Impaired host defense to Klebsiella pneumoniae infection in mice treated with the PDE4 inhibitor rolipram.
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-alpha (TNF-alpha) 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-alpha 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-alpha 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.
Immunopharmacology Laboratory, Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627-Pampulha, 31270-901 Belo Horizonte, Brazil.
A C
AC
Soares
D G
DG
Souza
V
V
Pinho
A T
AT
Vieira
M M
MM
Barsante
J R
JR
Nicoli
M
M
Teixeira
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007710:Klebsiella Infections / Q000276:immunology / Q000378:metabolism*; D007711:Klebsiella pneumoniae / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D020889:Rolipram / Q000494:pharmacology*
D016207:Cytokines; D004791:Enzyme Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram