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Role of Reactive Nitrogen Intermediate Production in Alveolar Macrophage-mediated Cytostatic Activity Induced by Bleomycin Lung Damage in Rats¹

Department of Pharmacology and the Vermont Regional Cancer Center, University of Vermont, Burlington, Vermont 05405

Bleomycin (BLM) is a useful anticancer agent sometimes associated with a diffuse pulmonary inflammation and fibrosis. Using an intratracheal model of BLM-induced pulmonary damage, we have further investigated alveolar macrophage (AM) activation following intratracheal BLM. From rats that had been treated with either a single, fibrogenic, intratracheal dose of BLM (BLM-AM) or a comparable volume of saline (C-AM), bronchoalveolar lavage fluid was collected, and AM were isolated using Percoll gradient centrifugation. Using a spectrophotometric assay, production of nitrites by AM was measured. C-AM released low levels of nitrites, whereas BLM-AM as well as C-AM activated in vitro with lipopolysaccharide released significant amounts of nitrites. The addition of N⁶-monomethylarginine, a substrate-specific inhibitor of the L-arginine-dependent effector mechanism in activated macrophages, reduced the amount of measurable nitrites released from both BLM-AM and activated C-AM. Similar results were observed when 12 x 10⁶ RBC were added to the cocultures. In the presence of N⁶-monomethylarginine, BLM-AM had no effect on two consequences of BLM-AM-induced cytostatic activity, DNA synthesis inhibition and aconitase activity reduction in the L1210 target cell. These results suggest that reactive nitrogen intermediates measured as nitrites are important moieties in our in vivo model of macrophage activation. Further, the identification of this effector molecule presents possibilities for therapeutic and biochemical manipulations.

¹ Research is supported in part by grants from the American Cancer Society (CH-380) and the National Cancer Institute (CA 24543). M. P. H. is an awardee of an RCDA from the National Cancer Institute (CA 01205).

² To whom requests for reprints should be addressed, at Department of Pharmacology, Given Medical Building, University of Vermont, Burlington, VT 05405.

Received 6/18/90. Accepted 9/14/90.

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