INDEPENDENT SUPPRESSION OF NITRIC-OXIDE AND TNF-ALPHA IN THE LUNG OF CONSCIOUS RATS BY ETHANOL

Tumor necrosis factor-alpha (TNF alpha) and nitric oxide (NO) mediate in part the microbicidal response of murine and rodent alveolar macrop hages (AM) and recruited neutrophils (PMN) to airborne infections. Eth anol (ETOH) suppresses intrapulmonary TNF alpha and NO release and imp airs pulmonary host defense mechanisms. We tested the concept that ETO H down-regulates NO by inhibiting production of TNF alpha. Male rats w ere given intratracheal (i.t.) saline (PBS), a polyclonal anti-TNF alp ha antibody (TNFab) or nonimmune IgG (22 mg/kg, i.m.) 2 h before givin g i.t. Escherichia coli endotoxin (LPS) to normal rats or rats pretrea ted with ETOH (5.5 g/kg, i.p.) 30 min before experimentation. AM and P MN were obtained from the bronchoalveolar lavage fluid (BAL) fluid of rats killed 2 and 4 h after administration of LPS. mRNA for inducible NO synthase (iNOS) and TNF alpha were measured in AM and PMN with comp etitor equalized RT-PCR techniques. The BAL fluid, AM, and PMN were as sayed for TNF alpha and NO2-, and NO3- (RNI) with the L929 bioassay an d chemiluminescence, respectively. TNFab abolished LPS-induced increas es in TNF alpha but did not suppress the NO content of the BAL fluid o r gene expression for iNOS by AM or PMN. ETOH suppressed LPS-induced i ncreases in mRNA for iNOS, production of RNI, and BAL fluid TNF alpha but did not affect LPS-induced increases in mRNA for TNF alpha. ETOH-i nduced attenuation of LPS-induced up-regulation of the iNOS system did not differ in rats pretreated with TNFab or IgG. Thus, ETOH down-regu lates iNOS gene expression and RNI production independent of its effec ts on TNF alpha. Acute ETOH administration suppresses iNOS at the leve l of transcription and TNF alpha at the level of translation or releas e of the peptide.