BIOCHEMICAL AND FUNCTIONAL-ANALYSIS OF RAT BRONCHOALVEOLAR MACROPHAGES CONTAINING CHEMICALLY-INDUCED PHOSPHOLIPID INCLUSIONS

Cationic amphiphilic drugs (CADs) are structurally characterized by hy drophobic ring structures and hydrophilic side chains, Studies have de monstrated that repeated administration of CADs to experimental animal s and humans may induce phospholipid (PL) accumulation within the cell s of various tissues. The immunomodulatory azaspiranes are novel CADs with ben eficial effects in a number of animal models of autoimmune di sease and transplantation. Although the mechanism of action of these c ompounds is unclear, efficacy in all of the disease models is accompan ied by the generation of suppressor cell (SC) activity in various lymp hoid organs. SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4, 5]de cane-2-propanamine hydrochloride) and two analogs, SK&F 106615 and SK& F 103811, were compared with chlorphentermine and chloroquine for thei r ability to induce PL accumulation and SC activity. Oral administrati on of SK&F 105685 and SK&F 106615 caused PL accumulation in bronchoalv eolar lavage macrophages (AM) but to a far lesser extent (three- to fi vefold) than chlorphentermine. Neither the immunologically unreactive azaspirane SK&F 103811 nor chloroquine affected PL levels, AM from rat s treated with SK&F 105685 or SK&F 106615 expressed more potent SC act ivity than chlorphentermine. Thus, SC activity did not correlate with the extent of PL accumulation. Neither SK&F 103811 nor chloroquine ind uced SC activity, AM from SK&F 105685-treated rats had an enhanced abi lity to kill the opportunistic pathogen Candida albicans in vitro indi cating that there was no impairment of macrophage-dependent host defen se mechanisms. (C) 1995 Academic Press, Inc.