Acetylsalicylic acid inhibits intravascular coagulation during Staphylococcus aureus–induced sepsis in mice

Abstract

Antiplatelet therapies have been proposed for the treatment of sepsis, a syndrome resulting from a dysregulated immune response and inappropriate activation of coagulation. Acetylsalicylic acid (ASA) may serve as a potential therapeutic strategy to prevent infection-induced coagulopathy and associated tissue damage. Using intravital microscopy, we found that Staphylococcus aureus infection induced neutrophil recruitment, platelet aggregation, and neutrophil extracellular trap (NET) release in the liver. Mice pretreated with ASA, or animals receiving ASA 3 hours postinfection, had significantly reduced platelet aggregation and NET release. Additionally, ASA-treated mice had reduced intravascular thrombin activity and microvascular occlusion as compared with untreated S aureus–infected mice. This inhibition of coagulation was accompanied by decreased levels of alanine aminotransferase and aspartate aminotransferase in the plasma, indicating less liver damage. Finally, bacterial loads (colony-forming units per milliliter) in liver, lung, and spleen were not different between groups, and the phagocytic capacity of Kupffer cells was preserved following ASA treatment. These results suggest that ASA may serve as a therapeutic approach to sepsis through its ability to reduce the deleterious action of immunothrombi while maintaining innate immune functions.

The Antidepressant Mirtazapine Activates Hepatic Macrophages, Facilitating Pathogen Clearance While Limiting Tissue Damage in Mice

“…The presence of smaller lesions in the mirtazapine-treated animals led us to assess vascular perfusion following S. aureus infection. Previous work has shown that infection-induced coagulation leads to vascular occlusion and associated tissue damage (27,28). Infection of mirtazapine-treated animals resulted in fewer occluded sinusoids ( Figure 5D), confirming reduced liver damage was associated with improved perfusion and less infection-induce coagulation.…”

“…We have previously demonstrated sinusoidal occlusion as the key driver in localized liver damage following infection (27,28). Thus, is it likely the reduced liver necrosis observed in mirtazapine-treated animals is associated with reduced vascular occlusion.…”

The influenza replication blocking inhibitor LASAG does not sensitize human epithelial cells for bacterial infections

“…Provided that S. aureus cannot internalize into epithelial cells to hide from the immune system in presence of LASAG, a combinatory antibiotic therapy might be an efficient alternative. Beyond that, LASAG is also reported to prevent infection-induced coagulopathy and associated tissue damage [41]. Thus, its administration during secondary bacterial infection might be another benefit.…”

Netting Liver Disease: Neutrophil Extracellular Traps in the Initiation and Exacerbation of Liver Pathology

“…83,84 However, in other studies, blocking NET formation in animal models of sepsis reduced liver injury, improved liver (micro)perfusion and function, and did not result in increased bacterial dissemination. 28,40,85 In these models of sepsis, it was suggested that the loss of immune protection provided by NETs was offset by a gain of function by other immune cells in the liver. It has been shown that mice in which NETs were degraded (DNase treatment) had preserved immune function, with KCs and splenic macrophages compensating for the loss of immunoprotection attributed to NETs.…”