Article

Targeting the Networks that Underpin Contiguous Immunity in Asthma and Chronic Obstructive Pulmonary Disease

Academic Unit of Respiratory Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, L Floor, Royal Hallamshire Hospital, Sheffield, UK.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 03/2007; 175(4):306-11. DOI: 10.1164/rccm.200606-777PP
Source: PubMed

ABSTRACT

Recent advances in the field of innate immunity have driven an important reappraisal of the role of these processes in airway disease. Various strands of evidence indicate that resident cells, such as macrophages and epithelial cells, have central importance in the initiation of inflammation. Macrophage activation has the potential to regulate not just typical aspects of innate immunity but also, via a variety of intricate cell-cell networks, adaptive responses and responses characterized by Th2-type cytokine production. In turn, such adaptive immune processes modify the phenotype and function of the innate immune system. Cooperative responses between monocytic cells and tissue cells are likely to be crucial to the generation of effective inflammatory responses, and a realization of the importance of these networks is providing a new way of identifying antiinflammatory therapies. Importantly, the repeated cycles of allergic and nonallergic inflammation that comprise chronic human airway disease are not necessarily well described by current terminology, and we propose and describe a concept of contiguous immunity, in which continual bidirectional cross-talk between innate and adaptive immunity describes disease processes more accurately.

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    • "Thus, these results indicated that dexamethasone failed to show a completely anti-inflammatory efficacy, subsequently resulting in reduced corticosteroid sensitivity in mice. Alveolar epithelial cells play an important role in the regulation of immune and inflammatory responses in the lung [34]. As a result we also studied inflammation in A549 epithelial cells in response to CSE. "
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    ABSTRACT: Purpose To investigate the effects of icariin, a major constituent of flavonoids isolated from the herb Epimedium, on cigarette smoke (CS) induced inflammatory responses in vivo and in vitro. Methods In vivo, BALB/c mice were exposed to smoke of 15 cigarettes for 1 h/day, 6 days/week for 3 months and dosed with icariin (25, 50 and 100 mg/kg) or dexamethasone (1 mg/kg). In vitro, A549 cells were incubated with icariin (10, 50 and 100 µM) followed by treatments with CSE (2.5%). Results We found that icariin significantly protected pulmonary function and attenuated CS-induced inflammatory response by decreasing inflammatory cells and production of TNF-α, IL-8 and MMP-9 in both the serum and BALF of CS-exposed mice and decreasing production of TNF-α and IL-8 in the supernatant of CSE-exposed A549 cells. Icariin also showed properties in inhibiting the phosphorylation of NF-κB p65 protein and blocking the degradation of IΚB-α protein. Further studies revealed that icariin administration markedly restore CS-reduced GR protein and mRNA expression, which might subsequently contribute to the attenuation of CS-induced respiratory inflammatory response. Conclusion Together these results suggest that icariin has anti-inflammatory effects in cigarette smoke induced inflammatory models in vivo and in vitro, possibly achieved by suppressing NF-κB activation and modulating GR protein expression.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Birth cohort studies suggest that there is a greatly increased risk of development of clinical features of asthma in children who suffer wheezing lower respiratory tract infections in early life, notably with rhinovirus and respiratory syncytial virus (RSV), on a background of sensitisation to aeroallergens (Kusel et al., 2007; Jackson et al., 2012; Kusel et al., 2012). The underlying mechanisms involved have not yet been defined, although there is much interest in the cross-talk between innate host defence responses (including the responses of airway epithelial cells) and the adaptive immune response (Sabroe et al., 2007; Holt and Strickland, 2010; Kumar et al., 2011). Birth cohort studies have also established that, whereas wheezing is common in early childhood, this is usually transient and resolves spontaneously (Taussig et al., 2003). "
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    ABSTRACT: Development of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but may involve epigenetic changes. To investigate this, we employed a novel mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or down-regulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNA exhibited marked up- or down-regulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNA included genes involved in immune/inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-γ, the latter increasing following chronic challenge. We conclude that in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation may play a role in the development of childhood asthma.
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    • " culture . Thus , the ALI culture technique may produce a barrier that is not so easily damaged and that contain several of the paracellular path - ways , and associated junction molecules , that are important for the transepithelial migration of leucocytes . The use of ALI epithelial cultures has been considered for several spe - cific purposes ( Sabroe et al . , 2007 ; Rothen - Rutishauser et al . , 2008 ; Kesimer et al . , 2009 ) , but their utility in studies of non - injurious egression of cells has not received much attention . ALI epithelial co - cultures with leucocytes should be helpful for studies of the pharmacology of transepithelial elimination of leucocytes . Kato et al . ( 2002 ) have d"
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    ABSTRACT: Removal of disease-driving inflammatory leucocytes is central to resolution of inflammation. The current pharmacological dogma teaches leucocyte elimination through apoptosis followed by phagocytosis. However, actual resolving roles of apoptotic-phagocytic processes have been difficult to demonstrate in the major diseases that are characterized by mucosal tissue inflammation. Many current in vivo observations rather demonstrate that leucocyte elimination occurs by transepithelial locomotion. Findings in diseased gut and bladder mucosae support this notion. Respiratory disease data are particularly compelling. Eosinophils and neutrophils abound in sputum and tracheal aspirates during treatment-induced recovery from severe asthma. Prolonged sputum neutrophilia, along with clinical improvement, follows upon smoking cessation in COPD. Eosinophils, neutrophils, lymphocytes, mast cells and dendritic cells also move in large numbers into the bronchial lumen at spontaneous inflammation resolution following allergen challenge in allergic rhinitis and asthma. A corresponding reduction of infiltrated cells in the bronchial mucosal tissue demonstrates efficiency of the transepithelial elimination pathway. Underscoring its operational role, drugs impeding transepithelial elimination of leucocytes aggravate mucosal/parenchymal inflammation. Hence, relying on lumen cell data alone can lead to paradoxical conclusions regarding anti-inflammatory drug efficacy. Conversely, drugs promoting non-injurious transepithelial elimination of leucocytes could resolve mucosal inflammatory diseases.
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