Tumor necrosis factor alpha (TNF-α) autoregulates its expression and induces adhesion molecule expression in asthma.

Subjects with mild asthma underwent repeated low-dose allergen exposure and bronchial biopsies were examined for the expression of TNF-α and adhesion molecules. Bronchial biopsies from moderately severe asthmatics were then tested in an explant culture system to assess the effect of Der p and CDP-870, a TNF-α blocking pegylated-antibody Fab, on expression of TNF-α and adhesion molecules. Low-dose allergen challenge significantly upregulated sub-mucosal mast cells, TNF-α(+) cells, and VCAM. When bronchial explants were exposed to Der p and CDP 870 for 24h, CDP 870 caused a significant reduction in TNF-α release both at baseline and following stimulation with Der p allergen. The bronchial biopsies showed significant upregulation of TNF-α positive cells and ICAM-1 following exposure to Der p (p=0.03) and this was reduced in the presence of CDP-870. So, allergen exposure up-regulates TNF-α expression in asthma and down-stream targets, including adhesion molecules that contribute to airway inflammation.

Is PDE4 too difficult a drug target?

The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.