Role of lipopolysaccharide and cecal ligation and puncture on blood coagulation and inflammation in sensitive and resistant mice models - PubMed (original) (raw)

Role of lipopolysaccharide and cecal ligation and puncture on blood coagulation and inflammation in sensitive and resistant mice models

Javier Corral et al. Am J Pathol. 2005 Apr.

Abstract

The hemostatic system is severely disturbed during endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent hypercoagulability is the critical factor in determining the clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of endotoxemia: lipopolysaccharide-injection and cecal ligation puncture. Genetic (knockout mice) and pharmacological (PJ34) blockade of the nuclear enzyme PARP-1 was used to achieve resistance to the endotoxemia. In both models, endotoxemia resulted in antithrombin deficiency, decreased platelets, and fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic shock. Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of fibrin deposition. On the other hand, a sublethal dose of lipopolysaccharide yielded significant fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by endotoxemia is severe and independent of the inflammatory response. However, such activation may act with fibrin deposition to have a minor influence on survival in sepsis.

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Figures

Figure 1

Figure 1

Evolution of antithrombin during endotoxemia. A: Plasma antithrombin activity levels in PARP-1−/− and PARP-1+/+ littermates. Results represent the percentage of the observed value in the same animal before lethal LPS injection. B: Plasma antithrombin activity levels associated with cecal ligation puncture in PARP-1−/−, PARP-1+/+ littermates, and PARP-1+/+/PJ34 littermates. Results represent the percentage of the mean value of five untreated animals.

Figure 2

Figure 2

Platelet counts in LPS (A)- and cecal ligation puncture (B)-induced endotoxemia.

Figure 3

Figure 3

Fibrin deposition in liver induced by LPS- and CLP-induced endotoxemia. A: Score of fibrin deposition in LPS-injected mice. B: Representative photographs of sections stained with H&E and stained for fibrin by means of immunohistochemistry (IH). Results shown correspond to livers of PARP-1+/+, PARP-1+/+/PJ34, and PARP-1−/− mice at 22 hours after the cecal ligation puncture, and one control (untreated) wild-type mouse, respectively. Original magnifications, ×40.

Figure 4

Figure 4

Circulating levels of cytokines in endotoxemia-challenged mice. Plasma levels of TNF-α (A) and IL-6 (B and C) were quantified by enzyme-linked immunosorbent assay at different times after LPS injection or CLP.

Figure 5

Figure 5

Cell infiltration in LPS-injected mice. A: Average number of cells/field in liver. B: Example of the histopathological features of livers and lungs of PARP-1+/+, PARP-1−/−, and PARP-1+/+/PJ34 mice at 12 hours after LPS injection as revealed by H&E staining under light microscopy. Nonparametric Student’s _t_-tests were performed in appropriate comparisons with PARP-1+/+ mice treated with 40 mg/kg of LPS (*, P < 0.05). Original magnifications, ×20.

Figure 6

Figure 6

Cell infiltration in the CLP model of sepsis. A: Average number of cells/field in liver. B: Example of the histopathological features of livers and lungs of PARP-1+/+, PARP-1−/−, and PARP-1+/+/PJ34 mice at 22 hours after CLP as revealed by H&E staining under light microscopy. Nonparametric Student’s _t_-tests were performed in appropriate comparisons with PARP-1+/+ mice (*, P < 0.05). Original magnifications, ×20.

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