ETHANOL SUPPRESSES MYCOBACTERIA TUBERCULOSIS-INDUCED MESSENGER-RNA FOR NITRIC-OXIDE SYNTHASE IN ALVEOLAR MACROPHAGES, IN-VIVO

Acute ingestion of alcohol [ethanol (ETOH)] adversely affects the immu nocompetence of both naive individuals as well as chronic alcohol abus ers. An increased incidence and severity of tuberculosis is found in c hronic alcohol abusers. Nitric oxide (NO) produced by alveolar macroph ages (AMs) may play a role in the in vitro killing of Mycobacterium av ium and Mycobacterium tuberculosis (MTB), Moreover, tumor necrosis fac tor-alpha (TNF-alpha) is believed to be a primary cytokine mediator of NO production by AMs. Recent studies from our laboratory demonstrated that ETOH suppressed endotoxin-induced increases in both TNF-alpha an d NO in AMs, in vivo. We tested the postulate that acute ingestion of ETOH can interfere with mycobacteria-induced upregulation of the NO sy stem in AMs, in vivo. We show that heat-killed M. avium complex (MAC) and human virulent MTB instilled into rat lungs rapidly increased mRNA for inducible NO synthase II (iNOS) of AMs in fluid obtained by bronc hoalveolar lavage (BAL fluid). This was associated with production of reactive nitrogen intermediates [(RNIs); NO2,- and NO3-] in BAL fluid, lung homogenate, and AMs in the absence of a significant increase in BAL fluid TNF-alpha. A single dose of ETCH (5.5 g/kg, ip) administered 30 min before intratracheal administration of MAC or MTB attenuated b oth MAC and MTB-induced increases in RNI in BAL fluid, lung, and AMs, and the increase in mRNA for iNOS. Thus, mycobacteria upregulate iNOS mRNA and enhance RNI production by AMs without any increase in the pro duction of TNF-alpha. Moreover, ETOH attenuates mycobacteria-induced u pregulation of mRNA for iNOS and RNI production in the absence of ETOH -mediated suppression of TNF. Speculatively, ETCH-mediated inhibition of the AM NO system may offer an explanation for the increased severit y of mycobacterial in. fections in alcoholics.