Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Airway mucosa inflammation plays a critical role in the pathogenesis of lower respiratory tract infections caused by respiratory syncytial virus (RSV), the major etiologic agent of bronchiolitis in infancy. Type and intensity of cellular infiltration are dictated by inflammatory chemokines, which are rapidly and abundantly induced in lung tissue by RSV. This process is, to a large extent, transcriptionally regulated by RSV-mediated activation of the nuclear factor-kappa B. The administration of a perfluorocarbon (PFC) liquid, such as perflubron, during partial liquid ventilation improves lung function and also reduces inflammation. In this study we demonstrate that treatment of BALB/c mice with perflubron intranasally 6 hours after RSV infection significantly inhibited lung cellular inflammation as well as the expression of the chemokines RANTES, MIP-1 alpha, MIP-1 beta, and MIP-2, compared with phosphate-buffered saline-treated control mice. However, perflubron treatment did not affect RSV replication. Strikingly, treatment with perflubron abrogated nuclear factor-kappa B activation in lung of RSV-infected mice. These results demonstrate a novel mechanism by which PFC may exert antiinflammatory activity and suggest that partial liquid ventilation with PFC may be considered in future clinical trials for infants with severe RSV infections requiring mechanical ventilation.
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PMID:Perflubron reduces lung inflammation in respiratory syncytial virus infection by inhibiting chemokine expression and nuclear factor-kappa B activation. 1201 8

We studied the influence of sex on the modulation by acute ethanol intoxication of lung polymorphonuclear leukocyte (PMN) recruitment, production of chemotactic factors, and nuclear factor kappa-B (NF-kappa B) activation in alveolar macrophages (AMs) of rats receiving an intrapulmonary challenge with endotoxin (ET). Male and female Charles River rats were given an intratracheal ET challenge [100 micro g in phosphate-buffered saline (PBS)], followed by an intravenous infusion of ethanol or saline for 2.5 h. At that time, bronchoalveolar lavage (BAL) fluid was obtained, and AMs and recruited PMNs were isolated. Acute ethanol treatment [primed 2.5-h intravenous infusion of ethanol, priming dose of 0.87 ml per 100 grams of body weight of 20% (vol./vol.) ethanol, followed by a continuous infusion of 20% ethanol at 0.15 ml per 100 grams of body weight per hour] suppressed ET-induced lung PMN recruitment equally in female and male rats. However, cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) in BAL fluid were suppressed only in female rats. Polymorphonuclear leukocytes of untreated female rats responded to MIP-2 and formyl-methionyl-leucyl-phenylalanine (fMLP) with lower chemotactic activity than did PMNs of male rats. Activation of NF-kappa B in AMs of female rats treated with ET or with ET plus ethanol was less than that in male rats, supporting the suggestion of transcriptional regulation of chemoattractant production, leading to reduced PMN recruitment. Because excessive PMN recruitment with subsequent release of granular contents is associated with tissue damage, these results indicate a potential protective mechanism against pulmonary damage in female rats.
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PMID:Sex differences in the modulation by ethanol of lung chemotaxis. 1245 40

When cells within the intrapulmonary compartment are exposed to pathogens or their products such as lipopolysaccharide, they produce CXC chemokines in order to attract circulating neutrophils into the lower respiratory tract. Previous studies have shown that as neutrophils (PMNs) enter the lung, bronchoalveolar lavage (BAL) chemokine levels are decreased. In this study, we determined the intrapulmonary and systemic responses to two important rat chemokines, cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2), to intratracheal (i.t.) LPS (100 microg in 0.5 mL of phosphate-buffered saline) under neutropenic (cyclophosphamide [CPA]) and neutrophilic (G-CSF) conditions. By 4 h after i.t. LPS, CPA pretreatment decreased PMN recruitment 83% and G-CSF increased PMN recruitment 91% compared with recruitment into the lung in vehicle-pretreated rats (42.7 +/- 19.3 million PMNs). Neutropenic rats had increased CINC and MIP-2 concentrations in BAL fluid 4 h after i.t. LPS when compared with levels seen in vehicle controls (P < 0.05). In vitro LPS-stimulated chemokine production by alveolar macrophages obtained from CPA- and vehicle-pretreated animals did not differ. The increase in BAL fluid chemokine levels in neutropenic rats corresponded to increased chemotaxis of neutrophils to BAL fluid from CPA-pretreated rats as compared with the chemotaxis response of PMN to BAL fluid from vehicle-pretreated rats. In contrast, G-CSF enhancement of neutrophil recruitment decreased chemotactic activity of BAL fluid collected 4 h after i.t. LPS. These data show that as neutrophils are recruited into the lung, they alter chemokine levels, which most likely serves to down-regulate the inflammatory response.
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PMID:Neutrophil modulation of the pulmonary chemokine response to lipopolysaccharide. 1246 65

Pseudomonas aeruginosa is a pathogen that frequently causes acute lung injury, bacteremia and sepsis in critically ill patients. As tissue macrophages are a major producer of inflammatory mediators that contribute to septic physiology, and are essential for eliminating bacteria from the circulation, we investigated the role of tissue macrophages in the generation of both inflammatory and anti-inflammatory cytokines in septic shock by using our mouse model of P. aeruginosa pneumonia. To see the effects of tissue macrophage depletion, we intravenously injected dichloromethylene-diphosphonate (Cl2MDP)-encapsulating liposomes in mice. Two days after the liposome injection, we instilled cytotoxic P. aeruginosa (PA103) into the lung that disseminates and causes septic shock. After the infection, we collected blood and bronchoalveolar lavage fluids. The samples were then analyzed for TNF-alpha, MIP-2, and IL-10 concentration. We compared these results to control mice that received either liposomes without Cl2MDP or phosphate buffered saline alone. Plasma TNF-alpha, MIP-2, and IL-10 levels were significantly decreased in the tissue macrophage-depleted mice compared to the control groups of mice. Although depletion of tissue macrophages by Cl2MDP-liposome administration did not affect the severity of bacteremia or the survival of infected mice, these results imply that tissue macrophages have a major role in the production of both proinflammatory and anti-inflammatory cytokines in the circulation and in the causing septic physiology associated with P. aeruginosa pneumonia.
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PMID:Effects of Cl2MDP-encapsulating liposomes in a murine model of Pseudomonas aeruginosa-induced sepsis. 1260 29

A technique allowing high-throughput synthesis and evaluation of molecularly imprinted polymer sorbents at a reduced scale (mini-MIPs) was developed and used for the optimization of MIPs for use in pure aqueous environments. The technique incorporated a 4-port liquid-handling robot for the rapid dispensing of monomers, templates, solvents and initiator into the reaction vessels of a 96-well plate. A library of 80 polymers, each ca. 50 mg, could thus be prepared in 24 h. The MIP rebinding capacity and selectivity could be rapidly assessed in the batch mode by quantifying nonbound fractions in parallel using a UV monochromator plate reader. This allowed a complete evaluation of the binding characteristics of an 80 polymer library in approximately 1 week. With the objective of optimizing a polymer imprinted with the local anaesthetic Bupivacaine for use in pure aqueous systems, a polymer library was prepared by varying the original poly(MAA-co-EDMA) MIP composition. The variable factors were the added amount of the hydrophilic comonomer, 2-hydroxyethyl methacrylate (HEMA), the cross-linking ratio, and the porogen. This optimization resulted in polymers showing high imprinting factors (IF = K(MIP)/K(NIP)) in water as a result, mainly, of reduced binding to the nonimprinted polymer. Normal scale batches of these materials showed strong retention of the template and low nonspecific binding when assessed as chromatographic stationary phases using pure phosphate buffer, pH 7.4, as mobile phase, by equilibrium batch rebinding experiments and as sorbents for extractions of the analyte from blood plasma samples.
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PMID:Water-compatible molecularly imprinted polymers obtained via high-throughput synthesis and experimental design. 1465 45

Aging of organophosphorus (OP)-compound-inhibited neuropathy target esterase (NTE) is the critical event that initiates OP-compound-induced delayed neurotoxicity (OPIDN). Aging has classically been considered to involve side-group loss from phosphylated NTE, rendering the enzyme refractory to reactivation. N,N'-Diisopropylphosphorodiamidofluoridate (mipafox, MIP)-inhibited NTE has been thought to age quickly; however, it can be reactivated under acidic conditions. The present study was undertaken to determine whether MIP-inhibited human recombinant NTE esterase domain (NEST) ages classically by isopropylamine loss. Diisopropylphosphorofluoridate (DFP), the oxygen analogue of MIP, was used for comparison. Kinetic values for DFP against NEST were as follows: k(i) = 17 200 +/- 180 M(-1) min(-1); reactivation t(1/2) approximately 90 min at pH 8.0 and approximately 60 min at pH 5.2; k(4) = 0.108 +/- 0.041 min(-1) at pH 8.0 and 0.181 +/- 0.034 min(-1) at pH 5.2. Kinetic values for MIP against NEST were as follows: k(i) = 1880 +/- 61 M(-1) min(-1); reactivation t(1/2) = 0 min at pH 8.0 and approximately 60 min at pH 5.2; aging was complete at all time points tested at pH 8.0, but no aging occurred at pH 5.2. Mass spectrometry revealed a mass shift of 123.0 +/- 0.6 Da for the active site peptide peak of aged DFP-inhibited NEST, corresponding to a monoisopropyl phosphate adduct. In contrast, the analogous mass shift for aged MIP-inhibited NEST was 162.8 +/- 0.6 Da, corresponding to the intact N,N'-diisopropylphosphorodiamido adduct. Thus, MIP-inhibited NEST does not age by isopropylamine loss. However, because kinetically aged MIP-inhibited NEST yields an intact adduct capable of reversible deprotonation, aging could occur by proton loss. Indeed, MIP-inhibited NEST does not age at pH 5.2 but ages immediately and completely at pH 8.0. Therefore, we conclude that the MIP-NEST conjugate ages by deprotonation rather than classical side-group loss.
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PMID:The mipafox-inhibited catalytic domain of human neuropathy target esterase ages by reversible proton loss. 1503 42

Polymorphonuclear neutrophil (PMN) extravasation/sequestration in the lung and a dysregulated inflammatory response characterize the pathogenesis of acute lung injury (ALI). Previously, we have shown that hemorrhage (Hem) serves to prime PMN such that subsequent septic challenge [cecal ligation and puncture (CLP)] produces a pathological, inflammatory response and consequent lung injury in mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) are murine CXC chemokines found elevated in the lungs and plasma following Hem/CLP and have been reported by others to share a common receptor (CXCR2). Based on these data, we hypothesize that blockade of CXCR2 immediately following Hem would suppress KC and MIP-2 priming of PMN, thereby reducing the inflammatory injury observed following CLP. To assess this, Hem mice (90 min at 35+/-5 mmHg) were randomized to receive 0, 0.4, or 1 mg antileukinate (a hexapeptide inhibitor of CXCRs) in 100 microl phosphate-bufferd saline (PBS)/mouse subcutaneously, immediately following resuscitation (Ringer's lactate-4x drawn blood volume). Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later. The results show that blockade of CXCR2 significantly (P<0.05, Tukey's test) reduced PMN influx, lung protein leak, and lung-tissue content of interleukin (IL)-6, KC, and MIP-2 and increased tissue IL-10 levels. Plasma IL-6 was significantly decreased, and IL-10 levels increased in a dose-dependent manner compared with PBS-treated mice. A differential effect was observed in plasma levels of KC and MIP-2. KC showed a significant reduction at the 0.4 mg antileukinate dose. In contrast, plasma MIP-2 was significantly elevated at both doses compared with the PBS-treated controls. Together, these data demonstrate that blockade of CXCR2 signaling attenuates shock-induced priming and ALI observed following Hem and subsequent septic challenge in mice.
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PMID:CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice. 1512 71

A variety of commercial DNA arrays specific for humans and rodents are widely available; however, microarrays containing well-characterized genes to study pathway-specific gene expression are not as accessible for domestic animals, such as cattle, sheep and pigs. Therefore, a small-scale application-targeted bovine immune-endocrine cDNA array was developed to evaluate genetic pathways involved in the immune-endocrine axis of cattle during periods of altered homeostasis provoked by physiological or environmental stressors, such as infection, vaccination or disease. For this purpose, 167 cDNA sequences corresponding to immune, endocrine and inflammatory response genes were collected and categorized. Positive controls included 5 housekeeping genes (glyceraldehydes-3-phosphate dehydrogenase, hypoxanthine phosphoribosyltransferase, ribosomal protein L19, beta-actin, beta2-microglobulin) and bovine genomic DNA. Negative controls were a bacterial gene (Rhodococcus equi 17-kDa virulence-associated protein) and a partial sequence of the plasmid pACYC177. In addition, RNA extracted from un-stimulated, as well as superantigen (Staphylococcus aureus enterotoxin-A, S. aureus Cowan Pansorbin Cells) and mitogen-stimulated (LPS, ConA) bovine blood leukocytes was mixed, reverse transcribed and PCR amplified using gene-specific primers. The endocrine-associated genes were amplified from cDNA derived from un-stimulated bovine hypothalamus, pituitary, adrenal and thyroid gland tissues. The array was constructed in 4 repeating grids of 180 duplicated spots by coupling the PCR amplified 213-630 bp gene fragments onto poly-l-lysine coated glass slides. The bovine immune-endocrine arrays were standardized and preliminary gene expression profiles generated using Cy3 and Cy5 labelled cDNA from un-stimulated and ConA (5 microg/ml) stimulated PBMC of 4 healthy Holstein cows (2-4 replicate arrays/cow) in a time course study. Mononuclear cell-derived cytokine and chemokine (IL-2, IL-1alpha, TNFalpha, IFN-gamma, TGFbeta-1, MCP-1, MCP-2 and MIP-3alpha) mRNA exhibited a repeatable and consistently low expression in un-stimulated cells and at least a two-fold increased expression following 6 and 24 h ConA stimulation as compared to 0 h un-stimulated controls. In contrast, expression of antigen presenting molecules, MHC-DR, MHC-DQ and MHC-DY, were consistently at least two-fold lower following 6 and 24 h ConA stimulation. The only endocrine gene with differential expression following ConA stimulation was prolactin. Additionally, due to the high level of genetic homology between ovine, swine and bovine genes, RNA similarly acquired from sheep and pigs was evaluated and similar gene expression patterns were noted. These data demonstrate that this application-targeted array containing a set of well characterized genes can be used to determine the relative gene expression corresponding to immune-endocrine responses of cattle and related species, sheep and pigs.
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PMID:Construction and application of a bovine immune-endocrine cDNA microarray. 1526 89

TGF-beta has been defined as a key mediator for the induction and maintenance of immunological tolerance. Concomitantly, it is essential for homeostasis of specialized epithelial dendritic cells, namely, Langerhans cells (LC). Our data reveal that TGF-beta induces migration of the immature LC, XS52, a cell line expressing the signaling components, TGF-beta type I and II receptors and Smad2, 3, and 4 mRNA. TGF-beta stimulation induced transient Smad3/4 oligomerization and Smad3/DNA binding. Antisense oligonucleotides (ASO) targeting Smad3 abrogated TGF-beta-induced XS52 chemotaxis, proving the involvement of this Smad protein in the TGF-beta-dependent migration. In contrast, the typical CCR6-dependent chemotaxis of immature LC induced by CCL20/MIP-3alpha was not affected by Smad3 ASO. Most notably, we also identified the lysophospholipid sphingosine 1-phosphate (S1P) as a potent chemoattractant for immature LC, which expressed mRNA transcripts of lysophospholipid receptors S1P(1-4). Additional experiments with specific ASO showed that the Galpha(i)-coupled receptors S1P(1) and S1P(3) were dominantly involved in the S1P-induced migration. In contrast, lysophosphatidic acid (LPA), also binding to members of the lysophospholipid receptor family, failed to induce XS52 migration. Intriguingly, we raised evidence that TGF-beta and S1P signal transduction pathways are indeed overlapping, as S1P augmented Smad activation and targeted DNA binding with kinetics comparable to TGF-beta. Finally, S1P failed to stimulate XS52 chemotaxis when Smad3 protein expression was abrogated. Thus, our data indicate a cross-communication between S1P and TGF-beta signaling that might be relevant for more than only migratory activities of immature LC.
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PMID:Overlapping signaling pathways of sphingosine 1-phosphate and TGF-beta in the murine Langerhans cell line XS52. 1572 87

Core-shell molecularly imprinted particles (CS-MIPs) have been synthesised using the technique of emulsion polymerisation with caffeine and theophylline being used in the surface template polymerisation with ethylene glycol dimethacrylate and oleylphenyl hydrogen phosphate. A radiolabelling study with caffeine-8-14C showed that the template was completely located at the particle surface during polymerisation. Caffeine could be specifically bound to a caffeine-imprinted CS-MIP to give a biphasic Scatchard binding curve, whereas the binding profile to a theophylline-imprinted CS-MIP was monophasic. The nanoparticles have the potential to be used in the molecular recognition of small molecules in a complex biological matrix. Water soluble highly-branched imidazole end-chain functionalised polymers of nanodimensions have also been synthesised via reversible addition-fragmentation chain transfer polymerisation. The polymers have lower critical solution temperatures which occur at sub-ambient temperatures and have proven useful in the affinity precipitation of proteins which are particularly temperature sensitive, e.g. the histidine-tagged protein fragment BRCA1. An overview of both of these areas of research is described outlining the diversity of these aqueous compatible polymers in molecular recognition processes at the nanoscale.
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PMID:Aqueous compatible polymers in bionanotechnology. 1644 Nov 76


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