Microthrombosis during endotoxemia: potential role of hepatic versus alveolar macrophages.
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)
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
D000305:Adrenal Cortex Hormones; D004731:Endotoxins; D008070:Lipopolysaccharides; D014859:Warfarin; D005167:Factor VII; D007213:Indomethacin