"Neuroimmune Interactions in the Lung." American Review of Respiratory Disease, 145(5), pp. 1230–1235
Cytokines play a critical role in orchestrating and perpetuating inflammation in allergic diseases and several specific cytokine inhibitors now in development for the treatment of asthma and other allergic diseases. The effects of inhibiting the T helper 2 cytokines interleukin-5, interleukin-13 and interleukin-9 are discussed, together with inhibition of tumor necrosis factor-alpha. Inhibitory cytokines, such as interleukin-10, interferons and interleukin-12, are also being considered in the treatment of allergic diseases.
Of the five cloned muscarinic receptor subtypes, human airways express only three receptor subtypes (M1, M2 and M3) and these subtypes are differentially distributed in the airways [1]. M1-receptors are localised to alveolar walls, parasympathetic ganglia and submucosal glands, whereas M3-receptors are predominant in airway smooth muscle and submucosal glands. In contrast, M2-receptors are localised to airway smooth muscle of small airways, although there is little evidence that these receptors play an important functional role in the regulation of airway smooth muscle tone, at least in human airways. Functional studies suggest that M2-receptors play an important role in regulating the release of acetylcholine from parasympathetic nerves in the airways. M2-receptors which inhibit cholinergic neural contraction have been demonstrated in functional studies of human airways in vitro and pre-junctional M2-receptors inhibit the release of acetylcholine in animal and human airways [2,4]. There is considerable evidence that M2-receptors may be dysfunctional in patients with asthma and this might contribute to exaggerated cholinergic reflex bronchoconstriction in asthma [4]. There are several possible mechanisms that might result in dysfunction of M2-receptors, including viral infections, eosinophil basic proteins and oxidants. The inflammatory process may also result in impaired function of M2-receptors.
Background The incidence and prognostic impact of major bleeding (MB) after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for left main coronary artery disease (LMCAD) are unknown. Objectives The goal of this study was to investigate the rates and outcomes of MB after LMCAD revascularization. Methods In the EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, 1,905 patients with unprotected LMCAD were randomized to undergo PCI (n = 948) or CABG (n = 957) and followed up for 5 years. MB was defined as TIMI major or minor bleeding, BARC (Bleeding Academic Research Consortium) types 3 to 5 bleeding, or any overt bleeding requiring blood transfusion. The association between MB and subsequent mortality was assessed in time-adjusted Cox regression models. Results At 5 years, 217 patients (11.4%) had at least 1 MB event. Rates of 5-year MB were 7.9% after PCI vs 14.8% after CABG (OR: 0.48; 95% CI: 0.36-0.65; P < 0.0001). However, in-hospital MB was lower after PCI (3.8% vs 13.5%; OR: 0.25; 95% CI: 0.17-0.37), whereas postdischarge MB was lower after CABG (4.5% vs 2.0%; OR: 2.33; 95% CI: 1.33-3.09; P interaction < 0.0001). All 41 postdischarge MB events after PCI occurred in patients receiving dual antiplatelet therapy. MB events within 5 years were associated with a higher subsequent risk of all-cause mortality (adjusted HR: 2.71; 95% CI: 1.95-3.77; P < 0.0001), whether in-hospital or postdischarge (P interaction = 1.00) and after both PCI and CABG (P interaction = 0.95), driven both by increased cardiovascular and non-cardiovascular mortality. Conclusions In the EXCEL trial, CABG resulted in higher 5-year rates of all MB and in-hospital MB, although postdischarge MB was more frequent after PCI. MB after both procedures was associated with increased cardiovascular and noncardiovascular mortality within 5 years. (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization [EXCEL]; NCT01205776)
Nitric oxide (NO) may play an important role in regulating airway function and in the pathophysiology of inflammatory airway diseases. Endothelium-derived NO may be important in regulating airway blood flow and, indirectly, plasma exudation. NO is the neurotransmitter of bronchodilator nerves in human airways and counteracts the bronchoconstriction due to cholinergic neural mechanisms. NO synthase (iNOS) is expressed in human epithelial cells in response to pro-inflammatory cytokines and oxidants, probably via activation of the transcription factor nuclear factor kappa B (NF-KB). There is increased expression of iNOS in the epithelium of asthmatic patients and in lung macrophages in bronchiectasis. This may account for the increased concentration of NO in the exhaled air of patients with inflammatory airways disease. Increased NO production in the airways may result in hyperaemia, plasma exudation, mucus secretion and indirectly in increased proliferation of Th2 lymphocytes responsible for eosinophilic inflammation. Glucocorticoids inhibit the induction of iNOS in epithelial cells and reduce the elevated exhaled NO to normal values. Selective inhibitors of iNOS may be useful in the treatment of inflammatory airway diseases, such as asthma, in the future.
Abstract Information available in the literature concerning the composition of lipids in wheat germ and in wheat germ oil is critically reviewed. After a brief introduction to the botanical and technological aspects of wheat germ, the yield of oil and its physico‐chemical properties are described followed by the composition of fatty acids, acyl lipids and non‐saponifiable components. The importance of distinguishing between dissected germ and commercial wheat germ and between germ oil and germ lipids is emphasised. The triglycerides account for the major part of the fatty acids, of which linoleic acid is the principal component, and the content of free fatty acids depends on the rancidity of the germ and also on possible post‐extraction processing in the case of commercial oil. Polar lipids consist mainly of phospholipids and available information suggests that glycolipids are present only at very low concentration and that galactosyl glycerides may be absent from the embryo of the quiescent wheat grain. Most reports of tocopherol composition concern wheat germ oil and there is less information about the tocopherols of dissected wheat germ. α‐ and β‐tocopherols are found in wheat germ but tocotrienols are probably absent from dissected germ and only occur in commercial germ as a result of bran and endosperm contamination. Wheat germ oil exhibits a range of sterols. 4‐methyl sterols and triterpenoid alcohols, and β‐sitosterol and campesterol are the major components. The hydrocarbon composition of wheat germ oil has been reported but the significance of the results is uncertain. Flavonoid pigments, xanthophyll and xanthophyll esters have been shown to be present in wheat germ. Most of the studies of the non‐saponifiable fraction were based on germ oil and commercial wheat germ and little is known of the nature of this fraction in dissected wheat germ.
Platelet-activating factor (PAF) is a highly potent lipid mediator which has been implicated in inflammation and particularly in allergic inflammation, including asthma.1–3 It is released from many of the inflammatory cells which are known to be activated in asthma and has many inflammatory effects on airways. This has suggested that PAF antagonists might be useful in the therapy of asthma and other pulmonary inflammatory diseases.45 The purpose of this chapter is to review the potential role of PAF in inflammatory diseases of the airways, and to discuss the effects of recently developed PAF receptor antagonists.
