Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Combitube is a relatively new device used for blind insertion emergency intubation. We report a case of successful Combitube treatment of an acute respiratory arrest secondary to an acute asthma exacerbation. An advanced EMT-II (National Park Service Parkmedic) utilized this device. Our review of the literature revealed no reported cases of an advanced EMT-II, nor any other cases, using the Combitube in asthma-related respiratory failure.
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PMID:Successful intubation with the Combitube in acute asthmatic respiratory distress by a Parkmedic. 893 15

A soluble form of the human IL-5R alpha-chain (IL-5Ra) that contains the extracellular IL-5 binding domain has been evaluated for its effect on IL-5 binding to and activation of human eosinophils and basophils. The truncated receptor was expressed in Escherichia coli and recovered in biologically active form following renaturation and anion exchange chromatography. The soluble receptor formed a 1/1 complex with IL-5 in solution and bound IL-5 with affinity comparable to that of cell-associated IL-5Ra. Soluble IL-5Ra also competed with IL-5 for binding to the native alpha beta IL-5R on human cells and inhibited IL-5-mediated receptor activation and inflammatory mediator production. In this regard, the soluble receptor prevented IL-5-induced tyrosine phosphorylation of JAK2 kinase and IL-5R beta-chain and inhibited IL-5 priming of leukotriene C4 release by human basophils. However, the E. coli-derived receptor failed to inhibit IL-5 in longer term assays, including eosinophil survival and TF-1 cell proliferation, possibly due to its propensity to aggregate in a time- and temperature-dependent manner. In contrast, we observed that a soluble IL-5Ra derived from baculovirus-infected cells was less prone to aggregate and effectively antagonized IL-5-induced cell proliferation and survival. These findings indicate that the extracellular portion of the human IL-5Ra chain can prevent association of IL-5 with cell surface receptors and can attenuate signal transduction, mediator release, and survival of inflammatory cells. As such, soluble IL-5R may be useful in treating diseases such as human asthma, in which pulmonary injury is associated with the activity of IL-5R-bearing cells.
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PMID:Attenuation of IL-5-mediated signal transduction, eosinophil survival, and inflammatory mediator release by a soluble human IL-5 receptor. 937 92

We tried to use eosinophil counts in induced sputum samples as a marker of airway inflammation, and as a guide for reducing inhaled corticosteroids in patients with well-controlled persistent asthma. The eosinophil count in induced sputum smears was defined as follows: Eos%; eosinophil percentage of 200-400 leukocytes in properly cell-separated fields, TEC; total eosinophil counts in the 5 most eosinophil-dense high power view fields (x 400). First, the eosinophil count in induced sputum samples was compared between 29 asthmatic subjects treated with inhaled corticosteroid and 15 age- and sex-matched healthy controls. Second, inhaled corticosteroid was reduced by 50% in 20 patients with green-zone asthma (morning PEF > 80% of patient's best PEF). PEF measurements were followed prospectively for 12 weeks thereafter. Once PEF decreased below 70% of their best PEF, subjects were considered as treatment "failures". Both Eos% and TEC were significantly higher than in the controls, even in well-controlled (morning PEF > 80% of their best) asthmatic patients (p = 0.001, 0.03). The chance of treatment "failure" was significantly higher in those having more eosinophils (Eos% > 10%, TEC > 100) in their initial induced sputum sample (p = 0.03, 0.001). Airway inflammation still persists in many well-controlled chronic asthmatic patients, and induced sputum eosinophilia predicts an early decrease of PEF after reduction of inhaled corticosteroids.
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PMID:[Eosinophil count in induced sputum samples as a marker of airway inflammation and adequacy of corticosteroid inhalation treatment in asthmatic patients]. 961 40

Eosinophils, along with mast cells are key cells involved in the innate immune response against parasitic infection whereas the adaptive immune response is largely dependent on lymphocytes. In chronic parasitic disease and in chronic allergic disease, IL-5 is predominantly a T cell derived cytokine which is particularly important for the terminal differentiation, activation and survival of committed eosinophil precursors. The human IL-5 gene is located on chromosome 5 in a gene cluster that contains the evolutionary related IL-4 family of cytokine genes. The human IL-5 receptor complex is a heterodimer consisting of a unique alpha subunit (predominantly expressed on eosinophils) and a beta subunit which is shared between the receptors for IL-3 & GM-CSF (more widely expressed). The alpha subunit is required for ligand-specific binding whereas association with the beta subunit results in increased binding affinity. The alternative splicing of the alpha IL-5R gene which contains 14 exons can yield several alpha-IL-5R isoforms including a membrane-anchored isoform (alpha IL-5Rm) and a soluble isoform (alpha IL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1, and STAT5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of alpha IL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased alpha IL-5R mRNA expression. We have also shown that the subset of activated eosinophils that expressed mRNA for membrane bound alpha IL-5r inversely correlated with FEV1, whereas the subset of activated eosinophils that expressed mRNA for soluble alpha IL-5r directly correlated with FEV1. Hence, not only does this data suggest that the presence of eosinophils expressing alpha IL-5R mRNA contribute towards the pathogenesis of bronchial asthma, but also that the eosinophil phenotype with respect to alpha IL-5R isoform expression is of central importance. Finally, there are several animal, and more recently in vitro lung explant, models of allergen induced eosinophilia, late airway responses (LARS), and bronchial hyperresponsiveness (BHR)--all of which support a link between IL-5 and airway eosinophilia and bronc
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PMID:IL-5 and IL-5 receptor in asthma. 969 19

Cytokines are important regulators of hematopoiesis. They exert their actions by binding to specific receptors on the cell surface. Interleukin-5 (IL-5) is a critical cytokine that regulates the growth, activation, and survival of eosinophils. Because eosinophils play a seminal role in the pathogenesis of asthma and allergic diseases, an understanding of the signal transduction mechanism of IL-5 is of paramount importance. The IL-5 receptor is a heterodimer of alpha- and beta-subunits. The alpha-subunit is specific, whereas the beta-subunit is common to IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) receptors and is crucial for signal transduction. It has been shown that there are two major signaling pathways of IL-5 in eosinophils. IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the Ras-MAPK and JAK-STAT pathways. Studies suggest that Lyn, Syk, and JAK2 tyrosine kinases and SHP-2 tyrosine phosphatase are important for eosinophil survival. In contrast to their survival-promoting activity, Lyn and JAK2 appear to have no role in eosinophil degranulation or expression of surface adhesion molecules. Raf-1 kinase, on the other hand, is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5 stimulation of B cell function. However, it does not appear to be important for eosinophil function. Thus a clear segregation of signaling molecules based on their functional importance is emerging. This review describes the signal transduction mechanism of the IL-3/GM-CSF/IL-5 receptor system and compares and contrasts IL-5 signaling between eosinophils and B cells.
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PMID:The mechanism of IL-5 signal transduction. 973 Sep 44

Airway inflammation associated with asthma is characterized by massive infiltration of eosinophils, mediated in part by specific chemoattractant factors produced in the lung. Allergen-specific Th2 cells appear to play a central role in asthma; for example, adoptively transferred Th2 cells induced lung eosinophilia associated with induction of specific chemokines. Interestingly, Th2 supernatant alone administered intranasally to naive mice induced eotaxin, RANTES, monocyte-chemotactic protein-1, and KC expression along with lung eosinophilia. We tested the major cytokines individually and found that IL-4 and IL-5 induced higher levels of macrophage-inflammatory protein-1alpha and KC; IL-4 also increased the production of monocyte-chemotactic protein-1; IL-13 and IL-4 induced eotaxin. IL-13 was by far the most potent inducer of eotaxin; indeed, a neutralizing anti-IL-13 Ab removed most of the eotaxin-inducing activity from Th2 supernatants, although it did not entirely block the recruitment of eosinophils. While TNF-alpha did not stimulate eotaxin production by itself, it markedly augmented eotaxin induction by IL-13. IL-13 was able to induce eotaxin in the lung of JAK3-deficient mice, suggesting that JAK3 is not required for IL-13 signaling in airway epithelial cells; however, eosinophilia was not induced in this situation, suggesting that JAK3 transduces other IL-13-mediated mechanisms critical for eosinophil recruitment. Our study suggests that IL-13 is an important mediator in the pathogenesis of asthma and therefore a potential target for asthma therapy.
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PMID:Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. 1007 86

Receptor antagonists block all receptor-coupled signaling pathways indiscriminately. We introduce a novel class of peptide inhibitors that is designed to block a specific signal from a receptor while keeping other signals intact. This concept was tested in the model of IL-5 signaling via Lyn kinase. We have previously mapped the Lyn-binding site of the IL-5/GM-CSF receptor common beta (beta c) subunit. In the present study, we designed a peptide inhibitor using the Lyn-binding sequence. The peptide was N-stearated to enable cellular internalization. The stearated peptide blocked the binding of Lyn to the beta c receptor and the activation of Lyn. The lipopeptide did not affect the activation of Janus kinase 2 or its association with beta c. The inhibitor blocked the Lyn-dependent functions of IL-5 in vitro (e.g., eosinophil differentiation from stem cells and eosinophil survival). It did not affect eosinophil degranulation. When applied in vivo, the Lyn-binding peptide significantly inhibited airway eosinophil influx in a mouse model of asthma. The lipopeptide had no effect on basophil histamine release or on the proliferation of B cells and T cells. To our knowledge, this is the first report on an inhibitor of IL-5 that blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. This novel strategy to develop peptide inhibitors can be applied to other receptors.
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PMID:A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. 1039 90

The survival and apoptosis of eosinophils is of pivotal importance for controlling allergic diseases such as asthma and rhinitis. In this study we have investigated the role for cAMP in regulating eosinophil survival and apoptosis in the absence of eosinophil-active cytokines. The treatment with dibutyryl cyclic AMP (dbcAMP) increased eosinophil survival with a concomitant decrease of apoptosis in a dose-dependent manner. The pretreatment with a protein kinase A (PKA) inhibitor blocked the effects of dbcAMP on survival and apoptosis of eosinophils. The catalytic subunit of PKA was translocated to nucleus in parallel with a robust increase of intracellular cAMP levels upon exposure to dbcAMP but not IL-5, suggesting the separation of PKA activation from the IL-5-induced suppression of eosinophil apoptosis. When eosinophils were treated with pharmacological inhibitors of protein kinases prior to exposure to dbcAMP or IL-5, only the mitogen-activating protein kinase (MAPK) inhibitor, PD098059, was partly able to block dbcAMP-induced augmentation of eosinophil viability, whereas both Janus kinase 2 and MAPK inhibitors effectively interrupted the IL-5-induced prolongation of eosinophil survival. The effects of dbcAMP and these protein kinase inhibitors on eosinophil apoptosis were confirmed by morphologic analysis. We propose that a cAMP-dependent pathway may constitute an important component for regulating eosinophil survival/apoptosisand that cAMP may inhibit eosinophil apoptosis through the activation of PKA and of subsequent MAPK in part.
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PMID:Role of cAMP-dependent pathway in eosinophil apoptosis and survival. 1091 59

The study compares the psychometric properties of four different approaches to patient-assessed health outcomes in asthma, including the Asthma Quality of Life Questionnaire (AQLQ), Newcastle Asthma Symptoms Questionnaire (NASQ), SF-12 and EuroQol. The instruments were administered by means of a self-completed postal questionnaire to 394 patients recruited from general practices in the North East of England. Patients completed a follow-up questionnaire at 6 months. The levels of missing data were assessed and instrument scores compared using correlational analysis. Scores were related to self-reports of smoking behaviour, socioeconomic status and health transition. Responsiveness was assessed using standardized response means. Two hundred and thirty-five patients took part in the study giving a response rate of 59.6%. There was a relatively large amount of missing data for the individualized section of the AQLQ. Correlational analysis provided evidence of convergent validity between the specific instruments; the largest correlation was found between NASQ scores and the asthma symptoms scale of the AQLQ (r = 0.84). The NASQ was found to be the most powerful at discriminating between smokers and non-smokers. All four instruments were linearly related to self-reported asthma transition (P<0.05); the specific instruments having the strongest association. The specific instruments showed good levels of responsiveness with the NASQ producing a large SRM of 0.82. SRMs for the AQLQ were of a moderate to large size (0.32-0.77) and the SRMs for the SF-12 and EuroQol were of a small size. The two specific instruments are capable of greater levels of discrimination between groups of patients and are more responsive to changes in health than the generic SF-12 and EuroQol. The greater responsiveness of the NASQ is probably due to its focus being restricted to symptoms of asthma compared to the broader focus of the AQLQ domains. The NASQ has a strong relationship with the AQLQ and is a more practical instrument that is more acceptable to patients. However, the AQLQ does measure broader patient concerns. The SF-12 and EuroQol have greater potential to capture side-effects and have wider scope for application in economic evaluation.
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PMID:Patient-assessed measures of health outcome in asthma: a comparison of four approaches. 1092 66

X-linked, or Bruton's, agammaglobulinemia (XLA) was described in 1952 as the congenital inability to form antibodies. Patients were typically infants or young children with recurrent, severe bacterial infections. Other, milder cases of hypogammaglobulinemia were considered "acquired," and often presented later in life. Since the discovery of the defective gene in XLA in 1993, it has been shown that a significant number of male patients with sporadic or acquired hypogammaglobulinemia actually have XLA. We present here a case of atypical XLA and discuss similar cases in the literature. We conclude that any male with hypogammaglobulinemia, regardless of age of presentation, might have XLA. Males with low B-cell numbers are particularly likely to have XLA and should have Bruton's tyrosine kinase levels assessed.
Curr Allergy Asthma Rep 2001 Nov
PMID:The clinical spectrum of Bruton's agammaglobulinemia. 1189 85


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