Ellipticine mg It has been demonstrated that a significant i

It has been demonstrated that a significant increase in the area of airway smooth muscle occurs in chronic asthmatic inflammation. A growing body of evidence suggests that CysLTs may have a role in airway remodeling. Chronic overproduction of relatively low levels of CysLTs by mast Ellipticine mg or eosinophils may have subtle effects on structural cells of the airways, leading to bronchial hyperresponsiveness and possibly influencing pathways involved in airway wall remodeling. Evidence suggests that LTD4 can potentiate the induction of DNA synthesis and proliferation induced by the mitogen epidermal growth factor in human BSMC. In a mouse model, CysLTs appeared to be responsible for the increase in airway smooth muscle after repeated allergen challenge. The allergen-induced increases in airway smooth muscle were significantly reduced by treatment with a CysLT1R antagonist. In Brown Norway rats sensitized to ovalbumin, CysLTs induced airway smooth muscle and epithelial cell DNA synthesis as well as airway smooth muscle thickening after repeated allergen exposure. Studies also provide evidence that cytokines such as TGF-β, a TH3-type cytokine, may also play a role in airway remodeling. Data obtained by Cohen et al suggest that TGF-β1 can induce human BSMC proliferation by increasing the expression of IGFBP-3. Hence, the mitogenic action of TGF-β1 could be relevant in the hyperplastic nature of BSMC in chronic asthma. In normal human lung, the bronchial epithelial compartment appears to be the main source of TGF-β. The expression levels of this cytokine are dramatically increased in asthma and several other lung disorders.27, 29 The TH2-type cytokine IL-13 is also overexpressed in asthmatic patients. Interestingly, data suggest that both IL-4 and IL-13 cause inflammation, but only IL-13 causes subepithelial fibrosis. The tissue remodeling induced by IL-13 is mediated, to a great extent, by the production and activation of TGF-β1 in lung macrophages.12, 31 Data also support the role of IL-13 in airway remodeling by modulating the production of TGF-β2 from human bronchial epithelial cells. The release of TGF-β2 can activate the underlying myofibroblasts to secrete matrix proteins and smooth muscle mitogens to propagate remodeling changes into the submucosa. Interestingly, IFN-γ reduced the release of TGF-β2 induced by IL-13 in human bronchial epithelial cells.32, 33 Although IL-4 and IL-13 share a common receptor complex of IL-4Ra-IL-13RaI in airway smooth muscle cells and common signaling pathways involving STAT6 and ERK mitogen-activated protein kinase activation,34, 35 IL-4 neither upregulated CysLT1 receptor expression nor synergized with LTD4 for BSMC proliferation, in contrast to IL-13. A differential effect of IL-4 and IL-13 was also reported by Laporte et al in airway smooth muscle cells in which IL-13 but not IL-4 reduced β-adrenergic responsiveness. Conversely, Pype et al found IL-4 to inhibit IL-1b–induced MCP-1 and MCP-2 expression in BSMC, whereas IL-13 did not. Interestingly, gene chip experiments show a distinct although partially overlapping array of genes expressed by BSMC in response to IL-4 and IL-13.