Transcription factors in asthma: are transcription factors a new target for asthma therapy?
The essential features of persistent severe asthma include structural changes in the airway wall (remodelling). It is not known whether these are the sequelae of chronic inflammation or indeed its initiators. Several transcription factors have been implicated in the inflammatory process in asthma, including the glucocorticoid receptor (GR), NFkappaB, Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells (NF-AT), cyclic AMP Response Element Binding Protein and more recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome Proliferator-activated Receptor (PPAR) and the bZIP transcription factor, Nrf2. Could a pathological de-regulation of one of these transcription factors explain the broad spectrum of asthma pathology and can their modulation lead to better symptom control? Although some of the transcription factors seem to be valid targets (NFkappaB, Nrf2 or STAT6) or tools (PPARgamma, -alpha and C/EBP-alpha) for new therapeutic approaches, since many transcription factors play a central role in tissue and organ homeostasis, a longterm general suppression or overexpression, would cause severe side effects in other organs. Cell type specific application of decoy or antisense oligonucleotides for NFkappaB, Nrf2 or STAT6, or specific agonists for PPARgamma and -alpha may help to control the inflammatory response in lung epithelial cells and infiltrated immune cells, but additional, unwanted, effects on other resident cells of the lung cannot be excluded and a beneficial effect over known anti-asthma drugs has first to be proven. In order to progress with such novel therapeutic strategies, the only option seems to be to link transcription factor inhibitors/activators to a cell type specific delivery system.
Roth
M
M
Pneumology, Pulmonary Cell Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel Switzerland.
Black
J L
JL
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D050990:GATA3 Transcription Factor / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D050990:GATA3 Transcription Factor; D016328:NF-kappa B; D047495:PPAR gamma; D050800:STAT6 Transcription Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors