Eosinophil infiltration of the mucosa is a feature of asthmatic airways. Their adhesion to bronchial epithelial cells has been proposed to lead to the generation of inflammation mediators which may contribute to asthma pathology. Bronchial epithelial cells (BEAS-2B cell line) and peripheral blood eosinophils were cultured alone or in combination and the production of an inflammatory cytokine, IL-6, was measured. IL-6 was produced principally by epithelial cells and the production was enhanced more than 10-fold in the presence of eosinophils. Significant augmentation of epithelial IL-6 production persisted even when eosinophils were fixed with paraformaldehyde. The eosinophil-induced IL-6 production was extensively inhibited by inhibitors of p38 mitogen-activated protein (MAP) kinase or nuclear factor ??B (NF??B). (more…)

Airway remodelling is considered to be of major importance in the pathology of asthma, with subepithelial basement membrane thickening in particular being indicative of early development of the disease and characteristic of its progression. Airway fibroblasts are central cells in the processes of remodelling: increased deposition of fibroblast-derived connective tissue proteins and differentiation of fibroblasts into contractile myofibroblasts are consistent observations in morphological studies of moderate to severe asthmatic airways. The secretory function of fibroblasts is under the control of locally produced growth factors such as vascular endothelial cell growth factor (VEGF, see below) and platelet-derived growth factor (PDGF). (more…)

A role for Leukotriene B4 in the induction of airway hyper-responsiveness was explored through the use of transgenic mice deficient in the BLT1 receptor for LTB4 . Ovalbumin challenge of sensitized wild-type mice resulted in the usual features of experimental asthma, including goblet cell hyperplasia, hyper-responsiveness to inhaled methacholine and elevated BAL fluid concentrations of the Th2 cytokine IL-13. In contrast, BLT1 –/– mice (i.e. genetically modified mice lacking the gene coding for the BLT1 receptor) exhibited significantly lower responses. BLT1 –/– mice also exhibited lower numbers of IL-13-positive T lymphocytes of both the helper (CD4 T Cells) and cytotoxic/suppressor (CD8 + ) types. (more…)

Regulatory T cells Treg (picture above) is the existence of suppressor cells, which limit ongoing immune responses and prevent autoimmune disease, was postulated over 30 years ago. The recent phenotypic and functional characterization of these cells has led to a resurgence of interest in their therapeutic application in a number of immune-mediated diseases. Two broad subsets of CD3+CD4+ suppressive or Treg cells have been described: constitutive or naturally occurring versus adaptive or inducible Treg. (more…)

Vascular Endothelial Growth Factor (VEGF), originally described as a vascular permeability factor generating tissue oedema, has been found to exert a range of angiogenic actions, including epithelial cell proliferation, blood vessel formation and endothelial cell survival. Elevated levels of Vascular Endothelial Growth Factor have been detected in bronchial tissues and secretions of asthmatic bronchial individuals, raising questions regarding its possible pathogenetic role in asthma. Using transgenic mice in which local over expression of VEGF could be induced in the lungs by administration of a tetracycline antibiotic demonstrated induction of an asthma-like phenotype with airway inflammation and oedema, hyper-responsiveness and remodelling (airway, parenchymal and vascular). Antigen-induced airway inflammation was accompanied by VEGF production by epithelial cells and TH2 cells, with production by Th1 cells markedly lower. (more…)

Airway hyper-responsiveness in asthma may involve smooth muscle growth, a manifestation of airway remodelling. The involvement of inflammatory cells in the induction of airway smooth muscle growth was studied in vivo and ex vivo in a brown Norway rat model of asthma. Transfer of CD4 + T lymphocytes from ovalbuminsensitized animals induced an increase in airway smooth muscle mass in naive animals upon repeated ovalbumin challenge. Ex vivo, coculture of antigen-stimulated CD4 + T cells and airway smooth muscle cells led to myocyte proliferation and prolonged T-cell survival. (more…)

Contact of pathogens with the innate immune system will most frequently occur at epithelia, and the biology of the airway epithelium is of considerable importance in asthma. Airway epithelia express a range of innate immune receptors, allowing them to function as a line of first response to pathogens: their ability to detect and respond to pathogens must clearly be substantial, given that they form the main target for most respiratory viruses.

There are also potentially close relationships between epithelial cells and other cells of the innate immune system such as DCs and macrophages.

Cooperative networks that regulate airway inflammation are discussed in more detail below. Interestingly, defective responses to respiratory viruses are evident in epithelial cells from asthmatics, which may be relevant in the pathology of asthma exacerbations, and phenotypic differences in epithelia between asthmatics and normal subjects have been demonstrated. (more…)

Asthma is a continuing problem for healthcare, particularly in the industrialized world. Some 150 million people are estimated to suffer from asthma worldwide, with 5.2 million sufferers in the UK. Hospital admissions for asthma number 69 000 per annum in the UK, including 28 500 children. Approximately 1400 people die from asthma in the UK annually, of whom over 30% are under the age of 65. Asthma costs the UK National Health Service almost £90 million per annum (statistics from Asthma UK, http://www.asthma.org.uk). (more…)