Identifying targets for COPD treatment through gene expression analyses

Abstract

Despite the status of chronic obstructive pulmonary disease (COPD) as a major global health problem, no currently available therapies can limit COPD progression. Therefore, an urgent need exists for the development of new and effective treatments for COPD. An improved understanding in the molecular pathogenesis of COPD can potentially identify molecular targets to facilitate the development of new therapeutic modalities. Among the best approaches for understanding the molecular basis of COPD include gene expression profiling techniques, such as serial analysis of gene expression or microarrays. Using these methods, recent studies have mapped comparative gene expression profiles of lung tissues from patients with different stages of COPD relative to healthy smokers or non-smokers. Such studies have revealed a number of differentially-regulated genes associated with COPD progression, which include genes involved in the regulation of inflammation, extracellular matrix, cytokines, chemokines, apoptosis, and stress responses. These studies have shed new light on the molecular mechanisms of COPD, and suggest novel targets for clinical treatments.

Figure 1

Molecular Mechanisms in COPD pathogenesis and potential therapeutic targets. A number of signaling pathway components have been identified which regulate apoptosis, inflammation and fibrosis potentially associated with COPD pathogenesis. Many of these have been identified as possible targets for therapeutic intervention using small molecule inhibitors or antagonists. Abbreviations: COPD, chronic obstructive pulmonary disease; ECM, extracellular matrix; Egr-1, early growth response-1; HDAC, histone deacetylase; HO-1, heme oxygenase-1; Keap-1, Kelch-like ECH associating protein-1; MMP, matrix metalloproteinase; NF-κB, nuclear factor-kappa-B; Nrf-2, nuclear factor-E2-related factor-2; p38 MAPK, p38 mitogen-activated protein kinase; ROS, reactive oxygen species; TGFβ1, transforming growth factor-B1.

Figure 2

Epigenetic factors involved in the regulation of inflammation. Abbreviations: HDAC, Histone deacetylase; I-κB, Inhibitor of NF-κB; IKK, I-κB kinase; MKKK, mitogen-activated protein kinase-3; MKK3/6, mitogen-activated protein kinase kinase-3/6; NF-κB, nuclear factor-kappa-B; p-I-κB, phospho-I-κB; p38 MAPK, p38 mitogen-activated protein kinase; ROS, reactive oxygen species.