title: Microthrombosis during endotoxemia: potential role of hepatic versus alveolar macrophages.
abstract: Macrophages (M phi) produce multiple inflammatory mediators which may contribute to the pathophysiological processes seen during sepsis. Since diffuse microthrombosis has been implicated as a potential etiology for organ dysfunction and failure in sepsis, the present study examined the production of procoagulant activity (PCA) by M phi in response to endotoxin, characterized the activity, and evaluated methods to modify the response. Since hepatic and pulmonary dysfunction is a common complication of sepsis, rabbit M phi were isolated from both pulmonary (A-M phi) and hepatic (H-M phi) sites. Both M phi populations produced PCA in response to endotoxin in vitro. There is a rapid rise in activity with a peak at 20- to 30+ fold over background levels at 8 hr poststimulation. Although similar in their ability to enhance coagulation, the two M phi PCAs were shown to differ markedly in other biochemical and functional assays. The A-M phi PCA in contrast to the H-M phi PCA, was resistant to heat inactivation, serine protease inhibition, and warfarin pretreatment, while indomethacin (a prostaglandin synthesis inhibitor) blocked A-M phi PCA production but not the H-M phi response. Corticosteroids totally blocked PCA production by both M phi populations. Endotoxin, therefore, induces a rapid increase in M phi PCA, and the magnitude and rapidity of the response argue for a potentially significant pathophysiologic role, in vivo. Although derived from a common progenitor, A-M phi and H-M phi produce a functionally discreet PCA. This differential response may partially explain the contradictory results obtained in studies using various cellular metabolism inhibitors, e.g., indomethacin and steroids.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation; D004731:Endotoxins / Q000097:blood*; D005167:Factor VII / Q000032:analysis; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000502:physiology; D011817:Rabbits; D013927:Thrombosis / Q000209:etiology*; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000305:Adrenal Cortex Hormones; D004731:Endotoxins; D008070:Lipopolysaccharides; D014859:Warfarin; D005167:Factor VII; D007213:Indomethacin