Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages.
Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS)
Leeper-Woodford
S K
SK
Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond.
Fisher
B J
BJ
Sugerman
H J
HJ
Fowler
A A
AA
D000818:Animals; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004155:Diphenhydramine / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D006635:Histamine H2 Antagonists; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002927:Cimetidine; D006632:Histamine; D004155:Diphenhydramine; D007052:Ibuprofen