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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)
Insights
Macrophages produce procoagulant activity (PCA) in response to endotoxin, contributing to sepsis. Different lung and liver macrophage PCA responses to endotoxin and inhibitors were observed, impacting sepsis research.
Area of Science:
- Immunology
- Pathophysiology
- Hematology
Background:
- Macrophages (M phi) are key inflammatory mediators in sepsis.
- Microthrombosis is implicated in sepsis-induced organ dysfunction.
- Understanding M phi procoagulant activity (PCA) is crucial for sepsis research.
Purpose of the Study:
- To investigate endotoxin-induced PCA production by rabbit lung (A-M phi) and hepatic (H-M phi) macrophages.
- To characterize the biochemical and functional properties of M phi PCA.
- To evaluate methods for modifying M phi PCA response.
Main Methods:
- Isolation of rabbit A-M phi and H-M phi.
- In vitro stimulation with endotoxin.
- Assays for PCA quantification and characterization.
- Testing effects of heat, serine protease inhibitors, warfarin, indomethacin, and corticosteroids.
Main Results:
- Both A-M phi and H-M phi produced endotoxin-induced PCA, peaking at 8 hours.
- A-M phi PCA was heat-resistant, serine protease-resistant, and warfarin-resistant.
- Indomethacin inhibited A-M phi PCA but not H-M phi PCA; corticosteroids blocked both.
- Distinct functional properties of A-M phi and H-M phi PCA were identified.
Conclusions:
- Endotoxin rapidly increases M phi PCA, suggesting a significant in vivo role in sepsis pathophysiology.
- Lung and hepatic macrophages produce functionally distinct PCAs.
- Differential M phi PCA responses may explain conflicting results with cellular metabolism inhibitors in sepsis studies.