Microthrombosis during endotoxemia: Potential role of hepatic versus alveolar macrophages

Abstract

Macrophages (Mφ) 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 Mφ 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 Mφ were isolated from both pulmonary (A-Mφ) and hepatic (H-Mφ) sites. Both Mφ 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 Mφ PCAs were shown to differ markedly in other biochemical and functional assays. The A-Mφ PCA in contrast to the H-Mφ PCA, was resistant to heat inactivation, serine protease inhibition, and warfarin pretreatment, while indomethacin (a prostaglandin synthesis inhibitor) blocked A-Mφ PCA production but not the H-Mφ response. Corticosteroids totally blocked PCA production by both Mφ populations. Endotoxin, therefore, induces a rapid increase in Mφ 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-Mφ and H-Mφ 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. Therapeutic proposals must account for these potential selective sensitivities between various cellular populations.