Mike Yeadon's research while affiliated with Imperial College London and other places

Publications (20)

Article
Full-text available
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 o...
Article
Full-text available
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" prote...
Article
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) remode...
Article
Phosphodiesterase type 4 (PDE4) inhibition remains a seductive target for new drugs for treatment of a variety of diseases. In many of the cells thought to play a central role in the pathology and symptomatology of asthma, chronic obstructive pulmonary disease and allergic rhinitis, increases in the level of intracellular cAMP leads to suppression...
Article
Full-text available
Adenosine A(2A) receptor agonists may be important regulators of inflammation. Such conclusions have come from studies demonstrating that, (i) adenosine A(2A) agonists exhibit anti-inflammatory properties in vitro and in vivo, (ii) selective A(2A) antagonists enhance inflammation in vivo and, (iii) knock outs of this receptor aggravate inflammation...

Citations

... 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. ...
... 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). ...
... 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. ...
... 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. ...
... 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). ...
... 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. ...
... 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. ...
... This may be explained by the ability of these genera of bacteria to produce LPS and promote inflammation via toll-like receptor (TLR) or inflammasome cascades. [32][33][34] We also found a significant correlation between hepatic venous levels of IL-8 and Ruminococcus. In earlier studies, IL-8 receptor CXCR1 was found to be associated with hepatic inflammation, 35 while Ruminococcus has been linked to liver fibrosis. ...
... Oxidative stress can produce protein carbonylation ("carbonyl stress"), which results in the formation of neoantigens against which autoantibodies can form. There is evidence of autoantibodies against carbonyl-modified proteins in COPD patients, which may be complement-fixing and hence contribute to lung parenchymal damage [44]. ...
... 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. ...