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-1beta, 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-1alpha and IL-8. IL-8 can account for sputum neutrophil chemotactic activity. TNFalpha and IL-1beta stimulate macrophages to produce matrix metalloproteinase-9 [MMP-9], and bronchial epithelial cells to produce extracellular matrix glycoproteins. Increased expression of transforming growth factor-beta [TGFbeta) and epidermal growth factor [EGF] occurs in the epithelium and submucosal cells; gene array studies reveal an excess of TGFbeta1, CTGF and PDGFRA in COPD. TGFbeta 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 kappaB. Anti-IL-8 therapy has been tried with little effect on COPD, 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.
Chung
K F
KF
National Heart & Lung Institute, Imperial College & Royal Brompton Hospital, London SW3, UK. f.chung@imperial.ac.uk
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D010726:Phosphodiesterase Inhibitors; D018121:Receptors, Cytokine