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Journal articleKhorasani N, Baker J, Johnson M, et al., 2015,
Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD
, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 10, Pages: 283-291, ISSN: 1176-9106Background: Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructivepulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation isincreased in lung macrophages of COPD. We investigated whether p38 MAPK inhibitioncan modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patientswith COPD.Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed tolipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10-10–10-6 M),with dexamethasone (10-10–10-6 M), or with both. Phosphorylated glucocorticoid receptor (GR)was measured by Western blot.Results: Baseline (P,0.01) and LPS-induced (P,0.05) CXCL8 release was greater in PBMCsfrom COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone(10-6 M) was reduced, and baseline and LPS-induced p38 MAPK activation increasedin PBMCs of COPD. GW856553 (10-9 and 10-10 M) synergistically increased the inhibitoryeffect of dexamethasone (10-8 and 10-6 M) on LPS-induced CXCL8 release in COPD. Similarresults were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activatedphosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibitionof p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
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Journal articleChang P-J, Michaeloudes C, Zhu J, et al., 2015,
Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma
, American Journal of Respiratory and Critical Care Medicine, Vol: 191, Pages: 54-62, ISSN: 1073-449XRationale: Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA.Objectives: We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies.Measurements and Main Results: GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10−7 M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α–induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α–induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA.Conclusions: Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB–dependent gene promoters, may underlie CS insensitivity of severe asthma.
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Journal articleMortaz E, Adcock IM, Tabarsi P, et al., 2015,
Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.
, Journal of clinical immunology, Vol: 35, Pages: 1-10, ISSN: 0271-9142Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities.
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- Citations: 80
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Journal articleLiang Z, Zhang Q, Thomas CMR, et al., 2014,
Impaired macrophage phagocytosis of bacteria in severe asthma
, RESPIRATORY RESEARCH, Vol: 15- Author Web Link
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- Citations: 74
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Journal articleDubuis E, Wortley MA, Grace MS, et al., 2014,
Theophylline inhibits the cough reflex through a novel mechanism of action
, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 133, Pages: 1588-1598, ISSN: 0091-6749- Author Web Link
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- Citations: 25
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Journal articleBirrell MA, Bonvini SJ, Dubuis E, et al., 2014,
Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?
, Journal of Allergy and Clinical Immunology, Vol: 133, Pages: 679-687.e9, ISSN: 0091-6749BackgroundRecent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.ObjectiveThe aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.MethodsWe used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques.ResultsInhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes.ConclusionFor the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
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Journal articleBernardino de la Serna J, Hansen S, Berzina Z, et al., 2013,
Compositional and structural characterization of monolayers and bilayers composed of native pulmonary surfactant from wild type mice
, BBA: Biomembranes, Vol: 1828, Pages: 2450-2459, ISSN: 0005-2736This work comprises a structural and dynamical study of monolayers and bilayers composed of native pulmonary surfactant from mice. Spatially resolved information was obtained using fluorescence (confocal, wide field and two photon excitation) and atomic force microscopy methods. Lipid mass spectrometry experiments were also performed in order to obtain relevant information on the lipid composition of this material. Bilayers composed of mice pulmonary surfactant showed coexistence of distinct domains at room temperature, with morphologies and lateral packing resembling the coexistence of liquid ordered (lo)/liquid disordered (ld)-like phases reported previously in porcine lung surfactant. Interestingly, the molar ratio of saturated (mostly DPPC)/non-saturated phospholipid species and cholesterol measured in the innate material corresponds with that of a DOPC/DPPC/cholesterol mixture showing lo/ld phase coexistence at a similar temperature. This suggests that at quasi-equilibrium conditions, key lipid classes in this complex biological material are still able to produce the same scaffold observed in relevant but simpler model lipid mixtures. Also, robust structural and dynamical similarities between mono- and bi-layers composed of mice pulmonary surfactant were observed when the monolayers reach a surface pressure of 30 mN/m. This value is in line with theoretically predicted and recently measured surface pressures, where the monolayer–bilayer equivalence occurs in samples composed of single phospholipids. Finally, squeezed out material attached to pulmonary surfactant monolayers was observed at surface pressures near the beginning of the monolayer reversible exclusion plateau (~ 40 mN/m). Under these conditions this material adopts elongated tubular shapes and displays ordered lateral packing as indicated by spatially resolved LAURDAN GP measurements.
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Journal articleDamby DE, Horwell CJ, Baxter PJ, et al., 2013,
The respiratory health hazard of tephra from the 2010 Centennial eruption of Merapi with implications for occupational mining of deposits
, JOURNAL OF VOLCANOLOGY AND GEOTHERMAL RESEARCH, Vol: 261, Pages: 376-387, ISSN: 0377-0273- Author Web Link
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- Citations: 44
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Journal articleBernardino de la Serna J, Vargas R, Picardi V, et al., 2013,
Segregated ordered lipid phases and protein-promoted membrane cohesivity are required for pulmonary surfactant films to stabilize and protect the respiratory surface
, FARADAY DISCUSSIONS, Vol: 161, Pages: 535-548, ISSN: 1359-6640 -
Journal articleO'Rourke J, Wang WP, Donnelly L, et al., 1987,
Extravascular plasminogen activator and inhibitor activities detected at the site of a chronic mycobacterial-induced inflammation
, American Journal of Pathology, ISSN: 1525-2191
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