Molecular mechanisms in chronic obstructive pulmonary disease: potential targets for therapy.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.
de Boer
Willem I
WI
Netherlands Asthma Foundation, Leusden, The Netherlands. deboer.pim@hetnet.nl
Alagappan
Vijay K T
VK
Sharma
Hari S
HS
D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008954:Models, Biological; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000628:therapy*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C111835:CCL2 protein, human; C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors