EFFECTS OF ROLIPRAM ON CYCLIC-AMP LEVELS IN ALVEOLAR MACROPHAGES AND LIPOPOLYSACCHARIDE-INDUCED INFLAMMATION IN MOUSE LUNG

1 Our previous work demonstrated that bacterial lipopolysaccharide (LP S), 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 E-2 or dibutyryl cyclic AMP impaired both processes. In this study, the target cell for LPS an d 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 increa sed in the bronchoalveolar lavage fluid (BALF) of BALB/c mice, reachin g 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 w ere pretreated, i.p., with 20 mg kg(-1) rolipram, a selective inhibito r of phosphodiesterase type 4, TNF-alpha levels in the BALF were signi ficantly reduced and only 7.3% of alveolar macrophages were immunoposi tive 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 associ ated with a suppression of TNF-alpha mRNA expression. 5 Systemic treat ment with 20 mg kg(-1) rolipram almost completely inhibited the LPS-in duced neutrophil recruitment, whereas it did not significantly reduce the recruitment induced by rmTNF-alpha. 6 Our results indicate that al veolar macrophages may be the target cells for both the induction and control of the lung inflammatory response to LPS. They also suggest th at systemic treatment with cyclic AMP-elevating agents may be useful t o control local inflammation resulting from inhalation of bacterial en dotoxin.