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Effects of rolipram on cyclic AMP levels in alveolar macrophages and lipopolysaccharide-induced inflammation in mouse lung.

British Journal of Pharmacology

genetics, biosynthesis, Tumor Necrosis Factor-alpha, Rolipram, RNA, Messenger, pharmacology, Pyrrolidinones, prevention & control, chemically induced, Pneumonia, Phosphodiesterase Inhibitors, Mice, Inbred BALB C, Mice, Male, metabolism, drug effects, Macrophages, Alveolar, Lipopolysaccharides, Gene Expression Regulation, Cyclic AMP, Animals

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      Abstract

      1. Our previous work demonstrated that bacterial lipopolysaccharide (LPS), administered by aerosol, induced tumour necrosis factor (TNF-alpha) synthesis leading to the infiltration of neutrophils into mice lungs. The treatment of animals with prostaglandin E2 or dibutyryl cyclic AMP impaired both processes. In this study, the target cell for LPS and the modulation by cyclic AMP of TNF-alpha production and neutrophil recruitment were investigated. 2. One hour after inhalation of 2 ml of 0.3 mg ml(-1) LPS, TNF-alpha levels measured by an ELISA method increased in the bronchoalveolar lavage fluid (BALF) of BALB/c mice, reaching a maximal level 3 h after inhalation. The immunocytochemistry assay demonstrated that 1 h after inhalation, 21.2% of alveolar macrophages collected in the BALF were immunopositive for TNF-alpha. 3. When mice were pretreated, i.p., with 20 mg kg(-1) rolipram, a selective inhibitor of phosphodiesterase type 4, TNF-alpha levels in the BALF were significantly reduced and only 7.3% of alveolar macrophages were immunopositive for TNF-alpha. 4. Alveolar macrophages from rolipram-treated mice collected 30 min after inhalation of LPS had a significant increase in the intracellular concentrations of cyclic AMP. This was accompanied by a marked reduction of TNF-alpha levels in the BALF that were associated with a suppression of TNF-alpha mRNA expression. 5. Systemic treatment with 20 mg kg(-1) rolipram almost completely inhibited the LPS-induced neutrophil recruitment, whereas it did not significantly reduce the recruitment induced by rmTNF-alpha. 6. Our results indicate that alveolar macrophages may be the target cells for both the induction and control of the lung inflammatory response to LPS. They also suggest that systemic treatment with cyclic AMP-elevating agents may be useful to control local inflammation resulting from inhalation of bacterial endotoxin.

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      Journal
      10.1038/sj.bjp.0701649
      1565207
      9517381

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