Cytokines as Targets in Chronic Obstructive Pulmonary Disease
K. F. Chung
Affiliation: Experimental Studies Unit,National Heart&Lung Institute, Imperial College, Dovehouse St, LondonSW3 6LY, UK.
Chronic obstructive pulmonary disease [COPD] is characterised by airflow limitation of peripheral airways that is not fully reversible and progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. There is also intense airway wall remodelling and evidence of systemic inflammation. Increased interleukin [IL]-6, IL-1β, tumor necrosis factor-α [TNF-α], GRO-α, MCP-1 and IL-8 levels are measured in sputum, with further increases during exacerbations. The bronchiolar epithelium over-expresses MCP-1, MIP-1α and IL-8. IL-8 can account for sputum neutrophil chemotactic activity. TNFα and IL-1β stimulate macrophages to produce matrix metalloproteinase- 9 [MMP-9], and bronchial epithelial cells to produce extracellular matrix glycoproteins. Increased expression of transforming growth factor-β [TGFβ) and epidermal growth factor [EGF] occurs in the epithelium and submucosal cells; gene array studies reveal an excess of TGFβ1, CTGF and PDGFRA in COPD. TGFβ and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression. Anti-cytokine therapy could be in the form of soluble receptors or by neutralising antibodies, small compounds blocking cytokine receptors or incomplete and non-activating cytokines, inhibitors of protein activation and inhibitors of signal transduction and transcription such as via inhibition of mitogen-activated protein kinases [MAPK] and of transcription factor, nuclear factor κB. Anti-IL-8 therapy has been tried with little effect on COPD, and current trials are on-going with TNF-α inhibitors. Other treatments such as phosphodiesterase 4 inhibitors have anti-cytokine effects that may underlie their beneficial effects in COPD.
Keywords: Chronic obstructive pulmonary disease, cytokines, interleukin-1β, tumour necrosis factor-α, transforming growth factor-β, epidermal growth factor, interleukin-8
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