Trends in Pharmacological Sciences
Acquired somatic mutations in the molecular pathogenesis of COPD
Section snippets
Somatic mutations in the pathogenesis of COPD
In this article, we advance the hypothesis that acquired somatic mutations caused by carcinogens present in cigarette smoke are a fundamental contributor to the molecular pathogenesis of COPD. Somatic mutations are sporadic changes in genes or gene regulatory regions that occur spontaneously only rarely, but dramatically increase in frequency in tissues exposed to mutagens [1]. Because somatic mutations do not affect the germ line, they are not heritable, although the susceptibility to
What is COPD?
COPD represents a group of progressive, terminal lung disorders, most often found together, that are characterized by irreversible airflow limitation that makes breathing exhaustingly laborious. COPD encompasses emphysema, the destruction of lung parenchyma that causes impaired gas exchange and small airway collapse, and chronic obstructive bronchitis, a chronic inflammatory cellular process that leads to small airway obstruction 4, 5. In addition, most patients also suffer from chronic
Inherited gene variations versus acquired somatic mutations
COPD risk varies with ethnicity. Approximately 5% of Asian smokers and 15% of Caucasian smokers appear to be susceptible to COPD [5]. Of these, ∼1–3% develop lung cancers. Importantly, impaired lung function is a risk factor for lung cancer [14]. These differences in susceptibility and evidence linking a degree of COPD risk to heritable mutations have led to the search for susceptibility loci in molecular genetic studies. Several candidate chromosome regions have been identified in whole-genome
How might somatic mutations contribute to COPD?
But how would these mutations actually cause or contribute to COPD? It is very unlikely that there is one single consequence of such diverse mutations. However, the cluster of mutations in the genes encoding PTEN, Ras, the EGF receptor and p53 suggests at least one well supported possibility: intensification of nuclear factor κB (NF-κB) and activator protein 1 (AP-1) signaling. One of the most compelling molecular pathways elucidated in COPD pathogenesis is the regulation of the ubiquitous
Implications and perspectives
What then are the implications for pharmacologists trying to find treatments and cures for COPD? First, the presence of somatic mutations will alter the nature of signal transduction in the lung. Targets, such as Akt and ERK kinases, that are not intuitive might emerge among the most attractive prospects as convergence points used by multiple signaling pathways. Chemopreventative strategies for COPD, analogous to recent successes in lung cancer chemoprevention, might be developed for high-risk
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