ENDOTOXIN ADMINISTRATION TO HUMANS PRIMES ALVEOLAR MACROPHAGES FOR INCREASED PRODUCTION OF INFLAMMATORY MEDIATORS

To elucidate potential mechanisms of the acute lung injury associated with endotoxemia, we evaluated the effect of intravenously administere d endotoxin on the ability of alveolar macrophages isolated by broncho alveolar lavage from normal subjects to produce inflammatory mediators . Within 1 hr of endotoxin (4 ng/kg body weight) administration, all 1 2 study subjects developed constitutional symptoms and leukopenia, and within 3 hr, low-grade fever. Resolution of symptoms and fever by 6 h r was accompanied by systemic granulocytosis. Although intravenously a dministered endotoxin appeared to activate a subset of circulating mon ocytes, it did not alter the bronchoalveolar lavage cell number, pheno type (95% macrophages), or constitutively expressed high levels of sur face HLA-DR and O2-. In contrast, intravenous endotoxin primed the alv eolar macrophages for enhanced lipopolysaccharide-induced secretion of interleukin-1 (11.8 to 25.8 U/ml; P = 0.04), tumor necrosis factor-al pha (titer, 6.8 to 13.6; P = 0.20), and prostaglandin E2 (38.4 to 116. 3 ng/ml; P = 0.035). These results demonstrate that low-dose intraveno us endotoxin primes human alveolar macrophages, which are already diff erentiated in situ, for enhanced secretion of inflammatory mediators. Such mediators may contribute to the pulmonary changes associated with endotoxemia and acute lung injury.