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Oxidative stress occurs when reactive oxygen species (ROS) are produced in excess of the antioxidant defence mechanisms and result in harmful effects, including damage to lipids, proteins and DNA. There is increasing evidence that oxidative stress is an important feature in inflammatory airway diseases, including chronic obstructive pulmonary disease (COPD) [, , ]. This area of research has received new impetus by the recent development of several techniques for measuring oxidative stress in the lungs []. However, the pathophysiological role of oxidative stress in airway diseases will only be firmly established when more potent antioxidants become available for clinical use.
<b>Rationale:</b> Pulmonary fibroblasts proliferate and produce extracellular matrix to repair the lung environment. In COPD, parenchymal-derived fibroblasts exhibit reduced proliferation possibly due to growth arrest via cellular senescence. However, the proliferative capabilities of small airway fibroblasts (SAF) are unknown. <b>Aim:</b> To investigate the proliferative capacity of SAF from COPD patients and age-matched non-smoker and smoker controls. <b>Method:</b> SAF were isolated from surgical lung resections from non-smokers, smokers and COPD patients. iCELLigence technology and propidium iodide (PI) staining were used to investigate SAF proliferation and phase of cell cycle arrest, respectively. Senescence was identified using Senescence Associated-β-Galactosidase (SA-β-Gal) staining and potential mechanisms studied by qPCR for gene expression of cell cycle checkpoints. <b>Results:</b> SAF from COPD patients showed significantly reduced proliferation rate compared to non-smokers and smokers (p<0.05 and p<0.001 respectively, n=4-7). PI staining suggested more COPD SAF were G1 phase arrested compared to NS SAF (p<0.01), and fewer in G2 (p<0.05, n=4-5). Senescence could be driving this, since more COPD SAF stained positive for SA-β-Gal compared to non-smokers (21% vs 11%, p<0.05, n=4-5). However, there was no change in p21, p16, p27 or CDK4 expression; but a trend in increased p15 (+116%, p=0.28) and p53 (+44%, p<0.05, n=7-11) expression. <b>Conclusion:</b> These data suggest COPD SAF display reduced proliferation compared to controls, arresting in G1 phase. This may be due to senescence, induced by p15 and p53. Further investigation into cell cycle arrest mechanisms in COPD may provide alternative targets for therapeutics.
No abstract is provided for this article.
Cross-section classification is a fundamental aspect of structural metallic design. This paper proposes slenderness parameters and a system of cross-section classification limits for elliptical hollow sections, developed on the basis of laboratory tests and numerical simulations. Four classes of cross-sections, namely Class 1 to 4 have been defined with limiting slenderness values. For the special case of elliptical hollow sections with an aspect ratio of unity, consistency with the slenderness limits for circular hollow sections in Eurocode 3 has been achieved. The proposed system of cross-section classification underpins the development of further design guidance for elliptical hollow sections.
As the pathophysiology of acute coronary syndromes (ACS) has been clarified in recent years, major advances have been made in the management of the disease. The magnitude of the thrombotic process triggered upon plaque disruption is modulated by different elements that determine plaque and blood thrombogenicity. Thrombin plays a pivotal role in ACS because of its extensive procoagulant and prothrombotic actions. Antithrombotic therapy and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI), have become central in the management of ACS. A number of options for anticoagulation regimens are available. However, many agents currently used have significant limitations, recognition of which has led to the development, evaluation and clinical introduction of the class of thrombin-specific anticoagulant agents. This paper will discuss the clinical development of the direct thrombin inhibitor bivalirudin as the core anticoagulant in the contemporary PCI setting and the implications for its use in ACS.
No abstract is provided for this article.
Many neuropeptides have recently been identified in airways, with potent effects on airway caliber, blood flow, and secretions, raising the possibility that they are involved in airway diseases, such as asthma. Neuropeptides in sensory nerves induce inflammatory effects and may also contribute to the pathology of asthma. These findings may have important therapeutic implications.
Mucus hypersecretion is a prominent feature of chronic inflammatory diseases of the airways, including asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, but little is known about the effects of current therapies for airway disease because of the difficulties in quantifying mucus hypersecretion in clinical studies. Anticholinergics may reduce mucus hypersecretion, whereas β2 agonists and mucolytics have little obvious effect. Corticosteroids are highly effective in inhibiting mucus hypersecretion in asthma by suppressing the underlying inflammatory process, but are ineffective in COPD and cystic fibrosis. Novel approaches in the future may include inhibition of sensory neuropeptides by tachykinin antagonists, modulators of sensory nerves or K+ channel openers. Inhibition of Th2 cytokines (interleukin [IL]4, IL9, IL13) may also be effective in asthma. In COPD inhibition of neutrophil-derived proteases by small molecule inhibitors or inhibiting neutrophilic inflammation in the airways by reducing neutrophil chemotaxis may also be effective strategies. Several novel targets involved in mucus hypersecretion have recently been identified, including epidermal growth factor receptors, MARCKs, Ca2+-activated Cl− channels and mitogen-activated protein kinases. However, the clinical benefits from inhibiting mucus hypersecretion are still not certain, casting some doubts on this therapeutic approach.
Extract: Asthma has now become one of the most common chronic diseases in industrialized countries and is predicted to increase throughout the world over the next decade, particularly in developing countries. Previously, asthma was viewed as a disease of bronchoconstriction (closing of the airways) and treated predominantly with bronchodilators (drugs which open up the airways), but more recently it has been seen as an inflammatory disease of the airways and the mainstay of modern management is treatment with inhaled corticosteroids. The airway inflammation in asthma is characterized by activation of mast cells, infiltration of eosinophils and increased activated T helper 2 (Th2) lymphocytes. Inhaled corticosteroids have revolutionized the management of asthma, leading to better control of asthma, reduced hospital admissions and a reduced mortality. Corticosteroids and long-acting beta2-agonists (salmeterol and formoterol) in fixed combination inhalers are currently the most effective therapy for asthma and are increasingly used in all patients with persistent symptoms.
