IN-VIVO EXPRESSION OF MONOKINE AND INDUCIBLE NITRIC-OXIDE SYNTHASE INEXPERIMENTALLY-INDUCED PULMONARY GRANULOMATOUS INFLAMMATION - EVIDENCE FOR SEQUENTIAL PRODUCTION OF INTERLEUKIN-1, INDUCIBLE NITRIC-OXIDE SYNTHASE, AND TUMOR-NECROSIS-FACTOR

The present study examined the temporal pattern and localization of in terleukin-1, tumor necrosis factor-alpha, and inducible nitric oxide s ynthase expression in lung tissue undergoing foreign body granuloma fo rmation. Pulmonary granulomas were induced by the intratracheal inject ion of dextran beads into genetically high granuloma responder, carryi ng Bcg(s) (BALB/c), and lower responder, carrying Bcg(r) (C3H/HeJ and DBA/2), mice. There was a pattern of sequential expression of these mo lecules in BALB/c mice. Thus, interleukin-1 alpha and inducible nitric oxide synthase were induced mostly in the cells accumulated around th e beads and also in some bronchiolar epithelial cells during the early phase (1 to 3 days), whereas tumor necrosis factor-alpha was induced in the cells around the beads at the later resolution phase (3 to 7 da ys). By contrast, in low responder mice, an increase in the expression of interleukin-1 alpha and inducible nitric oxide synthase was detect ed in lung macrophages as well as in alveolar cells and bronchiolar ep ithelial cells on day 1, but that of tumor necrosis factor-alpha was n ot detected throughout the periods. These results together with our pr evious findings on cytokine activity in granuloma extract suggest that interleukin-1 and nitric oxide produced by recruited macrophages may take part in the early, macrophage-dependent phase of granuloma format ion whereas tumor necrosis factor-alpha may be more crucial as a media tor responsible for the difference in innate resistance or susceptibil ity to granuloma formation.