Cytokines as targets in chronic obstructive pulmonary disease

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-1 beta, tumor necrosis factor-alpha [TNF-alpha], GRO-alpha, MCP-1 and IL-8 levels are measured in sputum, with further increases during exacerbations. The bronchiolar epithelium over-expresses MCP-1, MIP-1 alpha and IL-8. IL-8 can account for sputum neutrophil chemotactic activity. TNF alpha and IL-1 beta stimulate macrophages to produce matrix metalloproteinase-9 [MMP-9], and bronchial epithelial cells to produce extracellular matrix glycoproteins. Increased expression of transforming growth factor-P [TGF beta) and epidermal growth factor [EGF] occurs in the epithelium and submucosal cells; gene array studies reveal an excess of TGF beta 1, CTGF and PDGFRA in COPD. TGF beta 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 kappa B. Anti-IL-8 therapy has been tried with little effect on COPI), and current trials are on-going with TNF-alpha inhibitors. Other treatments such as phosphodiesterase 4 inhibitors have anti-cytokine effects that may underlie their beneficial effects in COPD.