Impaired host defense to Klebsiella pneumoniae infection in mice treated with the PDE4 inhibitor rolipram

Abstract

The increase in levels of cAMP in leukocytes by selective inhibitors of PDE4 may result in reduction of inflammation, and may be useful in the treatment of pulmonary inflammatory disorders in humans. Here, we have assessed whether oral treatment with the prototype PDE4 inhibitor, rolipram, interfered with the antibacterial host response following pulmonary infection of mice with Klebsiella pneumoniae. K. pneumoniae infection induced a marked increase in the recruitment of neutrophils to the lungs and the production of proinflammatory cytokines and chemokines, including tumor necrosis factor‐α (TNF‐α) and keratinocyte‐derived chemokine (KC), in bronchoalveolar (BAL) fluid and lung tissue. There were also detectable amounts of interleukin‐10 (IL‐10) and significant lethality. Treatment with rolipram (3–30 mg kg−1) was associated with earlier lethality and significant inhibition of the TNF‐α production. This was associated with enhanced production of IL‐10 in lung tissue of rolipram‐treated animals. Rolipram treatment did not affect KC expression and the recruitment of neutrophils in the lung tissue. Over 70% of neutrophils that migrated into the BAL fluid following K. pneumoniae infection ingested bacteria. Treatment with rolipram inhibited the percentage of neutrophils undergoing phagocytosis of K. pneumoniae in a dose‐dependent manner. Maximal inhibition (62%) occurred at doses equal to or greater than 10 mg kg−1. Thus, treatment of mice with the PDE4 inhibitor rolipram is accompanied by earlier lethality, enhanced bacterial load and decreased capacity of the responding host to produce TNF‐α and of neutrophils to phagocytose bacteria. It will be important to investigate whether the shown ability of PDE4 inhibitors to inhibit neutrophil phagocytosis and control experimental bacterial infection will translate into an inhibition of the ability of neutrophils to deal with infectious microorganisms in the clinical setting. British Journal of Pharmacology (2003) 140, 855–862. doi:

Impact of cigarette smoke exposure on host-bacterial pathogen interactions

“…The PDE4 inhibitor rolipram has also shown to be effective in preventing P. aeruginosa-induced epithelial damage [133]. Also, PDE4 inhibition seems to impair host defense to Klebsiella pneumoniae infection in the pneumonia mouse model [134]. Together, these observations reinforce the notion that caution should be taken to extrapolate the findings obtained with one pathogen to infections caused by different microorganisms.…”

Prostaglandin E2 Inhibits Alveolar Macrophage Phagocytosis through an E-Prostanoid 2 Receptor-Mediated Increase in Intracellular Cyclic AMP

“…PGE 2 has been shown to stimulate AM adenylate cyclase activity (44) and agents that enhance intracellular cAMP production generally inhibit phagocytosis (28,39,45,46). In human peripheral blood monocyte-derived macrophages, for example, PGE 2 suppression of phagocytosis was associated with increased intracellular cAMP generation (28).…”

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

“…Increases in intracellular levels of cAMP can inhibit LT synthesis by a variety of enzymatic mechanisms (90), and commonly used cAMP-elevating drugs such as ␤-adrenergic agonists, theophylline, and phosphodiesterase inhibitors have been reported to inhibit LT synthesis by leukocytes (91). Although its clinical significance is unclear, in vivo cAMP elevation has been reported to impair pulmonary bacterial clearance in an animal model of pneumonia (92). It must be noted, however, that elevated intracellular cAMP can itself suppress antimicrobial functions of phagocytes (93); therefore, the contribution of reduced LT biosynthesis in this context is uncertain.…”