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Differential kinetics of endothelial cell activation biomarkers E-selectin and endocan during nonlethal endotoxemia in 129Sv mice: a role for PMN-derived serine proteases in the transient decrease of circulating endocan levels
Critical Care volume 14, Article number: P42 (2010)
Severe septic syndrome remains one of the most frequent causes of death in ICUs. One of the main players in this pathology is the endothelium integrity. Our laboratory has demonstrated in preliminary clinical studies among the various biomarkers of endothelial dysfunction that blood levels of endocan (ESM-1), a pulmonary vascular endothelial cell-specific molecule participating in the control of endothelial-leukocyte interactions, are associated with the severity and evolution of septic states. On the other hand, we showed in vivo that antiprotease therapy is associated with a decrease of the leukocyte rolling and firm leukocyte adhesion to endothelium in sepsis. This decrease in the leukocyte-endothelial cell contacts was associated with an increase of blood endocan levels, suggesting a linkage between leukocyte proteases, endocan, and inflammation during sepsis.
In order to characterize this linkage, we set up a mouse model of nonlethal shock induced by endotoxin (LPS), in mice genetically deficient in cathepsin G (CG-/-) or double deficient in cathepsin G and elastase (CGEL-/-). The neutrophil and endothelial activation biomarkers included myeloperoxidase, sE-selectin, and endocan ELISAs in mouse serum. In vitro tests of endocan proteolysis were also performed.
During the nonlethal endotoxemia, clinical scores as well as E-selectin levels were maximal at 24 hours and progressively returned to the baseline. Circulating myeloperoxidase also increased early at 24 hours but remained elevated until 72 hours. By contrast, circulating endocan decreased early at day 1, remained undetectable at days 2 and 3, and then normalized at day 5. A strong inverse correlation was observed between endocan and myeloperoxidase levels. Similar findings were observed CG-/-. However,CGEL-/- gained 1 day in health recovery, and showed less important reduction in endocan levels. Incubation of mouse endocan with PMN supernatants from WT, CG-/-, or CGEL-/- generated a major proteolytic fragment of 14 kDa. The proteolytic activity was inhibited by α1-antichemotrypsin.
In nonlethal endotoxemia, both endothelial cells and PMN are activated. The kinetics of PMN activation matched with the decrease of circulating endocan. In vitro, the PMN-derived serine proteases induce endocan cleavage, which may relate to the decrease of circulating level of endocan. Our results detail for the first time the kinetics of endothelial cell and PMN activation markers in a mouse model of sepsis and revealed that a PMN-derived serine protease is involved in the degradation of endocan that differs from CG or EL.
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Pastré, J., De Freitas Caires, N., Delehedde, M. et al. Differential kinetics of endothelial cell activation biomarkers E-selectin and endocan during nonlethal endotoxemia in 129Sv mice: a role for PMN-derived serine proteases in the transient decrease of circulating endocan levels. Crit Care 14, P42 (2010). https://doi.org/10.1186/cc9145
- Leukocyte Rolling
- Strong Inverse Correlation
- Preliminary Clinical Study
- 129Sv Mouse
- Septic Syndrome