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


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.
    PLoS ONE 08/2014; 9(8):e102345. DOI:10.1371/journal.pone.0102345 · 3.23 Impact Factor
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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.
    British Journal of Pharmacology 11/2011; 165(7):2100-9. DOI:10.1111/j.1476-5381.2011.01772.x · 4.84 Impact Factor
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    • "Dendritic cells (DCs) have long been recognised as playing a crucial role in the induction of Th2 polarisation during an immunological response [20]. As is increasingly being understood, the development of allergic immunological responses may be determined by innate host defence responses after initial exposure to pathogens, allergens, or other irritants [21–23]. These lead to local generation of cytokines that stimulate DC, with effects including upregulation of the expression of costimulatory molecules such as CD40, CD80, CD86, Jagged-1, and OX40L, as well as the production of various chemokines (Figure 1) [24–27]. "
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    ABSTRACT: The pathogenesis of allergic asthma in childhood remains poorly understood. Environmental factors which appear to contribute to allergic sensitisation, with development of a Th2-biased immunological response in genetically predisposed individuals, include wheezing lower respiratory viral infections in early life and exposure to airborne environmental pollutants. These may activate pattern recognition receptors and/or cause oxidant injury to airway epithelial cells (AECs). In turn, this may promote Th2 polarisation via a "final common pathway" involving interaction between AEC, dendritic cells, and CD4+ T lymphocytes. Potentially important cytokines produced by AEC include thymic stromal lymphopoietin and interleukin-25. Their role is supported by in vitro studies using human AEC, as well as by experiments in animal models. To date, however, few investigations have employed models of the induction phase of childhood asthma. Further research may help to identify interventions that could reduce the risk of allergic asthma.
    Journal of Allergy 11/2011; 2011(1687-9783):257017. DOI:10.1155/2011/257017
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