September 2013
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445 Reads
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2 Citations
European Respiratory Journal
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Publications (20)
May 2012
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85 Reads
May 2012
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87 Reads
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3 Citations
American Journal of Respiratory and Critical Care Medicine
January 2012
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1,043 Reads
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194 Citations
Journal of Inflammation
COPD is a disease of innate immunity and bacterial infections are a dominant cause of exacerbations in the later stages resulting in poor health and high mortality. The pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) is sensed by immune cells through activation of the toll-like receptor 4 (TLR4). This leads to the activation of NADPH oxidase (NOX) and NF-κB which together drive COPD inflammation. In this study we show in human PBMCs that LPS stimulated proinflammatory cytokine release (CXCL8 and IL6) was inhibited by approximately 50% by the broad specificity phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Our results also demonstrate that activation of PI3K following LPS stimulation is mediated by a NOX4 dependent mechanism releasing endogenous H2O2, as the NOX4 inhibitor apocynin blocked LPS induced AKT phosphorylation. Moreover, LPS-induced PI3K activation was inhibited by the anti-oxidant N-acetylcysteine in a concentration dependent manner (IC50 ~100 μM). In addition, our data demonstrated that inhibition of small G proteins, by pre-treatment with pertussis toxin, inhibited LPS-induced AKT phosphorylation. Furthermore, the G-protein inhibitors pertussis toxin and mastoparan both inhibited LPS-induced CXCL8 and IL-6 release by approximately 50%. Together, these data indicate there is a mechanism in human PBMCs where TLR4 activation by LPS leads to ROS generation through NOX4 and activation of the PI3K pathway. This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines.
October 2011
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140 Reads
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7 Citations
October 2011
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380 Reads
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179 Citations
American Journal of Respiratory and Critical Care Medicine
There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins. To determine the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescence-activated cell sorter. Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein. Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.
June 2011
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53 Reads
Die Innere Medizin
Background: Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR-and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling. Methods: We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1 mg/kg, 5 mg/kg and 10 mg/kg/day) or sorafenib (10 mg/kg/day). PAB rats were treated with vehicle, sunitinib (10 mg/kg/day) or sorafenib (10 mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry. Results: Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function. Conclusion: We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.
May 2011
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24 Reads
May 2011
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16 Reads
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4 Citations
May 2011
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21 Reads
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1 Citation
Citations (11)
... It has a long duration of action both in vitro (t ½ > 80 h) and in vivo, and potently inhibits LPSinduced TNFa production in human whole blood (IC 50 1.7 nM) and LPS-induced neutrophilia in Brown Norway rats (intratracheal ED 50 30 µg/kg) [54]. PF-03715455 has further been shown to inhibit the production of various cytokines from U937, lung epithelial and peripheral blood monocytes with IC 50 values in the range 0.3 --12.1 nM [55], and to be effective in a murine model of COPD [56]. At 100 mg/kg intranasal, PF-03715455 substantially reduced tobacco-smoke--induced lung neutrophilia and inflammatory damage to the lungs. ...
- Citing Article
September 2013
European Respiratory Journal
... The overproduction of ROS may lead to inflammation via the activation of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB; Rahman, 2006). In addition, ROS can alter the conformation of proteins, which then may bind to antibodies and generate a false immune response, promoting smooth muscle cell hyperactivity via calcium influx (Tetley, 2005; Kirkham et al., 2011 ). ROS also stimulate TLR2 and TLR4 through MyD88- dependent pathways, inducing cellular damage and elevated levels of DAMPs (Hansel and Barnes, 2009). ...
- Citing Article
May 2012
American Journal of Respiratory and Critical Care Medicine
... As a GC receptor antagonist, Mifepristone (RU486) not only binds all receptors preventing GC binding, but also prevents the activation of the GC receptor inhibiting its nuclear translocation. 36 Delivery of RU486 to cells prior to GC delivery and subsequent transfection, completely eliminated any increase in transgene expression regardless of reporter gene (Figure 4a-c), with expression levels in RU486+GC delivery equal to transgene expression levels in unprimed cells. These results demonstrate that binding of the GC receptor is required for enhanced transfection outcomes. ...
- Citing Conference Paper
April 2009
... Pfizer is also investigating PF-4348235, a compound with subnanomolar affinity for human M 3 receptors (K i 0.8 nM) and potent agonist activity at b 2 receptors (3.7 nM) [102]. In vivo, PF-4348235 also inhibited the bronchoconstriction induced by either Ach or b-alanine neurokinin A, an effect which was not altered by infusion of propranolol [103,104]. Almirall has LAS190792 in preclinical development and AstraZeneca and Chiesi also have dual action compounds in their early pipeline. ...
- Citing Conference Paper
May 2011
... Infusion of propranolol throughout the experiment blocked the effects of salmeterol on ACh-induced bronchoconstriction, whereas both tiotropium and PF-3429281 were unaffected. Data generated in vitro using guinea pig isolated trachea suggest that the duration of action of the b2 component is longer than the M3 one (Patel et al., 2010). In an anaesthetized dog model of bronchoconstriction, PF-3429281 had an equivalent potency to ipratropium bromide and a superior therapeutic index and duration of action compared to salmeterol (Wright et al., 2010). ...
- Citing Conference Paper
May 2011
... Pfizer is also investigating PF-4348235, a compound with subnanomolar affinity for human M 3 receptors (K i 0.8 nM) and potent agonist activity at b 2 receptors (3.7 nM) [102]. In vivo, PF-4348235 also inhibited the bronchoconstriction induced by either Ach or b-alanine neurokinin A, an effect which was not altered by infusion of propranolol [103,104]. Almirall has LAS190792 in preclinical development and AstraZeneca and Chiesi also have dual action compounds in their early pipeline. ...
- Citing Conference Paper
May 2011
... A few of these inhaled PDE4 inhibitors have advanced into clinical trials for treatment of asthma and COPD. The inhaled PDE4 inhibitors have been previously reviewed (Yeadon et al., 2010;Tenor et al., 2011;Matera et al., 2014;Mulhall et al., 2015;Spina and Page, 2017). This review is a brief update summarizing the chemical structure, pharmacological, and clinical details of inhaled PDE4 inhibitors. ...
- Citing Article
September 2010
Progress in Respiratory Research
... Lipopolysaccharides (LPS), one of the molecules synthesized by pathogenic bacteria in the intestine, can trigger inflammatory responses in the host (Ngkelo et al., 2012). LPS can travel from the intestine to the blood and cause systemic inflammation (Tulkens et al., 2020). ...
- Citing Article
- Full-text available
January 2012
Journal of Inflammation
... Recent research has demonstrated other autoimmunity components associated with COPD. The serum antibody titer against carbonyl-modified proteins, resulting from the oxidation of various amino acid residues, is significantly elevated in COPD patients (GOLD 3) compared with healthy controls, which could lead to an autoimmune response (9). B cell-activating factor of tumor necrosis factor family (BAFF) overexpression is associated with autoimmune diseases, and it was found to be up-regulated in B cells in pulmonary lymphoid follicles (LFs), in blood and bronchoalveolar lavage samples from COPD patients (10). ...
- Citing Article
- Full-text available
October 2011
American Journal of Respiratory and Critical Care Medicine
... GDC-A was engineered using inhaled-by-design principles to target the drug more effectively within the lungs, while minimizing off-target systemic effects. The features of the drug substance needed for optimal targeting to the lungs are opposite to those required for drugs administered orally (Yeadon, 2011). For an oral tablet, the goal is to maximize oral bioavailability and maintain drug concentrations in the systemic circulation for as long as possible. ...
- Citing Article
October 2011