EXPRESSION AND MODULATION OF ICAM-1, TNF-ALPHA AND RANTES IN HUMAN ALVEOLAR MACROPHAGES FROM LUNG-TRANSPLANT RECIPIENTS IN-VITRO

Alveolar macrophages (AMs) play a central role in pulmonary inflammati on in response to local stimuli. As a model for investigating anti-inf lammatory drugs, we studied the effects of the cyclohexadepsipeptide a ntibiotic, fusafungine, and that of the glucocorticoid dexamethasone o n the expression of ICAM-1, TNF-alpha and RANTES, induced in vitro by rIFN-gamma in human AMs freshly isolated from bronchoalveolar lavage f luid (BAL) obtained in lung-transplanted patients. ICAM-1 antigen expr ession, induced on AMs after 24 h of culture, was significantly inhibi ted by fusafungine in a concentration-dependent manner, as measured by flow cytometry analysis using an anti-CD54 monoclonal antibody. TNF-a lpha production, but not RANTES release (measured by ELISA), was signi ficantly inhibited. mRNA studies, by means of polymerase chain reactio n amplification of complementary deoxyribonucleic acids (RT-PCR), show ed no significant modification of mRNA levels, suggesting that fusafun gine acts mainly at a post-transcriptional level. In the same conditio ns, dexamethasone significantly inhibited the release both of TNF-alph a and RANTES by AMs, mainly acting at the mRNA level, but had no effec t on ICAM-1 expression. Assessment of the cellular and molecular targe ts of anti-inflammatory drugs in this model of human AM activation sho uld lead to more appropriate treatment of inflammatory process of the respiratory tract. By virtue of its anti-inflammatory effects on alveo lar macrophages, combined with its antibacterial properties, fusafungi ne should prove particularly suitable for local treatment of bacterial infections of the respiratory tract.