Isozyme-selective cyclic nucleotide phosphodiesterase inhibitors: Biochemistry, pharmacology and therapeutic potential in asthma

Asthma is a disease characterized by airways obstruction resulting from acute constriction of the airways smooth muscle and mucosal inflammation with evident oedema [1]. The inflammation seems to correlate with the severity of the disease and has been linked with hyperresponsiveness to bronchoconstrictor agents [2]. Amongst the prominent features of this bronchial inflammation is an accumulation of inflammatory cell types, particularly eosinophils into the airway tissues and lumen [3, 4]. The numbers of mast cells and sometimes lymphocytes also are increased and, through the release of cytokines, may orchestrate the inflammatory response [5]. A significant proportion of the inflammatory cells may be in their activated, de-granulated state and high levels of cytotoxic proteins such as eosinophil cationic protein (ECP), major basic protein (MBP) and mast cell tryptase can be detected together with albumin, other plasma proteins and a range of putative asthma mediators. The ongoing inflammatory process is fuelled by these cytotoxic proteins and mediators and by extravasated pro-inflammatory proteins found in the inflammatory exudate as a result of leakage from the tracheobronchial microcirculation [6].