Essential role of alveolar macrophages in intrapulmonary activation of NF-kappa B

Acute inflammatory injury in rat lung induced by deposition of immunoglobul in G immune complexes requires expression of cytokines and chemokines as we ll as activation of the transcription factor nuclear factor (NF)-kappa B. T here is little direct evidence regarding the role of alveolar macrophages i n these activation events. In the present studies, rat lungs were depleted of alveolar macrophages by airway instillation of liposome-encapsulated dic hloromethylene diphosphonate. These procedures, which greatly reduced the n umber of retrievable alveolar macrophages, suppressed activation of lung NF -kappa B in the inflammatory model. In addition, bronchoalveolar lavage lev els of tumor necrosis factor-alpha (TNF-alpha) and the CXC chemokine, macro phage inflammatory protein-2, were substantially reduced. In parallel, upre gulation of the lung vascular adhesion molecule, intercellular adhesion mol ecule-1, was greatly reduced by intrapulmonary instillation of phosphonate- containing liposomes. Neutrophil accumulation and development of lung injur y were also substantially diminished. Lung instillation of TNF-alpha in alv eolar macrophage-depleted rats restored the NF-kappa B activation response in whole lung. These data suggest that, in this inflammatory model, initial activation of NF-kappa B occurs in alveolar macrophages and the ensuing pr oduction of TNF-alpha may propagate NF-kappa B activation to other cell typ es in the lung.