Ethanol suppresses Mycobacteria tuberculosis-induced mRNA for nitric oxide synthase in alveolar macrophages, in vivo.
Acute ingestion of alcohol [ethanol (ETOH)] adversely affects the immunocompetence of both naive individuals as well as chronic alcohol abusers. An increased incidence and severity of tuberculosis is found in chronic alcohol abusers. Nitric oxide (NO) produced by alveolar macrophages (AMs) may play a role in the in vitro killing of Mycobacterium avium and Mycobacterium tuberculosis (MTB). Moreover, tumor necrosis factor-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 and NO in AMs, in vivo. We tested the postulate that acute ingestion of ETOH can interfere with mycobacteria-induced upregulation of the NO system 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 bronchoalveolar 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 ETOH (5.5 g/kg, ip) administered 30 min before intratracheal administration of MAC or MTB attenuated both 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 production of TNF-alpha. Moreover, ETOH attenuates mycobacteria-induced upregulation of mRNA for iNOS and RNI production in the absence of ETOH-mediated suppression of TNF. Speculatively, ETOH-mediated inhibition of the AM NO system may offer an explanation for the increased severity of mycobacterial infections in alcoholics.
Greenberg
S
S
Department of Medicine, Louisiana State University Medical Center, New Orleans, USA.
Xie
J
J
Kolls
J
J
Nelson
S
S
Didier
P
P
Mason
C
C
D000435:Alcoholic Intoxication / Q000276:immunology; D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D000431:Ethanol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D019001:Nitric Oxide Synthase; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases