ArticleBritish journal of pharmacology2003
Impaired host defense to Klebsiella pneumoniae infection in mice treated with the PDE4 inhibitor rolipram.
Article in British journal of pharmacology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 30 citations in OpenAlex.
- Inhibition of Recruitment and Activation of Neutrophils by Pyridazinone-Scaffold-Based Compounds.International journal of molecular sciences · 2022Article
- Ablation of PDE4B protects from Pseudomonas aeruginosa-induced acute lung injury in mice by ameliorating the cytostorm and associated hypothermia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice.Antimicrobial agents and chemotherapy · 2018Article
- Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae.Antimicrobial agents and chemotherapy · 2015Article
- Metabolites from the induced expression of cryptic single operons found in the genome of Burkholderia pseudomallei.Journal of the American Chemical Society · 2011Article
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7 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
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-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.
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