Targeting airway inflammation: PMX464 and the epithelial bulls eye.
Increasing evidence places the epithelial cell at the centre of inflammatory processes in human airways. Crucial to this function and the maintenance of inflammatory homoeostasis is a balanced oxidant-antioxidant status in the airway, in part controlled by thioredoxin and thioredoxin reductase, which together can alter the NF-kappaB pathway. PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, has been investigated in endothelial cells, fibroblasts and colorectal cancer cell lines but in the present issue of the BJP, these investigations were extended to A549 airway epithelial cells. Thioredoxin inhibition was confirmed as was NF-kappaB and IKK suppression but siRNA knockdown of thioredoxin did not alter inflammatory marker expression or activity, suggesting that PMX464 has targets other than thioredoxin. Future consolidation of this evidence will involve concomitant knockdown of thioredoxin reductase, the use of primary airway epithelial cells and, potentially, the employment of three-dimensional (3D) culture systems for both A549 and primary cells.
Sexton
D W
DW
BioMedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK. d.sexton@uea.ac.uk
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D010084:Oxidation-Reduction; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
C515226:AW 464; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052160:Benzothiazoles; D003512:Cyclohexanones