Effects of Phosphodiesterase 4 (PDE4) inhibition on host defense

Of the 11 phosphodiesterase subtypes that have been identified, drug development activity has centered on two subtypes, PDE4 and PDE5. PDE4 has been targeted for the treatment of inflammation, and in particular asthma (for a full analysis of asthma therapeutics click here) and chronic obstructive disorder (COPD; emphysema & bronchitis).

Over recent years a number of major advances have been made with respect to PDE4 inhibition. Most of the PDE4 inhibitors so far tested clinically have had unacceptable side effects, particularly nausea and vomiting. The therapeutic margin does appear to be improving since roflumilast, cilomilast and V11294A are all relatively well tolerated; the current challenge is to increase the therapeutic margin of PDE4 inhibitors still further. Recent developments in PDE biology have opened up new channels for the optimization of PDE4 inhibitors (see our upcoming dossier “Phosphodiesterase 4 (PDE4): Pharmaceutical advances and new therapeutic indications”; click here for access). It is known that 4 subtypes of PDE4 (A-D) exist and inhibition of the PDE4D subtype has been associated with nausea. However the recent observation that PDE4D plays a major role in airway hyper-responsiveness suggests that it may not be possible to screen out PDE4D inhibition while maintaining optimal efficacy. Recent research has also revealed a large number of PDE4D splice variants which have tissue specific expression patterns and screening out specific splice forms may allow the optimization of PDE4 inhibitors.

In addition to nausea and vomiting another concern of PDE4 inhibitors relates to possible immunosupression. Neutrophils are known to contribute to the etiology of COPD and PDE4 inhibitors have been shown to limit the infiltration of this cell type into the airway. However neutrophils also represent a key component of host defense against invading pathogens. For example infection of mice with Klebsiella pneumoniae induces a marked increase in the recruitment of neutrophils to the lungs and the production of proinflammatory cytokines and chemokines. The risk therefore is that PDE4 inhibitors when used to inhibit airway inflammation may also increase the risk of airway infection. This is a major concern in patients with already compromised airway function.

Soares et al have recently evaluated this concept. In their BJP paper this group reported that rolipram treatment increased the number of infiltrating neutrophils. This intriguing observation is the opposite of earlier findings from other models demonstrating that rolipram and also cilomilast are able to reduce LPS induced neutrophilia. This suggests that the effect on neutrophil infiltration may be stimulus-specific. Rolipram was also associated with earlier lethality in mice infected with K. pneumoniae and this was related to a decreased capacity to phagocytose bacteria. Whether or not the development of more specific PDE4 inhibitors will be able to avoid this effect remains to be seen, however earlier studies showing that cilomilast failed to reduce bacterial phagocytosis should be noted.

This study is of interest since it suggests that the effects of PDE4 inhibition on neutrophil infiltration and mediator release may very much depend on the stimulus and/or the particular PDE4 inhibitor investigated. Clearly these issues need to be resolved in order to optimize the efficacy of this therapeutic class.

Entry date Wednesday, December 17, 2003

Adapted from Soares et al, Br J Pharmacol. 2003 Nov;140(5):855-62.