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

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.
 ...
PMID:Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. 205 27

A study was performed to find an ideal combination and sequence of cytokines, antibiotics and immunorestorative agents to enhance survival from serious infection. The effects of combinations of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF) alpha, the immune adjuvant muramyl dipeptide (MDP) and two systemic antibiotics were studied in a validated murine model of surgical infection. A single cotton suture containing absorbed Klebsiella pneumoniae was placed into the thighs of mice to produce local and systemic infection. Control mice received a volume of subcutaneous saline equal to that of the therapeutic agent; only 18 per cent survived 9 days after infection. The survival time of mice treated with any single agent was similar to that of controls. The group given maximal combined therapy (65 mice) received GM-CSF, TNF-alpha, MDP, and ampicillin-sulbactam or cefoxitin for 6 days. The survival rate in this group 9 days after the introduction of infection was 84-90 per cent (P < 0.0001), suggesting that specific combinations of cytokines, immunostimulants and antibiotics may be useful in combating lethal infection.
 ...
PMID:Improved survival in simulated surgical infection with combined cytokine, antibiotic and immunostimulant therapy. 795 94

IL-1 pretreatment prolongs survival in lethal infection in normal and in neutropenic mice. We investigated whether this protection occurs by interference with deleterious cytokine effects. The effect of IL-1 pretreatment on concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha circulating in vivo and the ex vivo cytokine production capacity of macrophages was assessed in uninfected, non-neutropenic and neutropenic Swiss mice, in Swiss mice infected with Klebsiella pneumoniae (non-neutropenic mice) or Pseudomonas aeruginosa (neutropenic mice), and in neutropenic C3H/HeN and C3H/HeJ mice infected with P. aeruginosa. In Swiss and C3H/HeN mice, IL-1 pretreatment enhanced survival and reduced circulating TNF-alpha and IL-6 as well as LPS-stimulated production of IL-1 alpha and TNF-alpha. In C3H/HeJ mice, a lack of IL-1-induced protection was associated with low cytokine concentrations and production. In contrast, up-regulation of mRNA for the IL-1 receptor antagonist (IL-1Ra) was observed in several organs of IL-1-pretreated mice, suggesting that IL-1Ra could attenuate deleterious IL-1 effects. In addition, IL-1 pretreatment down-regulated steady state mRNA for the type I IL-1R and the type I TNFR in several organs at the time of infection, suggesting desensitization of target cells as an additional mechanism of IL-1-induced protection. We conclude that the IL-1-induced protection is at least partially mediated by down-regulating cytokine production, and that the induction of IL-1Ra and the desensitization of target cells by receptor down-modulation may also contribute to this phenomenon.
 ...
PMID:Differential gene expression for IL-1 receptor antagonist, IL-1, and TNF receptors and IL-1 and TNF synthesis may explain IL-1-induced resistance to infection. 798 74

Prompt, cytokine-mediated restoration of hematopoiesis is a prerequisite for survival after irradiation. Therapy with biologic response modifiers (BRMs), such as LPS, 3D monophosphoryl lipid A (MPL), and synthetic trehalose dicorynomycolate (S-TDCM) presumably accelerates hematopoietic recovery after irradiation by enhancing expression of cytokines. However, the kinetics of the cytokine gene response to BRMs and/or irradiation are poorly defined. One hour after sublethal (7.0 Gy) 60Cobalt gamma irradiation, B6D2F1/J female mice received a single i.p. injection of LPS, MPL, S-TDCM, an extract from Serratia marcescens (Sm-BRM), or Tween 80 in saline (TS). Five hours later, a quantitative reverse transcription-PCR assay demonstrated marked splenic gene expression for IL-1 beta, IL-3, IL-6, and granulocyte-CSF (G-CSF). Enhanced gene expression for TNF-alpha, macrophage-CSF (M-CSF), and stem cell factor (SCF) was not detected. Injection of any BRM further enhanced cytokine gene expression and plasma levels of CSF activity within 24 h after irradiation and hastened bone marrow recovery. Mice injected with S-TDCM or Sm-BRM sustained expression of the IL-6 gene for at least 24 h after irradiation. Sm-BRM-treated mice exhibited greater gene expression for IL-1 beta, IL-3, TNF-alpha, and G-CSF at day 1 than any other BRM. When challenged with 2 LD50/30 of Klebsiella pneumoniae 4 days after irradiation, 100% of Sm-BRM-treated mice and 70% of S-TDCM-treated mice survived, whereas < or = 30% of mice treated with LPS, MPL, or TS survived. Thus, sublethal irradiation induces transient, splenic cytokine gene expression that can be differentially amplified and prolonged by BRMs. BRMs that sustained and/or enhanced irradiation-induced expression of specific cytokine genes improved survival after experimental infection.
 ...
PMID:Gene expression of hematoregulatory cytokines is elevated endogenously after sublethal gamma irradiation and is differentially enhanced by therapeutic administration of biologic response modifiers. 805 28

Intraperitoneal injection of Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) induces thymic atrophy in mice. The thymus weight, cell number, and viability began to decrease at 3 h, and reached their lowest level at 72 h. The thymocyte death was associated with DNA fragmentation of approximately 200 base pairs in ladder form. The kinetic study on histopathology revealed the process of thymocyte death and thymic atrophy. Flow-cytometric analysis showed that CD4+CD8+ thymocytes decreased predominantly. LPS caused thymocyte apoptosis, but only in LPS-responder mice, unlike Gram-negative bacteria that induced apoptosis in both LPS-responder (C3H/HeN) and LPS-nonresponder (C3H/HeJ). Gram-positive bacteria Streptococcus pneumoniae also caused apoptosis in LPS-nonresponder (C3H/HeJ) and LPS-responder mice (B6). The kinetics of serum TNF-alpha production after Gram-negative or Gram-positive bacteria injection was slightly different. E. coli induced serum TNF-alpha peak at 1 h in B6 mice, whereas S. pneumoniae induced a peak at 6 h in C3H/HeJ and at 9 h in B6 mice. Similarly, S. pneumoniae induced thymocyte apoptosis around 9 to 12 h, which was 6 to 9 h later than that observed with E. coli in B6 mice. Anti-TNF-alpha Ab completely blocked the E. coli-induced thymocyte apoptosis, but was only partially inhibitory on the S. pneumoniae-induced thymocyte apoptosis. Furthermore, thymocyte apoptosis induced by E. coli was inhibited by cycloheximide or actinomycin D. These data indicate that both Gram-negative and Gram-positive bacteria could induce thymus atrophy via apoptosis, and that TNF-alpha is a common denominator released and might be responsible for the thymocyte apoptosis.
 ...
PMID:Sepsis-induced apoptosis of the thymocytes in mice. 817 19

A hybridoma cell line secreting a human monoclonal antibody (humab) directed to an epitope in the lipid A region of lipopolysaccharides of Gram-negative bacteria was isolated. Peripheral blood lymphocytes (PBL) obtained from a healthy volunteer were immortalized by Epstein-Barr virus (EBV) transformation. Lymphoblastoid cell lines (LCL) secreting antibodies to the lipopolysaccharides of Gram-negative bacteria were determined by an enzyme-linked immunosorbent assay (ELISA) and subsequently fused with the human-mouse heteromyeloma cell line CB-F7 by polyethylenglycol (PEG)-mediated fusion. A hybridoma line producing a humab (LPD5H4), of the IgM/lambda isotype, which strongly reacted with the lipid A portion of Salmonella and E. coli spp. in ELISA, was established. The antibody was purified by hydrophobic interaction chromatography and gel filtration. Immunoblotting experiments showed a strong reactivity of the humab LPD5H4 with the lower molecular species of different rough and smooth lipopolysaccharide (LPS) types of the bacteria species Salmonella, E. coli, Klebsiella, and Neisseria meningitidis, whereas those of Pseudomonas spp. were negative. Binding of humab LPD5H4 to solid phase bound lipid A and different rough mutants of LPS could be inhibited by the corresponding antigens in solution. Competition assays with a murine monoclonal antibody to lipid A and with polymyxin B indicate that humab LPD5H4 recognizes its epitope in this extremely conserved part of the LPS molecule. In vitro tests demonstrated that the MAb is able to partially inhibit the LPS-induced release of TNF-alpha using isolated peripheral blood mononuclear cells (PBMC).
 ...
PMID:Generation and characterization of a human monoclonal IgM antibody that recognizes a conserved epitope shared by lipopolysaccharides of different gram-negative bacteria. 882 16

Alcohol has long been recognized as an immunosuppressive drug and a risk factor for a spectrum of infectious diseases. Among these infections, bacterial pneumonias are most closely correlated with alcohol abuse. One potential mechanism of ethanol-induced immunosuppression is through its ability to suppress alveolar macrophage production of tumor necrosis factor (TNF-alpha). This defect can be reversed by priming macrophages with interferon-gamma (IFN-gamma). We hypothesized that macrophage priming in vivo in a model of acute ethanol intoxication could augment pulmonary host defenses. To test this hypothesis, we used adenoviral-mediated gene transfer of the IFN-gamma gene. This strategy resulted in prolonged expression of IFN-gamma in vivo. Moreover, in a model of acute ethanol intoxication, this vector significantly enhanced lipopolysaccharide-induced TNF-alpha responses and lung polymorphonuclear leukocyte recruitment. Furthermore, pulmonary host defenses against Klebsiella pneumoniae were significantly augmented. These enhanced host defenses were not reversed with pretreatment with a polyclonal anti-TNF-alpha antibody, suggesting that IFN-gamma's effect was through a non-TNF-alpha-dependent mechanism. These data demonstrate that ethanol-induced suppression of pulmonary host defenses can be reversed with IFN-gamma gene therapy.
 ...
PMID:Adenoviral-mediated interferon-gamma gene therapy augments pulmonary host defense of ethanol-treated rats. 951 1

A vigorous host response is required to effectively clear pathogenic bacteria from the lungs and is dependent upon the recruitment and activation of neutrophils and macrophages. A family of chemotactic cytokines, referred to as chemokines, have been shown to participate in this complex protective response. In this study, we assessed the role of the C-X-C chemokine KC in lung antibacterial host defense using wild-type (wt) B6D2 mice or transgenic mice that had been bred on a B6D2 background expressing KC under the control of a Clara cell-specific promoter within the lung. The administration of Klebsiella pneumoniae to both wt and KC-transgenic mice resulted in a time-dependent expression of KC protein within the lung that peaked at 24 to 48 h postinoculation. When infected with K. pneumoniae, the KC-transgenic mice showed a striking improvement in survival compared with wt control mice. This improved survival was due to an increase in bacterial clearance, which occurred in association with a vigorous recruitment of neutrophils in the KC-transgenic mice compared with their wt control counterparts. No differences in the lung levels of the specific cytokines TNF-alpha, IFN-gamma, IL-12, and IL-10 were noted. However, inducible macrophage inflammatory protein-2 levels were significantly decreased in the KC-transgenic mice compared with the wt mice. This study indicates that the compartmentalized overexpression of KC in vivo results in increased lung bacterial clearance and improved survival, which occurs in association with enhanced polymorphonuclear leukocyte influx to the lung.
 ...
PMID:Lung-specific transgenic expression of KC enhances resistance to Klebsiella pneumoniae in mice. 972 41

Sepsis is often a fatal condition, and excessive production of host inflammatory mediators including cytokines, are considered to be responsible for its lethality. We investigated the biology of TNF-alpha, IL-1, IL-6, and IL-10 with particular emphasis on its role in murine gut-derived sepsis due to Pseudomonas aeruginosa and found that these cytokine levels in serum showed significant increases at lethal conditions. Furthermore, we studied the cytokine levels in serum and BALF of mice after pulmonary infection with Klebsiella pneumoniae. The results showed that inflammatory cytokines in BALF demonstrated high levels at the early stage of infection in response to local inflammation of the lung. On the other hand, cytokine levels in serum abruptly increased at the late stage of infection in response to systemic inflammation. These results revealed that it is important to discriminate between systemic inflammation and local inflammation to diagnose sepsis.
 ...
PMID:[Diagnosis of sepsis based on the host response]. 1043 65

We investigated whether oral administration of LPS exacerbated collagen-induced arthritis (CIA) in mice, which was an experimental model of autoimmune disease. CIA was induced by s.c. injection of type II collagen emulsified with CFA into the base of the tail (day 0) followed by a booster injection on day 21. To examine the ability of LPS to exacerbate CIA, varying doses of LPS were orally administered on day 50. The results showed that administration of LPS was followed by reactivation of CIA in a dose-related fashion. Histologically, on day 55 there were marked edema of synovium proliferated by day 50, new formation of fibrin, and intense infiltration of neutrophils accompanied with a large number of mononuclear cells. Severe destruction of cartilage and subchondral bone was also observed on day 70. The reactivation of CIA by oral administration of LPS was associated with increase in anti-type II collagen IgG and IgG2a Abs as well as varying kinds of cytokines including IL-12, IFN-gamma, IL-1beta, and TNF-alpha. Polymyxin B sulfate given either orally or i.v. suppressed the recurrence of CIA. Increased amounts of LPS were found in sera of mice given the endotoxin orally. LPS from Salmonella enteritidis, Salmonella typhimurium, and Klebsiella pneumoniae and its component, lipid A from Escherichia coli, also reactivated the disease. These findings suggest that LPS from intestinal bacteria may play a role in the exacerbation of autoimmune joint inflammation.
 ...
PMID:Oral administration of lipopolysaccharide exacerbates collagen-induced arthritis in mice. 1047 13


1 2 3 4 5 Next >>