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)

Bronchopulmonary hyperresponsiveness (BHR) is a hallmark of asthma and other inflammatory diseases of the airways. Animal models of BHR are available in which systemic or local immunizations, followed by acute allergenic provocations into the airways, augment responses to intravenous or intratracheal nonspecific bronchoconstrictor agents. Guinea-pig models are easy to manipulate but have serious handicaps: lack of proper genetics, lack of biomolecular tools, and frequent excess of eosinophils in the bronchoalveolar lavage fluid (BALF). Murine models have proper genetics and molecular tools, and they have the further advantage of being widely used for the study of other pathologies. In many of these studies, interleukin (IL)-5 appears as a major cytokine, produced by Th2 lymphocytes. Interleukin-5 promotes eosinophil differentiation and maturation, recruitment to the airways, and possibly activation. The presence of eosinophils in the airways and in the BALF may be necessary but is not sufficient to support BHR, since intense eosinophilia may be present in its absence. Bronchopulmonary hyperresponsiveness is also induced by the administration of lipopolysaccharide (LPS); in that case, eosinophils are not involved, and the role of neutrophils and of tumor necrosis factor-alpha, even though likely, has not been proven. Comparison of BHR induced by allergen (Th2- and largely eosinophil-dependent) and by LPS (probably macrophage-dependent) should allow for a better understanding of the mechanisms of BHR and for the development of important remedies.
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PMID:Modifications of experimental bronchopulmonary hyperresponsiveness. 935 87

We have shown that bone marrow microvascular endothelial cells (BMEC) support growth and differentiation of haemopoietic progenitors in vitro by elaboration of haemopoietic cytokines. Since generation of eosinophils can be observed in these coculture experiments, and BMEC do not produce interleukin (IL)-3, we evaluated BMEC for expression of IL-5, a specific growth factor for the eosinophilic lineage. Using RT-PCR, IL-5 mRNA was expressed by BMEC after stimulation (12 h) with lipopolysaccharide (LPS), IL-1, IL-2 and phorbol myristate acetate (PMA), but not by resting BMEC, after stimulation with TNF-alpha or interferon (IFN)-gamma. Moreover, IFN-gamma suppressed expression of IL-5 in response to LPS and IL-2. The identity of the PCR products was confirmed by restriction enzyme digestion, which resulted in fragments of the predicted size. T lymphocytes were not present in the endothelial cultures as demonstrated by absence of CD2 mRNA. Using a sensitive (1 pg/ml) ELISA assay. IL-5 was detected after 48 h incubation of BMEC with IL-2 (4.1 pg/10(6) cells) or with a combination of LPS and IL-2 (4.8 pg). However, the number of eosinophils generated after 4 weeks coculture of CD34+ haemopoietic cells with BMEC was not increased by addition of IL-2. RT-PCR revealed that BMEC in coculture with haemopoietic cells expressed IL-5 even without addition of exogenous cytokines or stimulating agents. In conclusion, expression of IL-5 by BMEC can be stimulated by cytokines (IL-1, IL-2), LPS, PMA, and coculture with proliferating haemopoietic cells. Thus, BMEC may support proliferation and differentiation of eosinophils in the bone marrow. IFN-gamma represents a cytokine with an inhibitory effect on IL-5 expression by BMEC. In addition, eosinophilia in response to circulating IL-2 or bacterial products (LPS) in vivo may be partially mediated by BMEC or vascular endothelium.
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PMID:Expression of interleukin-5 by human bone marrow microvascular endothelial cells: implications for the regulation of eosinophilopoiesis in vivo. 943 15

Tissue eosinophilia is a hallmark of allergic and parasitic diseases. Priming mechanisms may play an important role in mediating the process of eosinophil accumulation in these conditions. We have previously shown that blockade of tumour necrosis factor alpha (TNFalpha) inhibited the capacity of lipopolysaccharide to prime skin sites for chemoattractant-induced eosinophil recruitment. The present study was carried out to investigate the capacity of TNFalpha to prime an inflammatory site for enhanced eosinophil accumulation. Initial experiments investigated the capacity of TNFalpha itself to induce eosinophil accumulation. Intradermal injection of murine TNFalpha (10-300 ng per site) in the guinea-pig induced significant accumulation of 111In-eosinophils. Kinetic studies showed the response to be delayed in onset and inhibited by cycloheximide, consistent with a dependency on protein synthesis. Trafficking of 111In-eosinophils to sites treated for 2 h with TNFalpha (10-100 ng per site) was inhibited by monoclonal antibodies (mAbs) against beta2 or alpha4 integrins. Intradermal injection of a low dose (3 ng) of TNFalpha (which by itself had no significant effect on eosinophil trafficking) prior to chemoattractants or antigen in sensitized skin sites, induced significant priming of eosinophil accumulation. Recruitment of both 111In-eosinophils and endogenous eosinophils was enhanced. Trafficking to TNFalpha-primed responses was dependent on protein synthesis and beta2 integrins. In contrast, the alpha4 integrin mAb failed to inhibit the TNFalpha primed response. Thus, TNFalpha can induce and also prime eosinophil recruitment in guinea-pig skin. Our results provide further evidence that this cytokine may be an important mediator of allergic- or parasite-induced eosinophilic inflammation.
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PMID:Priming and induction of eosinophil trafficking in guinea-pig cutaneous inflammation by tumour necrosis factor alpha. 986 51

The purpose of this study was to evaluate the effect of longterm exposure to airborne dust and endotoxin on the respiratory system of pigs. A continuous flow exposure chamber was built for the purpose of exposing pigs to selected airborne contaminants. Pigs (n = 6) were exposed to a combination of a very fine corn/soybean meal (40.6 mg/m3) with added lipopolysaccharide (LPS; 12.4 microg/m3) for 8 h/d over 5 d for 15 wk (75 d of exposure). Control pigs (n = 6) were housed in a room with minimal contamination of these airborne contaminants. Surprisingly, dust in the exposure chamber and the control room was highly contaminated with peptidoglycan. Changes in the lung were monitored by collecting bronchoalveolar lavage (BAL) fluid for cytology at 5 different time points throughout the exposure period. Blood samples were collected at the same time for hematology. A non-specific respiratory inflammatory response was found in exposed and control pigs, as suggested by the increased neutrophils in BAL fluid and the small inflammatory areas in the lung tissue. No macroscopic lung lesions were observed in control or exposed pigs. The findings in the control pigs imply that even low dust concentrations and possibly peptidoglycan contamination can induce cellular changes in the BAL fluid and that a true control pig does not exist. In addition, the exposed pigs developed a mild eosinophilia, indicating an allergic response to the airborne contaminants.
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PMID:A 15-week experimental exposure of pigs to airborne dust with added endotoxin in a continuous flow exposure chamber. 1036 71

Corticosteroids (CS) are potent immunosuppressive agents that are known to affect T cell-mediated inflammation by the inhibition of proliferation and cytokine production, as well as the immunostimulatory function of monocytes and macrophages. Not much is known of the effect of corticosteroids on dendritic cells (DC), the professional T cell stimulatory antigen-presenting cells. We report that the endogenous CS hydrocortisone and the synthetic CS clobetasol-17-propionate strongly inhibited the production of the inflammatory mediators interleukin (IL)-12 p70, tumor necrosis factor alpha (TNF-alpha), and IL-6 by lipopolysaccharide (LPS)-stimulated monocyte-derived immature DC (iDC) in vitro. In contrast, the stimulatory capacity, antigen uptake, and the expression of costimulatory molecules were not affected. In accordance with the decreased production of IL-12 p70, CS-treated iDC induced less production of the inflammatory Th1 cytokine interferon-y and enhanced levels of the Th2 cytokines IL-10 and IL-5 in staphylococcal enterotoxin B-stimulated CD4+ Th cells. Furthermore, CS inhibited the maturation of iDC as assessed by the lack of expression of CD83 as well as by the prevention of the loss of antigen uptake capacities. These type 3 DC (DC3) matured in the presence of CS produce less IL-12 p70 and have a decreased T cell stimulatory capacity. Moreover, uncommitted T cells that encounter the CS-induced DC3 develop into Th2-biased cells, which may additionally decrease the Th1-mediated tissue damage but, on the other hand, Th2 cytokines may promote undesirable elevation of IgE and eosinophilia. These findings indicate that suppression of T cell-mediated inflammation by CS not only relies on direct effects on T cells, but also on various effects on DC, their professional antigen-presenting cells.
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PMID:Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3. 1044 54

The anti-inflammatory/antiallergic activity of a novel second-generation p38 mitogen-activated protein kinase inhibitor, SB 239063[trans-1-(4-hydroxycyclohexyl) -4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole], was investigated in vivo and in vitro. SB 239063 had an IC(50) of 44 nM for inhibition of recombinant purified human p38alpha. In lipopolysaccharide-stimulated human peripheral blood monocytes, SB 239063 inhibited interleukin-1 and tumor necrosis factor-alpha production (IC(50) values = 0.12 and 0.35 microM, respectively). A role for p38 kinase in cytokine-associated inflammation in the mouse was shown by p38 activation in the lung and inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production by SB 239063 (ED(50) = 5.8 mg/kg p.o.). Antiallergic activity was demonstrated by essential abolition (approximately 93% inhibition) of inhaled ovalbumin (OA)-induced airway eosinophilia by SB 239063 (12 mg/kg p.o.), measured by bronchoalveolar lavage (BAL) in OA-sensitized mice. In addition, p38 kinase was found by Western analysis to be activated in guinea pig lung. Administration of SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced ( approximately 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h after antigen. SB 239063 (10 mg/kg b.i.d. p.o.) administered after leukotriene D(4) inhalation, reduced by 60% the persistent airway eosinophilia seen at 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL was increased by SB 239063 (1-10 microM) in the presence of interleukin-5. These results indicate that SB 239063 is a potent inhibitor of inflammatory cytokine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells. Collectively, the results support the potential utility of p38 kinase inhibitors, such as SB 239063, for the treatment of asthma and other inflammatory disorders.
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PMID:SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence. 1073 80

Macrophage migration inhibitory factor (MIF) has recently been forwarded as a critical regulator of inflammatory conditions, and it has been hypothesized that MIF may have a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Hence, we examined effects of MIF immunoneutralization on the development of allergen-induced eosinophilic inflammation as well as on lipopolysaccharide (LPS)-induced neutrophilic inflammation in lungs of mice. Anti-MIF serum validated with respect to MIF neutralizing capacity or normal rabbit serum (NRS) was administered i.p. repeatedly during allergen aerosol exposure of ovalbumin (OVA)-immunized mice in an established model of allergic asthma, or once before instillation of a minimal dose of LPS into the airways of mice, a tentative model of COPD. Anti-MIF treatment did not affect the induced lung tissue eosinophilia or the cellular composition of bronchoalveolar lavage fluid (BALF) in the asthma model. Likewise, anti-MIF treatment did not affect the LPS-induced neutrophilia in lung tissue, BALF, or blood, nor did it reduce BALF levels of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-1alpha (MIP-1alpha). The present data suggest that MIF is not critically important for allergen-induced eosinophilic, and LPS-induced neutrophilic responses in lungs of mice. These findings do not support a role of MIF inhibition in the treatment of inflammatory respiratory diseases.
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PMID:Role of macrophage migration inhibitory factor (MIF) in allergic and endotoxin-induced airway inflammation in mice. 1087 50

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.
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PMID:Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787. 1196 Oct 80

Excessive local production of nitric oxide (NO) has been suggested to play a role in rodent models of airway inflammation and in pulmonary diseases such as asthma. However, even given the plethora of data available including gene expression data, pharmacological data, and gene deletion studies in animal models, it is still not clear which nitric-oxide synthase (NOS) isoform is involved in eosinophilic airway inflammation. In this rat study, the nonselective NOS inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester), but not a selective inducible NOS (iNOS) inhibitor 1400W (N-3-(aminomethyl)benzyl)acetamidine), impacted on Sephadex-induced inflammation by significantly inhibiting lung edema, eosinophil infiltration, tumor necrosis factor alpha, interleukin-13, and eotaxin levels in the lung tissue. Furthermore, iNOS gene expression was not induced following Sephadex administration, which confirms that iNOS does not play a role in this model. To demonstrate that this phenomenon was not restricted to this model of asthma, L-NAME, but not 1400W, was shown to reduce eosinophilia in an antigen-induced model. However, in contrast to the Sephadex model, there was an induction of iNOS gene expression after antigen challenge. In a model of aerosolized lipopolysaccharide-induced inflammation, where iNOS gene expression is increased, 1400W inhibited the increased neutrophilia. These data suggest that the compound has been administered using an appropriate dosing regimen for iNOS inhibition in the rat lung. In conclusion, it appears that constitutive, not inducible, NOS isoforms are important in NO production in models of allergic inflammation, which questions whether there is a role for iNOS inhibitors as therapy for the treatment of asthma.
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PMID:Pharmacological assessment of the nitric-oxide synthase isoform involved in eosinophilic inflammation in a rat model of sephadex-induced airway inflammation. 1260 8

V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic.
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PMID:Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. 1267 Jul 78


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