Rat lung macrophage tumor cytotoxin production: impairment by chronic in vivo cigarette smoke exposure.
Macrophages in the presence of bacteria-derived lipopolysaccharide (LPS) stimuli produce a soluble cytotoxin which is toxic to tumor cells. In this study, we examined various parameters of cytotoxin production from pulmonary lavage cells obtained from Fisher 344 cesarean-derived rats. Cultures of macrophages were derived from pulmonary lavage cells and stimulated in vitro with LPS. Cytotoxin production was assayed in vitro using an L-929 cell target assay. Pulmonary lavage preparations contained a relatively pure population of macrophages, and adherence studies revealed that nonadherent lavage cells contributed negligible amounts of cytotoxin, indicating that macrophages were responsible for cytotoxin production. After LPS stimulation, cytotoxin production became maximal within 10 h and thereafter plateaued. Doses of LPS above 0.1 microgram/ml were optimal for production, and in the absence of LPS, no cytotoxin was detected. Because cigarette smoke is the major etiological factor in the development of lung cancers and because smoking is known to profoundly alter the function of alveolar macrophages in humans and experimental animals, subsequent experiments examined the role of chronic cigarette smoke exposure on tumoricidal activity of lung macrophages. Rats were exposed in vivo for 8 wk to either cigarette smoke or air (sham-treated controls). When lavage cells were cultured and stimulated with LPS (1 microgram/ml), 5- to 10-fold less cytotoxin was produced by lavage cells from rats exposed to cigarette smoke. Similarly, using a direct cytotoxicity assay, lung macrophages of smoke-exposed animals also revealed marked impairment in cytotoxicity against L-929 cell targets, and this was noted over a wide range of macrophage:tumor target cell ratios. Another product of macrophages, interferon, was also decreased in rats exposed in vivo to cigarette smoke when compared to sham-treated controls. These results suggest that cigarette smoke exposure may impair pulmonary macrophage-mediated tumor defense mechanisms.
Flick
D A
DA
Gonzalez-Rothi
R J
RJ
Harris
J O
JO
Gifford
G E
GE
D000818:Animals; D003603:Cytotoxins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D007372:Interferons / Q000096:biosynthesis; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009374:Neoplasms, Experimental / Q000276:immunology*; D010947:Plants, Toxic; D051381:Rats; D011916:Rats, Inbred F344; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
D003603:Cytotoxins; D008070:Lipopolysaccharides; D012906:Smoke; D007372:Interferons