Tumor necrosis factor alpha (TNF-alpha) responses of alveolar macrophages (AMs) and peritoneal macrophages (PMs) were studied in rats after intravenous injection of lipopolysaccharide (LPS). High levels of plasma TNF-alpha, increased pulmonary myeloperoxidase activity, and leukopenia occurred within 2 h after LPS injection. Alveolar spaces exhibited a strict compartment property, as manifested by only slightly increased LPS and TNF-alpha levels in alveolar lavage fluid and an unchanged capacity of AMs to produce TNF-alpha. By contrast, the peritoneal cavity had greatly increased local LPS and TNF-alpha levels and a diminished PMs TNF-alpha response to LPS. The amount of LPS in the alveolar spaces was less than 0.2% of the level in peritoneal fluid. These results indicate that activation of resident macrophages is dependent on the amounts of local LPS and, in addition, suggest that resident AMs neither participate in the plasma TNF-alpha response nor contribute to neutrophil sequestration in the lung during the early stages of endotoxemia.