ALTERATION OF THE CYTOKINE PHENOTYPE IN AN EXPERIMENTAL LUNG GRANULOMA MODEL BY INHIBITING NITRIC-OXIDE

Pulmonary granulomatous inflammation modulated by IFN-gamma and IL-12 is also associated with augmented inducible nitric oxide synthase (NOS II), To address the role of increased nitric oxide synthesis in this model, mice received daily i,p, injections of N-G-nitro-L-arginine-met hyl ester (L-NAME; 8 mg/kg) during both the 2-wk immunization period w ith purified protein-derivative (PPD) and the subsequent lung challeng e with PPD-coated Sepharose beads, Other groups of animals received sa line, L-NAME or N-G-nitro-D-arginine-methyl ester (D-NAME; 8 mg/kg) du ring the pulmonary embolization period and not the PPD sensitization p eriod, On day 4 post-PPD bead challenge, PCR analysis of the whole lun g revealed that NOS II expression appeared to be similar in both of th e L-NAME treatment protocols, L-NAME-treated mice in both dosing proto cols had lung lesions that were significantly larger than granuloma le sions measured in mice that received saline or D-NAME, The enlarged le sions from L-NAME-treated mice contained markedly greater numbers of n eutrophils and eosinophils, Equivalent numbers of PPD-activated disper sed cells from whole lungs of L-NAME-treated mice produced significant ly higher levels of IL-4 and IL-10 and smaller amounts of IL-12 and IF N-gamma compared with similar lung cultures derived from control or D- NAME-treated mice, Levels of C-C chemokines such as monocyte chemoattr actant protein-1 (MCP-1), C10, and macrophage inflammatory protein-1 a lpha (MIP-1 alpha) were also significantly elevated in lung cultures f rom L-NAME-treated mice compared with controls, Thus, nitric oxide reg ulates the size and cellular composition of the Th1-type lung granulom a, possibly through its effects on the cytokine and chemokine profile associated with this lesion.