa and Serratia culture filtrates. All these LPS preparations showed tumor necrotizing activity accompanied by toxicity (body weight loss) in C3H/HeN mice. However, MBT-2 tumors grown in an endotoxin-resistant strain (C3H/HeJ) of mice did not respond to LPS, even at a very high dose. In vitro, the LPS showed no cytotoxic effect on MBT-2 cells. For comparison, systemic administration of tumor necrosis factor (cachexin ) did not affect the i.d. tumor growth. These data indicate that host reactions to LPS (endotoxicity) plays a pivotal role in the expression of tumor necrosis. Accordingly, comparisons of tumor response between endotoxin sensitive and resistant mice avoid potential overestimation of the therapeutic value of certain bacterial products and/or LPS contaminated agents.
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PMID:Effect of bacterial lipopolysaccharide on growth of murine bladder cancer, MBT-2. 251 Mar 88

In this paper, the effects of recombinant human interleukin-1 (IL-1) on non-specific resistance to infection are reviewed. In experiments in neutropenic mice, a single injection of a low dose of IL-1 (8-800 ng) appears to protect against death from lethal Pseudomonas aeruginosa and Candida albicans infections. In non-neutropenic mice protection can also be obtained with such dosages of IL-1 in infection caused by Klebsiella pneumoniae or Listeria monocytogenes. Low dosages of IL-1 are also able to prevent lethal cerebral malaria in mice. No effect has been found in murine cytomegalovirus infection. With the exception of C. albicans infection and malaria, protection is only obtained if IL-1 is given before the infection. The mechanism of protection has not been elucidated; in the Pseudomonas and Klebsiella infection, it could be demonstrated that survival was not due to a direct antibacterial effect of IL-1, not due to the action of granulocytes or increased hematopoietic recovery and not due to activation of macrophages and increased bactericidal mechanisms. In the experimental Listeria infection however, animals treated with IL-1 had lower bacterial counts in their organs. Since the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) are much less potent than IL-1 in these protection experiments, it is very unlikely that they are endogenous mediators of the protection induced by IL-1. The effect is not mediated via the cyclooxygenase pathway, since premedication with ibuprofen does not influence the protective effect of IL-1. Taking these data together, it is felt that IL-1 holds promise as a therapeutic agent in humans.
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PMID:Options for the treatment of serious infections with interleukin-1. 270 46

Natural and synthetic immunomodulators that increase non-specific resistance to infection induce the production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Therefore, we investigated the effect of IL-1 and of TNF on the survival of lethally-infected mice. Mice were injected with 1 x 10(6) Klebsiella pneumoniae in the thigh muscle. When recombinant human IL-1 beta was given as a single i.p. injection 24 h before the infection, survival was increased. Using 80 ng IL-1 beta per mouse, survival compared to control animals was 80% versus 20% 48 h after the infection (p less than 0.001). No effect of IL-1 was observed when it was given 1/2 h before or 6 h after the infection. IL-1 alpha proved to be at least as potent as IL-1 beta. Numbers of bacteria cultured from the blood, thigh muscle, liver, spleen, and kidney were similar in IL-1-treated and control animals. Protection against death by IL-1 was also investigated in granulocytopenic mice with a Pseudomonas aeruginosa infection. Administration of the cyclooxygenase-inhibitor, ibuprofen, did not affect the beneficial effect of IL-1. In this model human recombinant TNF was at least tenfold less active than IL-1 beta. Pretreatment with IL-1 also had a significant effect on survival of mice that received a high dose of bacterial lipopolysaccharide.
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PMID:The effects of recombinant interleukin-1 and recombinant tumor necrosis factor on non-specific resistance to infection. 307 57

To evaluate the cause of the vulnerability to infections in the elderly, the ability of neutrophil to generate reactive oxygen species was assessed by a luminol-dependent chemiluminescence (CL) assay after stimulation with non-opsonized zymosan, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans and lumispheres in elderly patients aged 70 to 93 years. The integrated CL for 20 minutes of whole blood and neutrophils induced by zymosan in the elderly was significantly lower than that in healthy young adults, and the integrated CL of neutrophils induced by lumispheres was also significantly lower in the elderly aged 80 years and over. When bacterial infection occurred in the elderly, the levels of CL were elevated and decreased in the convalescence. This response is proper for host-defense mechanism against infection. However, whole blood CL response was not fully activated in any patients of the elderly during bacterial infection. In these cases lower white blood cell counts, lower neutrophil counts, or the decreased level of the serum total protein, albumin, total cholesterol or cholinesterase were observed. Relationship between malnutrition and the ability of neutrophil to generate reactive oxygen species was suggested. Furthermore, I evaluated the priming effect of lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) on whole blood CL. The CL responses stimulated with non-opsonized zymosan or P. aeruginosa were enhanced by pretreatment with TNF-alpha and LPS in healthy young adults. On the other hand, no significant priming effect was observed when blood from elderly patients were incubated with each primer. These findings suggest that the impairment in the generation of reactive oxygen species of the neutrophils and the decrease in reactivity to LPS and TNF-alpha that activate neutrophils at the site of infection and potentiate host defense against invading bacteria, may contribute to susceptibility to infection in the elderly.
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PMID:[Study of neutrophil dysfunctions in the elderly using a chemiluminescence method]. 782 5

The aim of this study was to characterize the cytokine secretion patterns of human T helper cells from healthy donors reactive with somatic antigens from various bacteria, the nematode Anisakis and tetanus toxoid. From the peripheral blood of four healthy donors we have established 70 T cell lines reactive with antigens from Yersinia, Salmonella, Morganella, Klebsiella, Serratia, Escherichia, Chlamydia, Shigella, Streptococcus, tetanus toxoid and Anisakis, respectively. Our results show that all T cells reactive with bacteria produce interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), but no interleukin (IL)-4 and no or very little IL-2 and IL-10 and, thus, belong to the Th1 subset, while T cells reactive with tetanus toxoid or Anisakis belong to the Th0 subset with production of IFN-gamma, IL-2, IL-4, IL-10 and TNF-alpha. In summary, our data further substantiate the concept of a functional diversity of human T helper cells with respect to their cytokine profiles. Furthermore, they indicate that a Th1 cytokine profile is not restricted to intracellular bacteria.
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PMID:Human T helper cells reactive with somatic bacterial antigens belong to the Th1 subset. 799 90

The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P < 0.05) against KpS (1.99 +/- 0.52 ng/ml) than against KpR (1.40 +/- 0.17 ng/ml). Against the KpR strain, the levels observed with ceftriaxone were significantly higher (P < 0.05) than those obtained with the other therapeutic regimens (0.70 to 0.80 ng/ml). On the day of sacrifice, effective regimens were associated with low TNF levels. We concluded that TNF production depends on (i) the antiobiotic's mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy.
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PMID:Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae. 806 31

During the last decade, episodes of sepsis have increased and Escherichia coli has remained the most frequent clinical isolate. Lipopolysaccharides (LPS; endotoxin) are the major toxic and antigenic components of gram-negative bacteria and qualify as targets for therapeutic interventions. Molecules that neutralize the toxic effects of LPS are actively investigated. In this paper, we describe a murine monoclonal antibody (MAb; WN1 222-5), broadly cross-reactive and cross-protective for smooth (S)-form and rough (R)-form LPS. As shown in enzyme-linked immunosorbent assay and the passive hemolysis assay, WN1 222-5 binds to the five known E. coli core chemotypes, to Salmonella core, and to S-form LPS having these core structures. In immunoblots, it is shown to react with both the nonsubstituted core LPS and with LPS carrying O-side chains, indicating the exposure of the epitope in both S-form and R-form LPS. This MAb of the immunoglobulin G2a class is not lipid A reactive but binds to E. coli J5, an RcP+ mutant which carries an inner core structure common to many members of the family Enterobacteriaceae. Phosphate groups present in the inner core contribute to the epitope but are not essential for the binding of WN1 222-5 to complete core LPS. Cross-reactivity for clinical bacterial isolates is broad. WN1 222-5 binds to all E. coli clinical isolates tested so far (79 blood isolates, 80 urinary isolates, and 21 fecal isolates) and to some Citrobacter, Enterobacter, and Klebsiella isolates. This pattern of reactivity indicates that its binding epitope is widespread among members of the Enterobacteriaceae. WN1 222-5 exhibits biologically relevant activities. In vitro, it inhibits the Limulus amoebocyte lysate assay activity of S-form and R-form LPS in a dose-dependent manner and it neutralizes the LPS-induced release of clinically relevant monokines (interleukin 6 and tumor necrosis factor). In vivo, WN1 222-5 blocks endotoxin-induced pyrogenicity in rabbits and lethality in galactosamine-sensitized mice. The discovery of WN1 222-5 settles the long-lasting controversy over the existence of anti-core LPS MAbs with both cross-reactive and cross-protective activity, opening new possibilities for the immunotherapy of sepsis caused by gram-negative bacteria.
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PMID:A broadly cross-protective monoclonal antibody binding to Escherichia coli and Salmonella lipopolysaccharides. 835 7


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