Exposure of mice to lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) or to quartz increases nitric oxide (NO) production, which has been proposed to play a role in the resulting pulmonary damage and inflammation. To determine the role of NO in these acute lung reactions, the responses of inducible nitric oxide synthase knockout (iNOS KO) versus C57BL/6J wild type (WT) mice to aspiration of LPS+IFN-gamma or quartz were compared. Male mice (6-8 weeks) were exposed by aspiration to LPS (1.2 mg/kg) + IFN-gamma (5000 U), quartz (40 mg/kg), or saline vehicle. At 24 hours post-exposure, lungs were lavaged with 10 aliquots (1 ml each) of Ca+2 and Mg+2 free phosphate-buffered saline. The acellular fluid from the first bronchoalveolar lavage (BAL) was analyzed for total antioxidant capacity, lactate dehydrogenase (LDH) activity, albumin, tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2). The cellular fraction of the total BAL fluid was assayed for alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and AM zymosan-stimulated chemiluminescence (AM-CL). Exposure to LPS + IFN-gamma decreased total antioxidant capacity, increased BAL AMs and PMNs, LDH, albumin, TNF-alpha and MIP-2, and enhanced AM-CL to the same extent in both iNOS KO and WT mice. Exposure to quartz decreased AM yield, increased PMNs, LDH, albumin, TNF-alpha and MIP-2, and enhanced AM-CL. However, iNOS KO mice exhibited less AM activation (activation status was defined as an increased AM-CL and decreased AM yield) than WT mice. These data suggest that NO may play a role in the acute pulmonary response to quartz exposure; however, evidence for a role of NO in the acute reaction to LPS+IFN-gamma was not obtained.
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah