Emerging role of MAP kinase pathways as therapeutic targets in COPD.
Studies examining the cellular mechanisms of inflammation and protease production in the lung tissue and airways of COPD patients have shed light on the important role of kinase-based signaling cascades. These pathways can be activated by environmental stimuli such as tobacco smoke, and by endogenous signals such as cytokines, growth factors, and inflammation-derived oxidants. The three most widely characterized cascades are those directed by the classical mitogen activated protein (MAP) kinase (ERK1/2), stress activated protein kinase/c-Jun N-terminal protein kinase, and p38 enzymes. These phosphorylation cascades transmit and amplify extracellular, receptor-mediated signals through the cytoplasm of the cell to activate nuclear transcription factors which bind and induce expression of target genes. The result is tight control of diverse cellular events, and rapid responses to external stimuli. However, recent research suggests that constitutive or aberrant activation of MAP kinases contributes to several COPD-associated phenotypes, including mucus overproduction and secretion, inflammation, cytokine expression, apoptosis, T cell activation, matrix metalloproteinase production, and fibrosis. This review explores the biological functions of the MAP kinase pathways in the pathogenesis of COPD, their activation by cigarette smoke, and discusses the potential role of MAP kinase inhibitors in COPD therapy.
Mercer
Becky A
BA
Institute of Human Nutrition, Division of Molecular Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032, USA. bam55@columbia.edu
D'Armiento
Jeanine M
JM
D017209:Apoptosis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008168:Lung / Q000166:cytology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology* / Q000209:etiology; D012907:Smoking / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases