Emerging role of MAP kinase pathways as therapeutic targets in COPD

Abstract

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.

Figure 1

The ERK1/2 pathway in airway epithelial cell responses to cigarette smoke. Cigarette smoke exposure has been shown to activate the EGFR in lung epithelial cells. Following dimerization and autophosphorylation of EGFR, a cascade of adaptor molecules and GTPases leads to the recruitment of Raf1 to the plasma membrane and its activation. Raf1 is a MAP kinase kinase kinase, which phosphorylates the MAP kinase kinase MEK1/2. MEK1/2 activation leads to phosphorylation of ERK1/2 MAP kinase, which can translocate to the nucleus and phosphorylate transcription factors which bind to regulatory elements in the promoters of target genes, inducing their expression. Transcription factors that are phosphorylated by ERK1/2 include Sp1, Ets1, AP-1, and ELK-1. Cigarette smoke-mediated activation of this cascade in lung epithelial cells is associated with hyperplasia, MMP-1 expression, MUC5AC expression, and release of EGF ligand. The list of transcription factors and cell responses is not comprehensive.

Figure 2

Cigarette smoke-induced MAP kinase activation and lung injury in COPD. The many chemicals, oxidants, and metabolites of cigarette smoke stimulate MAP kinase cascades within resident and inflammatory cells of the airways and parenchyma. Comparison of MAP kinase activities in the lung tissue of smokers, nonsmokers, and COPD patients has identified significant differences in these cascades. These signaling modules are linked to the indicated cellular processes, many of which are associated with COPD pathogenesis.

Figure 3

Transcriptional regulation by MAP kinases. Activated MAP kinases enter the nucleus and phosphorylate transcription factors such as Ets, AP-1, or ATF2. Transcription factor binding to cis-elements in the promoters of genes enhances transcription. Transcriptional control is also mediated via histone acetyltransferase (HAT) or histone deactylase (HDAC), which generally mediate activation or repression, respectively. Dashed lines indicate that kinase movement across the nuclear membrane occurs in both directions. Phosphorylation of transcription factors can also take place in the cytoplasm.

Figure 4

Model of the potential for MAP kinase inhibitors as COPD treatment strategies. COPD treatment branches are numerous, targeting the most destructive and debilitating processes, including airway inflammation, infection, exacerbations, and airway obstruction. Ongoing research to design drugs that reduce protease activity and oxidant injury will be critical in future COPD treatment. The potential for MAP kinase inhibitors is another promising area of research. These drugs have already demonstrated efficacy in reducing apoptosis, inflammation, cytokine production, fibrosis, and MMP expression. Future studies may result in the inclusion of MAP kinase inhibitors to COPD therapeutic strategies.